Hot off the presses! May 01 Nature genetics

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Latest Articles Include:

• Conventional wisdom
  - Nature Genetics 42(5):363 (2010)
  Nature Genetics | Editorial Conventional wisdom Journal name:Nature GeneticsVolume:42,Page:363Year published:(2010)DOI:doi:10.1038/ng0510-363 Recent agreement on stable reference sequences for reporting human genetic variants now allows us to mandate the use of the allele naming conventions developed by the Human Genome Variation Society. View full text Additional data
• Copy number variation and human genome maps
  McCarroll SA - Nature Genetics 42(5):365-366 (2010)
  Maps of human genome copy number variation (CNV) are maturing into useful resources for complex disease genetics. Four new studies increase the resolution of CNV maps and seek to locate human phenotypic variation on these maps.
• Chipping away at the genetics of smoking behavior
  Amos CI Spitz MR Cinciripini P - Nature Genetics 42(5):366-368 (2010)
  Three large consortia present comprehensive analyses that identify genetic factors influencing smoking initiation, intensity and cessation. The genetic architecture of these three phases of smoking behavior appears to be largely distinct.
• Fanconi anemia and breast cancer susceptibility meet again
  Levy-Lahad E - Nature Genetics 42(5):368-369 (2010)
  A new study reports biallelic mutations in RAD51C in a Fanconi anemia–like disorder, while a second study reports monoallelic mutations in the same gene associated with increased breast cancer risk. These findings strengthen the link between Fanconi anemia and breast cancer–associated pathways.
• Research highlights
  - Nature Genetics 42(5):371 (2010)
  
• Genetic loci influencing kidney function and chronic kidney disease
  Chambers JC Zhang W Lord GM van der Harst P Lawlor DA Sehmi JS Gale DP Wass MN Ahmadi KR Bakker SJ Beckmann J Bilo HJ Bochud M Brown MJ Caulfield MJ Connell JM Cook HT Cotlarciuc I Smith GD de Silva R Deng G Devuyst O Dikkeschei LD Dimkovic N Dockrell M Dominiczak A Ebrahim S Eggermann T Farrall M Ferrucci L Floege J Forouhi NG Gansevoort RT Han X Hedblad B van der Heide JJ Hepkema BG Hernandez-Fuentes M Hypponen E Johnson T de Jong PE Kleefstra N Lagou V Lapsley M Li Y Loos RJ Luan J Luttropp K Maréchal C Melander O Munroe PB Nordfors L Parsa A Peltonen L Penninx BW Perucha E Pouta A Prokopenko I Roderick PJ Ruokonen A Samani NJ Sanna S Schalling M Schlessinger D Schlieper G Seelen MA Shuldiner AR Sjögren M Smit JH Snieder H Soranzo N Spector TD Stenvinkel P Sternberg MJ Swaminathan R Tanaka T Ubink-Veltmaat LJ Uda M Vollenweider P Wallace C Waterworth D Zerres K Waeber G Wareham NJ Maxwell PH McCarthy MI Jarvelin MR Mooser V Abecasis GR Lightstone L Scott J Navis G Elliott P Kooner JS - Nature Genetics 42(5):373-375 (2010)
  Nature Genetics | Brief Communication Genetic loci influencing kidney function and chronic kidney disease * John C Chambers1, 2, 66 Search for this author in: * NPG journals * PubMed * Google Scholar * Weihua Zhang1, 2, 66 Search for this author in: * NPG journals * PubMed * Google Scholar * Graham M Lord3, 4, 5 Search for this author in: * NPG journals * PubMed * Google Scholar * Pim van der Harst6 Search for this author in: * NPG journals * PubMed * Google Scholar * Debbie A Lawlor7 Search for this author in: * NPG journals * PubMed * Google Scholar * Joban S Sehmi2, 8 Search for this author in: * NPG journals * PubMed * Google Scholar * Daniel P Gale9 Search for this author in: * NPG journals * PubMed * Google Scholar * Mark N Wass10 Search for this author in: * NPG journals * PubMed * Google Scholar * Kourosh R Ahmadi11 Search for this author in: * NPG journals * PubMed * Google Scholar * Stephan J L Bakker6 Search for this author in: * NPG journals * PubMed * Google Scholar * Jacqui Beckmann12 Search for this author in: * NPG journals * PubMed * Google Scholar * Henk J G Bilo6 Search for this author in: * NPG journals * PubMed * Google Scholar * Murielle Bochud13 Search for this author in: * NPG journals * PubMed * Google Scholar * Morris J Brown14 Search for this author in: * NPG journals * PubMed * Google Scholar * Mark J Caulfield15 Search for this author in: * NPG journals * PubMed * Google Scholar * John M C Connell16 Search for this author in: * NPG journals * PubMed * Google Scholar * H Terence Cook17 Search for this author in: * NPG journals * PubMed * Google Scholar * Ioana Cotlarciuc11 Search for this author in: * NPG journals * PubMed * Google Scholar * George Davey Smith7 Search for this author in: * NPG journals * PubMed * Google Scholar * Ranil de Silva2, 8 Search for this author in: * NPG journals * PubMed * Google Scholar * Guohong Deng18 Search for this author in: * NPG journals * PubMed * Google Scholar * Olivier Devuyst19 Search for this 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Google Scholar * Xijin Han30 Search for this author in: * NPG journals * PubMed * Google Scholar * Bo Hedblad31 Search for this author in: * NPG journals * PubMed * Google Scholar * Jaap J Homan van der Heide32 Search for this author in: * NPG journals * PubMed * Google Scholar * Bouke G Hepkema33 Search for this author in: * NPG journals * PubMed * Google Scholar * Maria Hernandez-Fuentes3, 4, 5 Search for this author in: * NPG journals * PubMed * Google Scholar * Elina Hypponen34 Search for this author in: * NPG journals * PubMed * Google Scholar * Toby Johnson35 Search for this author in: * NPG journals * PubMed * Google Scholar * Paul E de Jong36 Search for this author in: * NPG journals * PubMed * Google Scholar * Nanne Kleefstra36 Search for this author in: * NPG journals * PubMed * Google Scholar * Vasiliki Lagou37 Search for this author in: * NPG journals * PubMed * Google Scholar * Marta Lapsley22 Search for this author in: * NPG journals * PubMed * Google Scholar * Yun Li30 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journals * PubMed * Google Scholar * Marketa Sjögren31 Search for this author in: * NPG journals * PubMed * Google Scholar * Johannes H Smit43, 44, 45 Search for this author in: * NPG journals * PubMed * Google Scholar * Harold Snieder37 Search for this author in: * NPG journals * PubMed * Google Scholar * Nicole Soranzo11 Search for this author in: * NPG journals * PubMed * Google Scholar * Timothy D Spector11 Search for this author in: * NPG journals * PubMed * Google Scholar * Peter Stenvinkel57 Search for this author in: * NPG journals * PubMed * Google Scholar * Michael J E Sternberg10 Search for this author in: * NPG journals * PubMed * Google Scholar * Ramasamyiyer Swaminathan58 Search for this author in: * NPG journals * PubMed * Google Scholar * Toshiko Tanaka26 Search for this author in: * NPG journals * PubMed * Google Scholar * Lielith J Ubink-Veltmaat59 Search for this author in: * NPG journals * PubMed * Google Scholar * Manuela Uda53 Search for this author in: * NPG journals * PubMed * Google Scholar * Peter Vollenweider60 Search for this author in: * NPG journals * PubMed * Google Scholar * Chris Wallace61 Search for this author in: * NPG journals * PubMed * Google Scholar * Dawn Waterworth62 Search for this author in: * NPG journals * PubMed * Google Scholar * Klaus Zerres24 Search for this author in: * NPG journals * PubMed * Google Scholar * Gerard Waeber60 Search for this author in: * NPG journals * PubMed * Google Scholar * Nicholas J Wareham28 Search for this author in: * NPG journals * PubMed * Google Scholar * Patrick H Maxwell9 Search for this author in: * NPG journals * PubMed * Google Scholar * Mark I McCarthy47, 48, 49 Search for this author in: * NPG journals * PubMed * Google Scholar * Marjo-Riitta Jarvelin1, 42, 46, 63 Search for this author in: * NPG journals * PubMed * Google Scholar * Vincent Mooser62 Search for this author in: * NPG journals * PubMed * Google Scholar * Goncalo R Abecasis30 Search for this author in: * NPG journals * PubMed * Google Scholar * Liz Lightstone64, 66 Search for this author in: * NPG journals * PubMed * Google Scholar * James Scott8, 66 Search for this author in: * NPG journals * PubMed * Google Scholar * Gerjan Navis6, 66 Search for this author in: * NPG journals * PubMed * Google Scholar * Paul Elliott1, 65, 66 Search for this author in: * NPG journals * PubMed * Google Scholar * Jaspal S Kooner2, 8, 66 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorsJournal name:Nature GeneticsVolume:42,Pages:373–375Year published:(2010)DOI:doi:10.1038/ng.566Received10 September 2009Accepted15 March 2010Published online11 April 2010 Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Using genome-wide association, we identify common variants at 2p12–p13, 6q26, 17q23 and 19q13 associated with serum creatinine, a marker of kidney function (P = 10−10 to 10−15). Of these, rs10206899 (near NAT8, 2p12–p13) and rs4805834 (near SLC7A9, 19q13) were also associated with chronic kidney disease (P = 5.0 × 10−5 and P = 3.6 × 10−4, respectively). Our findings provide insight into metabolic, solute and drug-transport pathways underlying susceptibility to chronic kidney disease. View full text Author information * Author information * Supplementary information Primary authors * These authors contributed equally to the work. * John C Chambers, * Weihua Zhang, * Liz Lightstone, * James Scott, * Gerjan Navis, * Paul Elliott & * Jaspal S Kooner Affiliations * Department of Epidemiology and Biostatistics, School of Public Health, Imperial College of London, London, UK. * John C Chambers, * Weihua Zhang, * Marjo-Riitta Jarvelin & * Paul Elliott * Ealing Hospital National Health Service (NHS) Trust, Middlesex, UK. * John C Chambers, * Weihua Zhang, * Joban S Sehmi, * Ranil de Silva & * Jaspal S Kooner * Department of Nephrology and Transplantation, King's College London, UK. * Graham M Lord, * Maria Hernandez-Fuentes & * Esperanza Perucha * Medical Research Council (MRC) Centre for Transplantation, King's College London, UK. * Graham M Lord, * Maria Hernandez-Fuentes & * Esperanza Perucha * National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre, Guy's and St. Thomas' NHS Foundation Trust and King's College London, London, UK. * Graham M Lord, * Maria Hernandez-Fuentes & * Esperanza Perucha * University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. * Pim van der Harst, * Stephan J L Bakker, * Henk J G Bilo & * Gerjan Navis * MRC Centre for Causal Analyses in Translational Epidemiology, University of Bristol, Bristol, UK. * Debbie A Lawlor & * George Davey Smith * National Heart and Lung Institute, Hammersmith Hospital Campus, Imperial College London, London, UK. * Joban S Sehmi, * Ranil de Silva, * James Scott & * Jaspal S Kooner * Division of Medicine, University College London, London, UK. * Daniel P Gale & * Patrick H Maxwell * Structural Bioinformatics Group, Imperial College London, London, UK. * Mark N Wass & * Michael J E Sternberg * Twin Research and Genetic Epidemiology Department, King's College London, St. Thomas' Hospital Campus, London, UK. * Kourosh R Ahmadi, * Ioana Cotlarciuc, * Nicole Soranzo & * Timothy D Spector * Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland. * Jacqui Beckmann * University Institute of Social and Preventive Medicine, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland. * Murielle Bochud * Clinical Pharmacology Unit, University of Cambridge, Addenbrookes Hospital, Cambridge, UK. * Morris J Brown * Clinical Pharmacology and The Genome Centre, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, London, UK. * Mark J Caulfield & * Patricia B Munroe * Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK. * John M C Connell & * Anna Dominiczak * Department of Histopathology, Imperial College, Hammersmith Hospital, London, UK. * H Terence Cook * Department of Gastroenterology and Hepatology, Imperial College London, London, UK. * Guohong Deng * Division of Nephrology, Université Catholique de Louvain Medical School, Brussels, Belgium. * Olivier Devuyst & * Céline Maréchal * Isala Clinics, Zwolle, The Netherlands. * Lambert D Dikkeschei * Center for Renal Diseases, Zvezdara University Medical Center, Belgrade, Serbia. * Nada Dimkovic * South West Thames Institute for Renal Research, Epsom and St. Helier University Hospitals NHS Trust, Carshalton, UK. * Mark Dockrell & * Marta Lapsley * London School of Hygiene and Tropical Medicine, London, UK. * Shah Ebrahim * Department of Human Genetics, Rheinisch-Westfaelische Technische Hochschule University Hospital Aachen, Aachen, Germany. * Thomas Eggermann & * Klaus Zerres * Cardiovascular Medicine, University of Oxford, Wellcome Trust Centre for Human Genetics, Oxford, UK. * Martin Farrall * National Institute of Aging, Clinical Research Branch–Longitudinal Studies Section, Baltimore, Maryland, USA. * Luigi Ferrucci & * Toshiko Tanaka * Department of Nephrology and Clinical Immunology, RWTH University Hospital Aachen, Aachen, Germany. * Jurgen Floege & * Georg Schlieper * MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK. * Nita G Forouhi, * Ruth J F Loos, * Jian'an Luan & * Nicholas J Wareham * Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. * Ron T Gansevoort & * Marc A J Seelen * Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, USA. * Xijin Han, * Yun Li & * Goncalo R Abecasis * Department of Clinical Sciences, Lund University, Malmö, Sweden. * Bo Hedblad, * Olle Melander & * Marketa Sjögren * Department of Nephrology, University Medical Center Groningen, Groningen, The Netherlands. * Jaap J Homan van der Heide * Department of Transplantation Immunology, University Medical Center Groningen, Groningen, The Netherlands. * Bouke G Hepkema * Centre of Epidemiology for Child Health, University College London Institute of Child Health, London, UK. * Elina Hypponen * Department of Medical Genetics, University of Lausanne and the Swiss Institute of Bioinformatics, Lausanne, Switzerland. * Toby Johnson * Langerhans Medical Research Group, Zwolle, The Netherlands. * Paul E de Jong & * Nanne Kleefstra * Unit of Genetic Epidemiology and Bioinformatics, Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. * Vasiliki Lagou & * Harold Snieder * Department of Molecular Medicine and Surgery, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden. * Karin Luttropp & * Louise Nordfors * Division of Nephrology, University of Maryland School of Medicine, Baltimore, Maryland, USA. * Afshin Parsa * Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK. * Leena Peltonen * Institute for Molecular Medicine Finland (FIMM), Nordic European Molecular Biology Laboratory (EMBL) Partnership for Molecular Medicine, Biomedicum Helsinki 2U and University of Helsinki, Helsinki, Finland. * Leena Peltonen * National Institute for Health and Welfare, Helsinki, Finland. * Leena Peltonen, * Anneli Pouta & * Marjo-Riitta Jarvelin * Department of Psychiatry, Institute for Research in Extramural Medicine (EMGO), Neuroscience Campus, Vrije Universiteit (VU) Medical Center, Amsterdam, The Netherlands. * Brenda W Penninx & * Johannes H Smit * Department of Psychiatry, Leiden University Medical Center, Leiden, The Netherlands. * Brenda W Penninx & * Johannes H Smit * Department of Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. * Brenda W Penninx & * Johannes H Smit * Institute of Health Sciences, University of Oulu, Oulu, Finland. * Anneli Pouta & * Marjo-Riitta Jarvelin * Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. * Inga Prokopenko & * Mark I McCarthy * Oxford Centre for Diabetes, Endocrinology and Metabolism, Oxford, UK. * Inga Prokopenko & * Mark I McCarthy * Oxford NIHR Biomedical Research Centre, Oxford, UK. * Inga Prokopenko & * Mark I McCarthy * University of Southampton, Southampton, UK. * Paul J Roderick * Institute of Clinical Medicine, Department of Clinical Chemistry, University of Oulu, Oulu, Finland. * Aimo Ruokonen * Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Leicester, UK. * Nilesh J Samani * Istituto di Neurogenetica e Neurofarmacologia, Consiglio Nazionale delle Ricerche, Cagliari, Italy. * Serena Sanna & * Manuela Uda * Department of Molecular Medicine and Surgery, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden. * Martin Schalling * Laboratory of Genetics, US National Institutes of Health Biomedical Research Center, National Institute on Aging, Baltimore, Maryland, USA. * David Schlessinger * Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, Maryland, USA. * Alan R Shuldiner * Division of Renal Medicine K56, Karolinska University Hospital at Huddinge, Stockholm, Sweden. * Peter Stenvinkel * Chemical Pathology, Guy's and St Thomas' Hospitals Trust, London, UK. * Ramasamyiyer Swaminathan * General Practice 't Veen, Hattem, The Netherlands. * Lielith J Ubink-Veltmaat * Department of Internal Medicine, University Hospital Center, University of Lausanne, Lausanne, Switzerland. * Peter Vollenweider & * Gerard Waeber * Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge, UK. * Chris Wallace * Medical Genetics, Clinical Pharmacology and Discovery Medicine, GlaxoSmithKline, King of Prussia, Pennsylvania, USA. * Dawn Waterworth & * Vincent Mooser * Biocenter Oulu, University of Oulu, Oulu, Finland. * Marjo-Riitta Jarvelin * Renal Section, Division of Medicine, Hammersmith Hospital Campus, Imperial College London, London, UK. * Liz Lightstone * MRC-HPA Centre for Environment and Health, Department of Epidemiology and Public Health, Imperial College of London, London, UK. * Paul Elliott Contributions J.C.C., P.E., L.L., J.S., G.N. and J.S.K. designed the study. J.C.C., W.Z., D.A.L. and P.v.d.H. led the data analysis. J.C.C., P.E., L.L., J.S., G.N. and J.S.K. wrote the manuscript, with contributions from all the authors. Competing financial interests The authors declare no competing financial interests. Corresponding authors Correspondence to: * John C Chambers (john.chambers@ic.ac.uk) or * Jaspal S Kooner (j.kooner@imperial.ac.uk) Supplementary information * Author information * Supplementary information PDF files * Supplementary Text and Figures (784K) Supplementary Methods, Supplementary Note, Supplementary Tables 1–6 and Supplementary Figures 1–6 Additional data
• New loci associated with kidney function and chronic kidney disease
  Köttgen A Pattaro C Böger CA Fuchsberger C Olden M Glazer NL Parsa A Gao X Yang Q Smith AV O'Connell JR Li M Schmidt H Tanaka T Isaacs A Ketkar S Hwang SJ Johnson AD Dehghan A Teumer A Paré G Atkinson EJ Zeller T Lohman K Cornelis MC Probst-Hensch NM Kronenberg F Tönjes A Hayward C Aspelund T Eiriksdottir G Launer LJ Harris TB Rampersaud E Mitchell BD Arking DE Boerwinkle E Struchalin M Cavalieri M Singleton A Giallauria F Metter J de Boer IH Haritunians T Lumley T Siscovick D Psaty BM Zillikens MC Oostra BA Feitosa M Province M de Andrade M Turner ST Schillert A Ziegler A Wild PS Schnabel RB Wilde S Munzel TF Leak TS Illig T Klopp N Meisinger C Wichmann HE Koenig W Zgaga L Zemunik T Kolcic I Minelli C Hu FB Johansson A Igl W Zaboli G Wild SH Wright AF Campbell H Ellinghaus D Schreiber S Aulchenko YS Felix JF Rivadeneira F Uitterlinden AG Hofman A Imboden M Nitsch D Brandstätter A Kollerits B Kedenko L Mägi R Stumvoll M Kovacs P Boban M Campbell S Endlich K Völzke H Kroemer HK Nauck M Völker U Polasek O Vitart V Badola S Parker AN Ridker PM Kardia SL Blankenberg S Liu Y Curhan GC Franke A Rochat T Paulweber B Prokopenko I Wang W Gudnason V Shuldiner AR Coresh J Schmidt R Ferrucci L Shlipak MG van Duijn CM Borecki I Krämer BK Rudan I Gyllensten U Wilson JF Witteman JC Pramstaller PP Rettig R Hastie N Chasman DI Kao WH Heid IM Fox CS - Nature Genetics 42(5):376-384 (2010)
  Nature Genetics | Article New loci associated with kidney function and chronic kidney disease * Anna Köttgen1, 2, 80 Search for this author in: * NPG journals * PubMed * Google Scholar * Cristian Pattaro3, 4, 80 Search for this author in: * NPG journals * PubMed * Google Scholar * Carsten A Böger5, 80 Search for this author in: * NPG journals * PubMed * Google Scholar * Christian Fuchsberger3, 4, 80 Search for this author in: * NPG journals * PubMed * Google Scholar * Matthias Olden5, 6 Search for this author in: * NPG journals * PubMed * Google Scholar * Nicole L Glazer7, 8 Search for this author in: * NPG journals * PubMed * Google Scholar * Afshin Parsa9 Search for this author in: * NPG journals * PubMed * Google Scholar * Xiaoyi Gao10 Search for this author in: * NPG journals * PubMed * Google Scholar * Qiong Yang11 Search for this author in: * NPG journals * PubMed * Google Scholar * Albert V Smith12, 13 Search for this author in: * NPG journals * PubMed * Google Scholar * Jeffrey R O'Connell9 Search for this author in: * NPG journals * PubMed * Google Scholar * Man Li1 Search for this author in: * NPG journals * PubMed * Google Scholar * Helena Schmidt14 Search for this author in: * NPG journals * PubMed * Google Scholar * Toshiko Tanaka15, 16 Search for this author in: * NPG journals * PubMed * Google Scholar * Aaron Isaacs17 Search for this author in: * NPG journals * PubMed * Google Scholar * Shamika Ketkar10 Search for this author in: * NPG journals * PubMed * Google Scholar * Shih-Jen Hwang18, 19 Search for this author in: * NPG journals * PubMed * Google Scholar * Andrew D Johnson18, 19 Search for this author in: * NPG journals * PubMed * Google Scholar * Abbas Dehghan17, 20 Search for this author in: * NPG journals * PubMed * Google Scholar * Alexander Teumer21 Search for this author in: * NPG journals * PubMed * Google Scholar * Guillaume Paré22 Search for this author in: * NPG journals * PubMed * Google Scholar * Elizabeth J Atkinson23 Search for this author in: * NPG journals * PubMed * Google Scholar * Tanja Zeller24 Search for this author in: * NPG journals * PubMed * Google Scholar * Kurt Lohman25 Search for this author in: * NPG journals * PubMed * Google Scholar * Marilyn C Cornelis26 Search for this author in: * NPG journals * PubMed * Google Scholar * Nicole M Probst-Hensch27, 28 Search for this author in: * NPG journals * PubMed * Google Scholar * Florian Kronenberg29 Search for this author in: * NPG journals * PubMed * Google Scholar * Anke Tönjes30 Search for this author in: * NPG journals * PubMed * Google Scholar * Caroline Hayward31 Search for this author in: * NPG journals * PubMed * Google Scholar * Thor Aspelund12, 13 Search for this author in: * NPG journals * PubMed * Google Scholar * Gudny Eiriksdottir12 Search for this author in: * NPG journals * PubMed * Google Scholar * Lenore J Launer32 Search for this author in: * NPG journals * PubMed * Google Scholar * Tamara B Harris32 Search for this author in: * NPG journals * PubMed * Google Scholar * Evadnie Rampersaud33 Search for this author in: * NPG journals * PubMed * Google Scholar * Braxton D Mitchell9 Search for this author in: * NPG journals * PubMed * Google Scholar * Dan E Arking34 Search for this author in: * NPG journals * PubMed * Google Scholar * Eric Boerwinkle35 Search for this author in: * NPG journals * PubMed * Google Scholar * Maksim Struchalin36 Search for this author in: * NPG journals * PubMed * Google Scholar * Margherita Cavalieri37 Search for this author in: * NPG journals * PubMed * Google Scholar * Andrew Singleton38 Search for this author in: * NPG journals * PubMed * Google Scholar * Francesco Giallauria39 Search for this author in: * NPG journals * PubMed * Google Scholar * Jeffrey Metter39 Search for this author in: * NPG journals * PubMed * Google Scholar * Ian H de Boer40 Search for this author in: * NPG journals * PubMed * Google Scholar * Talin Haritunians41 Search for this author in: * NPG journals * PubMed * Google Scholar * Thomas Lumley42 Search for this author in: * NPG journals * PubMed * Google Scholar * David Siscovick8, 43 Search for this author in: * NPG journals * PubMed * Google Scholar * Bruce M Psaty44, 45, 46 Search for this author in: * NPG journals * PubMed * Google Scholar * M Carola Zillikens20, 47 Search for this author in: * NPG journals * PubMed * Google Scholar * Ben A Oostra17 Search for this author in: * NPG journals * PubMed * Google Scholar * Mary Feitosa10 Search for this author in: * NPG journals * PubMed * Google Scholar * Michael Province10 Search for this author in: * NPG journals * PubMed * Google Scholar * Mariza de Andrade23 Search for this author in: * NPG journals * PubMed * Google Scholar * Stephen T Turner48 Search for this author in: * NPG journals * PubMed * Google Scholar * Arne Schillert49 Search for this author in: * NPG journals * PubMed * Google Scholar * Andreas Ziegler49 Search for this author in: * NPG journals * PubMed * Google Scholar * Philipp S Wild24 Search for this author in: * NPG journals * PubMed * Google Scholar * Renate B Schnabel24 Search for this author in: * NPG journals * PubMed * Google Scholar * Sandra Wilde24 Search for this author in: * NPG journals * PubMed * Google Scholar * Thomas F Munzel24 Search for this author in: * NPG journals * PubMed * Google Scholar * Tennille S Leak50 Search for this author in: * NPG journals * PubMed * Google Scholar * Thomas Illig51 Search for this author in: * NPG journals * PubMed * Google Scholar * Norman Klopp51 Search for this author in: * NPG journals * PubMed * Google Scholar * Christa Meisinger51 Search for this author in: * NPG journals * PubMed * Google Scholar * H-Erich Wichmann51, 52, 53 Search for this author in: * NPG journals * PubMed * Google Scholar * Wolfgang Koenig54 Search for this author in: * NPG journals * PubMed * Google Scholar * Lina Zgaga55 Search for this author in: * NPG journals * PubMed * Google Scholar * Tatijana Zemunik56 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* Google Scholar * Yurii S Aulchenko17, 20 Search for this author in: * NPG journals * PubMed * Google Scholar * Janine F Felix17, 20 Search for this author in: * NPG journals * PubMed * Google Scholar * Fernando Rivadeneira17, 20, 47 Search for this author in: * NPG journals * PubMed * Google Scholar * Andre G Uitterlinden17, 20, 47 Search for this author in: * NPG journals * PubMed * Google Scholar * Albert Hofman17, 20 Search for this author in: * NPG journals * PubMed * Google Scholar * Medea Imboden27, 28 Search for this author in: * NPG journals * PubMed * Google Scholar * Dorothea Nitsch60 Search for this author in: * NPG journals * PubMed * Google Scholar * Anita Brandstätter29 Search for this author in: * NPG journals * PubMed * Google Scholar * Barbara Kollerits29 Search for this author in: * NPG journals * PubMed * Google Scholar * Lyudmyla Kedenko61 Search for this author in: * NPG journals * PubMed * Google Scholar * Reedik Mägi62, 63 Search for this author in: * NPG 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Badola68 Search for this author in: * NPG journals * PubMed * Google Scholar * Alexander N Parker68 Search for this author in: * NPG journals * PubMed * Google Scholar * Paul M Ridker69 Search for this author in: * NPG journals * PubMed * Google Scholar * Sharon L R Kardia70 Search for this author in: * NPG journals * PubMed * Google Scholar * Stefan Blankenberg24 Search for this author in: * NPG journals * PubMed * Google Scholar * Yongmei Liu71 Search for this author in: * NPG journals * PubMed * Google Scholar * Gary C Curhan72 Search for this author in: * NPG journals * PubMed * Google Scholar * Andre Franke59 Search for this author in: * NPG journals * PubMed * Google Scholar * Thierry Rochat73 Search for this author in: * NPG journals * PubMed * Google Scholar * Bernhard Paulweber61 Search for this author in: * NPG journals * PubMed * Google Scholar * Inga Prokopenko62, 63 Search for this author in: * NPG journals * PubMed * Google Scholar * Wei Wang56, 74 Search for this author in: * NPG journals * PubMed * Google Scholar * Vilmundur Gudnason12, 13 Search for this author in: * NPG journals * PubMed * Google Scholar * Alan R Shuldiner9 Search for this author in: * NPG journals * PubMed * Google Scholar * Josef Coresh1, 75 Search for this author in: * NPG journals * PubMed * Google Scholar * Reinhold Schmidt37 Search for this author in: * NPG journals * PubMed * Google Scholar * Luigi Ferrucci39 Search for this author in: * NPG journals * PubMed * Google Scholar * Michael G Shlipak76 Search for this author in: * NPG journals * PubMed * Google Scholar * Cornelia M van Duijn17, 20 Search for this author in: * NPG journals * PubMed * Google Scholar * Ingrid Borecki10 Search for this author in: * NPG journals * PubMed * Google Scholar * Bernhard K Krämer77 Search for this author in: * NPG journals * PubMed * Google Scholar * Igor Rudan55 Search for this author in: * NPG journals * PubMed * Google Scholar * Ulf Gyllensten58 Search for this author in: * NPG journals * PubMed * Google Scholar * James F Wilson55 Search for this author in: * NPG journals * PubMed * Google Scholar * Jacqueline C Witteman17, 20 Search for this author in: * NPG journals * PubMed * Google Scholar * Peter P Pramstaller3, 4 Search for this author in: * NPG journals * PubMed * Google Scholar * Rainer Rettig78 Search for this author in: * NPG journals * PubMed * Google Scholar * Nick Hastie31 Search for this author in: * NPG journals * PubMed * Google Scholar * Daniel I Chasman69, 81 Search for this author in: * NPG journals * PubMed * Google Scholar * W H Kao1, 75, 81 Search for this author in: * NPG journals * PubMed * Google Scholar * Iris M Heid6, 51, 81 Search for this author in: * NPG journals * PubMed * Google Scholar * Caroline S Fox18, 19, 79, 81 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorsJournal name:Nature GeneticsVolume:42,Pages:376–384Year published:(2010)DOI:doi:10.1038/ng.568Received15 September 2009Accepted01 March 2010Published online11 April 2010 Abstract * Abstract * Author information * Supplementary information Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Chronic kidney disease (CKD) is a significant public health problem, and recent genetic studies have identified common CKD susceptibility variants. The CKDGen consortium performed a meta-analysis of genome-wide association data in 67,093 individuals of European ancestry from 20 predominantly population-based studies in order to identify new susceptibility loci for reduced renal function as estimated by serum creatinine (eGFRcrea), serum cystatin c (eGFRcys) and CKD (eGFRcrea < 60 ml/min/1.73 m2; n = 5,807 individuals with CKD (cases)). Follow-up of the 23 new genome-wide–significant loci (P < 5 × 10−8) in 22,982 replication samples identified 13 new loci affecting renal function and CKD (in or near LASS2, GCKR, ALMS1, TFDP2, DAB2, SLC34A1, VEGFA, PRKAG2, PIP5K1B, ATXN2, DACH1, UBE2Q2 and SLC7A9) and 7 loci suspected to affect creatinine production and secretion (CPS1, SLC22A2, TMEM60, WDR37, SLC6A13, WDR72 and BCAS3). These results further our understanding of the biolo! gic mechanisms of kidney function by identifying loci that potentially influence nephrogenesis, podocyte function, angiogenesis, solute transport and metabolic functions of the kidney. View full text Figures at a glance * Figure 1: Genome-wide −log10P value plot from stage 1. (–) Plots show discovery analysis of eGFRcrea (), CKD () and eGFRcys (). The dotted line indicates the genome-wide significance threshold at P = 5 × 10−8. * Figure 2: Comparison of magnitude of association with eGFR estimated from serum creatinine (eGFRcrea) and cystatin c (eGFRcys) for SNPs identified in stage 1 discovery analyses. Note the break in the y axis and the position of CST3. * Figure 3: Distribution of the genetic risk score in the discovery samples and relation of risk score categories to mean eGFRcrea and prevalence of CKD. Grey squares indicate mean eGFRcrea; white circles indicate CKD prevalence. Error bars represent 95% confidence intervals. The number of individuals in each risk score category is indicated. Author information * Abstract * Author information * Supplementary information Primary authors * These authors contributed equally to this work. * Anna Köttgen, * Cristian Pattaro, * Carsten A Böger & * Christian Fuchsberger Affiliations * Department of Epidemiology, Johns Hopkins University, Baltimore, Maryland, USA. * Anna Köttgen, * Man Li, * Josef Coresh & * W H Kao * Renal Division, University Hospital of Freiburg, Freiburg, Germany. * Anna Köttgen * Institute of Genetic Medicine, European Academy Bozen/Bolzano (EURAC), Bolzano, Italy. * Cristian Pattaro, * Christian Fuchsberger, * Cosetta Minelli & * Peter P Pramstaller * Affiliated Institute of the University of Lübeck, Germany, Viale Druso, Bolzano, Italy. * Cristian Pattaro, * Christian Fuchsberger, * Cosetta Minelli & * Peter P Pramstaller * Department of Internal Medicine II, University Medical Center Regensburg, Regensburg, Germany. * Carsten A Böger & * Matthias Olden * Department of Epidemiology and Preventive Medicine, University Medical Center Regensburg, Regensburg, Germany. * Matthias Olden & * Iris M Heid * Cardiovascular Health Research Unit, University of Washington, Seattle, Washington, USA. * Nicole L Glazer * Department of Medicine, University of Washington, Seattle, Washington, USA. * Nicole L Glazer & * David Siscovick * University of Maryland Medical School, Baltimore, Maryland, USA. * Afshin Parsa, * Jeffrey R O'Connell, * Braxton D Mitchell & * Alan R Shuldiner * Division of Statistical Genomics, Washington University School of Medicine, St. Louis, Missouri, USA. * Xiaoyi Gao, * Shamika Ketkar, * Mary Feitosa, * Michael Province & * Ingrid Borecki * Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA. * Qiong Yang * Icelandic Heart Association, Kopavogur, Iceland. * Albert V Smith, * Thor Aspelund, * Gudny Eiriksdottir & * Vilmundur Gudnason * University of Iceland, Reykjavik, Iceland. * Albert V Smith, * Thor Aspelund & * Vilmundur Gudnason * Department of Neurogeriatrics, Austrian Stroke Prevention Study, Institute of Molecular Biology and Biochemistry and University Clinic of Neurology, Medical University Graz, Graz, Austria. * Helena Schmidt * Clinical Research Branch, National Institute on Aging, Baltimore, Maryland, USA. * Toshiko Tanaka * Medstar Research Institute, Baltimore, Maryland, USA. * Toshiko Tanaka * Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands. * Aaron Isaacs, * Abbas Dehghan, * Ben A Oostra, * Yurii S Aulchenko, * Janine F Felix, * Fernando Rivadeneira, * Andre G Uitterlinden, * Albert Hofman, * Cornelia M van Duijn & * Jacqueline C Witteman * The National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, USA. * Shih-Jen Hwang, * Andrew D Johnson & * Caroline S Fox * Center for Population Studies, Framingham, Massachusetts, USA. * Shih-Jen Hwang, * Andrew D Johnson & * Caroline S Fox * Netherlands Genomics Initiative (NGI)-sponsored Netherlands Consortium for Healthy Aging (NCHA), Leiden, The Netherlands. * Abbas Dehghan, * M Carola Zillikens, * Yurii S Aulchenko, * Janine F Felix, * Fernando Rivadeneira, * Andre G Uitterlinden, * Albert Hofman, * Cornelia M van Duijn & * Jacqueline C Witteman * Interfaculty Institute for Genetics and Functional Genomics, Ernst-Moritz-Arndt University Greifswald, Greifswald, Germany. * Alexander Teumer & * Uwe Völker * Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada. * Guillaume Paré * Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota, USA. * Elizabeth J Atkinson & * Mariza de Andrade * Department of Medicine II, University Medical Center Mainz, Mainz, Germany. * Tanja Zeller, * Philipp S Wild, * Renate B Schnabel, * Sandra Wilde, * Thomas F Munzel & * Stefan Blankenberg * Department of Biostatistical Sciences, Wake Forest University, Division of Public Health Sciences, Winston-Salem, North Carolina, USA. * Kurt Lohman * Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA. * Marilyn C Cornelis & * Frank B Hu * Swiss Tropical and Public Health Institute, Basel, Switzerland. * Nicole M Probst-Hensch & * Medea Imboden * University of Basel, Basel, Switzerland. * Nicole M Probst-Hensch & * Medea Imboden * Division of Genetic Epidemiology, Innsbruck Medical University, Innsbruck, Austria. * Florian Kronenberg, * Anita Brandstätter & * Barbara Kollerits * Department of Medicine, University of Leipzig, Leipzig, Germany. * Anke Tönjes, * Michael Stumvoll & * Peter Kovacs * Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, Scotland, UK. * Caroline Hayward, * Alan F Wright, * Susan Campbell, * Veronique Vitart & * Nick Hastie * Laboratory of Epidemiology, Demography and Biometry, National Institute on Aging, Bethesda, Maryland, USA. * Lenore J Launer & * Tamara B Harris * Miami Institute for Human Genomics, Miami, Florida, USA. * Evadnie Rampersaud * McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. * Dan E Arking * Human Genetics Center, University of Texas Health Science Center, Houston, Texas, USA. * Eric Boerwinkle * Department of Epidemiology and Biostatistics, Department of Forensic Molecular Biology, Rotterdam, The Netherlands. * Maksim Struchalin * Department of Neurogeriatrics, Austrian Stroke Prevention Study, University Clinic of Neurology, Medical University Graz, Graz, Austria. * Margherita Cavalieri & * Reinhold Schmidt * Laboratory of Neurogenetics, National Institute on Aging, Bethesda, Maryland, USA. * Andrew Singleton * Clinical Research Branch, National Institute on Aging, Baltimore, Maryland, USA. * Francesco Giallauria, * Jeffrey Metter & * Luigi Ferrucci * Kidney Research Institute and Division of Nephrology, University of Washington, Seattle, Washington, USA. * Ian H de Boer * Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA. * Talin Haritunians * Department of Biostatistics, University of Washington, Seattle, Washington, USA. * Thomas Lumley * Department of Epidemiology, University of Washington, Seattle, Washington, USA. * David Siscovick * Department of Medicine, Cardiovascular Health Research Unit, University of Washington and Group Health Research Institute, Seattle, Washington, USA. * Bruce M Psaty * Department of Epidemiology, University of Washington and Group Health Research Institute, Seattle, Washington, USA. * Bruce M Psaty * Department of Health Services, University of Washington, Seattle, Washington, USA. * Bruce M Psaty * Department of Internal Medicine, Erasmus University, Rotterdam, The Netherlands. * M Carola Zillikens, * Fernando Rivadeneira & * Andre G Uitterlinden * Department of Internal Medicine,Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA. * Stephen T Turner * Institute for Medical Biometry and Statistics, University at Lübeck, Lübeck University Hospital Schleswig-Holstein, Campus Lübeck, Germany. * Arne Schillert & * Andreas Ziegler * Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. * Tennille S Leak * Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany. * Thomas Illig, * Norman Klopp, * Christa Meisinger, * H-Erich Wichmann & * Iris M Heid * Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany. * H-Erich Wichmann * Klinikum Grosshadern, Munich, Germany. * H-Erich Wichmann * Zentrum für Innere Medizin, Klinik für Innere Medizin II–Kardiologie, Universitätsklinikum Ulm, Ulm, Germany. * Wolfgang Koenig * Centre for Population Health Sciences, University of Edinburgh Medical School, Edinburgh, Scotland, UK. * Lina Zgaga, * Sarah H Wild, * Harry Campbell, * Igor Rudan & * James F Wilson * Croatian Centre for Global Health, University of Split Medical School, Split, Croatia. * Tatijana Zemunik, * Mladen Boban & * Wei Wang * Andrija Stampar School of Public Health, Medical School, University of Zagreb, Zagreb, Croatia. * Ivana Kolcic & * Ozren Polasek * Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden. * Åsa Johansson, * Wilmar Igl, * Ghazal Zaboli & * Ulf Gyllensten * Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany. * David Ellinghaus, * Stefan Schreiber & * Andre Franke * Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, UK. * Dorothea Nitsch * First Department of Internal Medicine, Paracelsus Medical University, Salzburg, Austria. * Lyudmyla Kedenko & * Bernhard Paulweber * Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. * Reedik Mägi & * Inga Prokopenko * Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK. * Reedik Mägi & * Inga Prokopenko * Institute of Anatomy and Cell Biology, Ernst-Moritz-Arndt University Greifswald, Greifswald, Germany. * Karlhans Endlich * Institute for Community Medicine, Ernst-Moritz-Arndt University Greifswald, Greifswald, Germany. * Henry Völzke * Institute of Pharmacology, Ernst-Moritz-Arndt University Greifswald, Greifswald, Germany. * Heyo K Kroemer * Institute of Clinical Chemistry and Laboratory Medicine, Ernst-Moritz-Arndt University Greifswald, Greifswald, Germany. * Matthias Nauck * Amgen, Cambridge, Massachusetts, USA. * Sunita Badola & * Alexander N Parker * Brigham and Women's Hospital, Boston, Massachusetts, USA. * Paul M Ridker & * Daniel I Chasman * Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, Michigan, USA. * Sharon L R Kardia * Department of Epidemiology and Prevention, Wake Forest University, Division of Public Health Sciences, Winston-Salem, North Carolina, USA. * Yongmei Liu * Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. * Gary C Curhan * University Hospitals of Geneva, Geneva, Switzerland. * Thierry Rochat * School of Public Health and Family Medicine, Capital Medical University, Beijing, China. * Wei Wang * Welch Center for Prevention, Epidemiology and Clinical Research, Johns Hopkins University, Baltimore, Maryland, USA. * Josef Coresh & * W H Kao * General Internal Medicine, University of California, San Francisco, San Francisco, California, USA. * Michael G Shlipak * Department of Medicine V, Mannheim University Hospital, University of Heidelberg, Mannheim, Germany. * Bernhard K Krämer * Institute of Physiology, Ernst-Moritz-Arndt University Greifswald, Greifswald, Germany. * Rainer Rettig * Brigham and Women's Hospital Department of Endocrinology and Harvard Medical School, Boston, Massachusetts, USA. * Caroline S Fox * These authors jointly directed this work. * Daniel I Chasman, * W H Kao, * Iris M Heid & * Caroline S Fox Contributions A.K., C.P., C.A.B., C.F., N.L.G., A.P., X.G., W.H.K., I.M.H., C.S.F. L.J.L., T.B.H., V.G., A.P., E.B., J.C., A.K., L.F., J.M., N.L.G., T.L., D.S., B.M.P., M.G.S., B.A.O., C.M.v.D., I.B., M.P., C.S.F., Q.Y., S.K., M.d.A., E.J.A., Y.L., C.A.B., I.M.H., T.I., H.-E.W., N.K., C.M., I.R., P.P.P., F.B.H., G.C.C., U.G., J.F.W., S.H.W., A.F.W., H.C., A.H., N.M.P.-H., M.I., D.N., T.R., B.P., R.R., K.E., H.V., P.K., A.T., M.B., W.W., O.P., N.H., C.H., V.V., D.I.C., G.P., A.N.P., P.M.R., S.B., T.F.M. G.E., L.J.L., T.B.H., V.G., A.P., B.D.M., A.R.S., E.B., J.C., W.H.K., J.M., D.S., B.M.P., M.G.S., A.I., M.C.Z., B.A.O., C.M.v.D., I.B., M.P., C.S.F., S.K., M.d.A., C.A.B., I.M.H., M.O., B.K., W.K., T.I., H.-E.W., C.M., I.R., L.Z., T.Z., C.P., C.F., P.P.P., M.C.C., F.B.H., G.C.C., A.J., G.Z., U.G., J.F.W., S.H.W., A.G.U., F.R., N.M.P.-H., M.I., T.R., B.K.K., L.K., B.P., F.K., R.R., K.E., H.V., M.S., A.T., M.B., O.P., N.H., C.H., V.V., D.I.C., G.P., S.B., A.N.P., P.M.R. G.E., T.B.H., V.G., B.D.M., A.R.S., J.C., L.F., B.M.P., B.A.O., C.M.v.D., C.S.F., S.T.T., T.I., H.-E.W., I.R., L.Z., T.Z., I.K., P.P.P., A.J., J.F.W., S.H.W., S.S., A.D., J.C.W., N.M.P.-H., M.I., D.N., T.R., B.P., R.R., H.V., A.T., M.B., O.P., C.H., S.B., T.Z., R.S. T.B.H., A.P., E.B., J.C., W.H.K., A.K., L.F., T.T., F.G., N.L.G., T.L., T.H., B.M.P., A.I., M.C.Z., B.A.O., C.M.v.D., I.B., M.P., X.G., C.S.F., Q.Y., S.-J.H., S.K., S.T.T., M.d.A., E.J.A., Y.L., T.S.L., C.A.B., I.M.H., M.O., B.K., W.K., I.R., T.Z., I.K., C.P., C.F., C.M., P.P.P., G.C.C., A.D.J., W.I., G.Z., U.G., J.F.W., S.H.W., A.D., Y.S.A., M.I., B.K., L.K., B.P., F.K., R.R., K.E., A.T., H.V., H.K.K., M.N., U.V., M.B., O.P., N.H., C.H., V.V., D.I.C., G.P., P.M.R. All authors. A.V.S., T.A., V.G., J.R.O., E.R., A.K., M.L., R.S., H.S., T.T., N.L.G., T.L., B.M.P., A.I., X.G., M.F., C.S.F., Q.Y., S.J.H., S.K., M.d.A., E.J.A., K.L., Y.L., C.A.B., I.M.H., M.O., N.K., C.P., C.F., C.M., M.C.C., A.J., W.I., D.E., A.F., A.D., F.R., Y.S.A., N.M.P.-H., B.K., F.K., A.T., U.V., R.M., I.P., C.H., V.V., D.I.C., G.P., A.Z., A.B., S.W., J.F.F., D.E.A. E.B., R.S., H.S., L.F., T.H., A.I., B.A.O., C.M.v.D., M.d.A., Y.L., T.I., H.-E.W., C.M., J.F.W., H.C., A.F., A.G.U., F.R., M.I., F.K., H.K.K., M.N., U.V., M.S., S.C., C.H., S.B., A.N.P., A.B., N.K. A.V.S., T.A., J.R.O., M.S., M.C., T.T., A.I., B.A.O., C.M.v.D., Q.Y., A.D.J., E.J.A., Y.L., C.A.B., I.M.H., M.O., C.P., C.F., M.C.C., A.J., W.I., D.E., A.D., F.R., Y.S.A., F.K., A.T., H.K.K., U.V., D.I.C., G.P., D.E.A. Competing financial interests C.A.B. has received lecture fees from Novartis Deutschland GmbH, Fresenius Medical Care Deutschland GmbH and Sandoz Pharmaceuticals GmbH. S.B. and A.N.P. are employees of Amgen. Corresponding authors Correspondence to: * Caroline S Fox (foxca@nhlbi.nih.gov) or * Iris M Heid (iris.heid@klinik.uni-regensburg.de) or * W H Kao (wkao@jhsph.edu) or * Daniel I Chasman (dchasman@rics.bwh.harvard.edu) Supplementary information * Abstract * Author information * Supplementary information PDF files * Supplementary Text and Figures (6M) Supplementary Note, Supplementary Tables 1–7 and Supplementary Figures 1 and 2 Additional data
• Mutation spectrum revealed by breakpoint sequencing of human germline CNVs
  Conrad DF Bird C Blackburne B Lindsay S Mamanova L Lee C Turner DJ Hurles ME - Nature Genetics 42(5):385-391 (2010)
  Nature Genetics | Article Mutation spectrum revealed by breakpoint sequencing of human germline CNVs * Donald F Conrad1 Search for this author in: * NPG journals * PubMed * Google Scholar * Christine Bird1 Search for this author in: * NPG journals * PubMed * Google Scholar * Ben Blackburne1 Search for this author in: * NPG journals * PubMed * Google Scholar * Sarah Lindsay1 Search for this author in: * NPG journals * PubMed * Google Scholar * Lira Mamanova1 Search for this author in: * NPG journals * PubMed * Google Scholar * Charles Lee2 Search for this author in: * NPG journals * PubMed * Google Scholar * Daniel J Turner1 Search for this author in: * NPG journals * PubMed * Google Scholar * Matthew E Hurles1 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorJournal name:Nature GeneticsVolume:42,Pages:385–391Year published:(2010)DOI:doi:10.1038/ng.564Received27 August 2009Accepted09 March 2010Published online04 April 2010 Abstract * Abstract * Author information * Supplementary information Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Precisely characterizing the breakpoints of copy number variants (CNVs) is crucial for assessing their functional impact. However, fewer than 10% of known germline CNVs have been mapped to the single-nucleotide level. We characterized the sequence breakpoints from a dataset of all CNVs detected in three unrelated individuals in previous array-based CNV discovery experiments. We used targeted hybridization-based DNA capture and 454 sequencing to sequence 324 CNV breakpoints, including 315 deletions. We observed two major breakpoint signatures: 70% of the deletion breakpoints have 1−30 bp of microhomology, whereas 33% of deletion breakpoints contain 1−367 bp of inserted sequence. The co-occurrence of microhomology and inserted sequence is low (10%), suggesting that there are at least two different mutational mechanisms. Approximately 5% of the breakpoints represent more complex rearrangements, including local microinversions, suggesting a replication-based strand switching! mechanism. Despite a rich literature on DNA repair processes, reconstruction of the molecular events generating each of these mutations is not yet possible. View full text Figures at a glance * Figure 1: Experimental overview. This diagram depicts the three stages of the experiment. First, test (green) and reference (red) DNAs are cohybridized to a CGH array. Second, the intensity data generated from the CGH experiment is summarized at each probe and the distribution of probe intensities is used to identify CNVs using the GADA segmentation algorithm18. The intensity data are then used to construct confidence intervals around each putative CNV breakpoint. A hybridization-based capture array is designed to these confidence intervals. Third, test and reference samples are cohybridized to the capture array. Fragments with at least partial homology to the target regions are preferentially retained and sequenced. Sequence reads are mapped to the genome; reads without CNV breakpoints show contiguous homology to the reference across all bases, whereas reads containing breakpoints appear to be split, with partial homology to either side of the CNV. * Figure 2: Confidence intervals. () We used our array CGH data to construct confidence intervals for both the 5′ and 3′ breakpoints of 350 CNVs with published breakpoint sequences. m2 confidence intervals (shown here as 700 horizontal gray lines) are drawn in base pairs 5′ or 3′ (<0 or >0, respectively) from the GADA-estimated breakpoint location. The true location for each sequenced breakpoint is represented as a red dot. There appears to be a strong positive correlation between confidence interval size and the accuracy of the GADA breakpoint estimates, indicating the CGH data contains useful information on the uncertainty in breakpoint location. () We confirmed this by modeling the relationship between confidence interval size and the accuracy of our breakpoint estimates. The best-fit line from least-squares regression is shown in red (test of slope = 0, P < 10−15). () A permutation test of the hypothesis that our confidence intervals cover more breakpoint locations than expected by chance. As o! ur test statistic, we used the number of true breakpoints covered by a set of confidence intervals. A null distribution for this statistic was generated using 1,000 permutations of m1 confidence intervals across CNVs (shown here as a black curve). The number of true breakpoints covered with the correctly assigned confidence intervals (indicated by a vertical red line) was 13 s.d. greater than the mean from the randomly assigned permutations. () The relationship between CNV log2 ratio between test and reference in the discovery CGH experiment and the breakpoint estimation error indicate that GADA breakpoint estimation accuracy decreases as the CNV signal is closer to the background. * Figure 3: Properties of the pulldown experiment. () Distribution of read lengths for all sequences, mapped sequences, and mapped and targeted sequences. () Integration of CGH data, confidence intervals and short-read sequencing facilitates rapid identification of CNV breakpoints. Shown here is an overview of the data for a deletion observed twice in the CGH experiment and then successfully recovered by split-read analysis. () Power of the pulldown experiment to identify breakpoints for 1,185 validated, non-VNTR loci, plotted as a function of haplotype sequence coverage. According to power simulations, the single best predictor of breakpoint sequencing success of non-VNTR loci was sequence coverage of the target region (Pearson R = 0.78). Using the BLAT pipeline, we estimated that our approach has 90% power to sequence a CNV breakpoint when both target regions of the CNV have an average of twofold haploid sequence coverage (Online Methods and Supplementary Note). * Figure 4: Summary of sequence content at deletion breaks. () Histogram summarizing the number of breakpoints showing blunt ends (red), microhomology (green) or inserted sequence (blue). For each class of breakpoint, events are binned by the number of bases in each feature; in the case of blunt ends, all events are in the same bin of 0 bases. () Nonrandom distribution of microhomology observed at deletion breakpoints. We derived an expected distribution of microhomology length by simulating random breakpoints while conditioning on the base content of CNV breakpoint regions. Here we have plotted the difference between the observed and expected amount of microhomology for our deletion breakpoints, which reveals two notable features of our data: (i) there are more deletion breakpoints showing microhomology than expected by chance; (ii) conditional on the presence of microhomology, there is an enrichment of breakpoints with 2−9 bases of microhomology. () The presence of inserted sequence within deletion breakpoints is more common in t! he absence of microhomology (P < 10−15, χ2 test). () Each deletion sequenced in the pulldown experiment is represented with a horizontal line. The deletions are parsed by sequence features into three groups: the top group shows no microhomology or inserted sequence, the second group shows at least 1 bp of inserted sequence, represented by a blue line, and the third groups shows at least 1 bp of microhomology at the breakpoints, represented by green lines. CNVs and sequence features are plotted on a log scale, and CNVs are sorted by size within groups. * Figure 5: Inverted sequence at complex CNV breakpoints. These schematic homology plots summarize into four classes the 12 interpretable cases of deletions with inverted sequence we observed. The plots represent the regions of similarity and orientation of these sequences within the CNV region as if we had plotted a dot plot of the reference (x axis) against the new allelic structure from assembly of the 454 reads (y axis). Sequences inverted within the new allele relative to the reference are colored red and orange; those in the same orientation are blue and purple. The black loops represent the deleted sequence. () A deletion plus an inverted sequence originating from within the larger deleted region; n = 8. () Deletion plus inverted sequence originating from the local vicinity; n = 2. () Deletion plus inverted sequence originating from the local vicinity, but owing to an incomplete assembly it is not clear whether it comes from within or outside the deletion region; n = 2. () In a single case, a deletion plus two separate inver! sions with sequence originating from the local vicinity of the breakpoint. Author information * Abstract * Author information * Supplementary information Affiliations * Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK. * Donald F Conrad, * Christine Bird, * Ben Blackburne, * Sarah Lindsay, * Lira Mamanova, * Daniel J Turner & * Matthew E Hurles * Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. * Charles Lee Contributions D.F.C. and M.E.H. designed the study. L.M. and D.J.T. performed pulldown and sequencing experiments. D.F.C., B.B., C.B., S.L. and M.E.H. analyzed the data. C.B. performed validation experiments. D.F.C. and M.E.H. wrote the paper with contributions from C.B., B.B. and C.L. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Matthew E Hurles (meh@sanger.ac.uk) Supplementary information * Abstract * Author information * Supplementary information Excel files * Supplementary Table 1 (112K) CNV breakpoint locations * Supplementary Table 2 (44K) PCR validation primers PDF files * Supplementary Text and Figures (432K) Supplementary Figures 1–5 and Supplementary Note Additional data
• From transcriptome analysis to therapeutic anti-CD40L treatment in the SOD1 model of amyotrophic lateral sclerosis
  Lincecum JM Vieira FG Wang MZ Thompson K De Zutter GS Kidd J Moreno A Sanchez R Carrion IJ Levine BA Al-Nakhala BM Sullivan SM Gill A Perrin S - Nature Genetics 42(5):392-399 (2010)
  Nature Genetics | Article From transcriptome analysis to therapeutic anti-CD40L treatment in the SOD1 model of amyotrophic lateral sclerosis * John M Lincecum1, 2 Search for this author in: * NPG journals * PubMed * Google Scholar * Fernando G Vieira1, 2 Search for this author in: * NPG journals * PubMed * Google Scholar * Monica Z Wang1 Search for this author in: * NPG journals * PubMed * Google Scholar * Kenneth Thompson1 Search for this author in: * NPG journals * PubMed * Google Scholar * Gerald S De Zutter1 Search for this author in: * NPG journals * PubMed * Google Scholar * Joshua Kidd1 Search for this author in: * NPG journals * PubMed * Google Scholar * Andrew Moreno1 Search for this author in: * NPG journals * PubMed * Google Scholar * Ricardo Sanchez1 Search for this author in: * NPG journals * PubMed * Google Scholar * Isarelis J Carrion1 Search for this author in: * NPG journals * PubMed * Google Scholar * Beth A Levine1 Search for this author in: * NPG journals * PubMed * Google Scholar * Bashar M Al-Nakhala1 Search for this author in: * NPG journals * PubMed * Google Scholar * Shawn M Sullivan1 Search for this author in: * NPG journals * PubMed * Google Scholar * Alan Gill1 Search for this author in: * NPG journals * PubMed * Google Scholar * Steven Perrin1 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorJournal name:Nature GeneticsVolume:42,Pages:392–399Year published:(2010)DOI:doi:10.1038/ng.557Received22 December 2009Accepted02 March 2010Published online28 March 2010 Abstract * Abstract * Accession codes * Author information * Supplementary information Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of motor neurons. Using unbiased transcript profiling in an ALS mouse model, we identified a role for the co-stimulatory pathway, a key regulator of immune responses. Furthermore, we observed that this pathway is upregulated in the blood of 56% of human patients with ALS. A therapy using a monoclonal antibody to CD40L was developed that slows weight loss, delays paralysis and extends survival in an ALS mouse model. This work demonstrates that unbiased transcript profiling can identify cellular pathways responsive to therapeutic intervention in a preclinical model of human disease. View full text Figures at a glance * Figure 1: Co-stimulatory pathway signaling in SOD1G93A skeletal muscle, spinal cord and sciatic nerve is upregulated during disease progression and is increased in a subset of blood samples from individuals with ALS. We assessed the statistical differences in gene expression between SOD1G93A and wild-type medial gastrocnemius, spinal cord and sciatic nerve at a given time point using the nonlinear Bayes methodology in the Bioconductor LIMMA package and overlaid the resulting analysis onto the genMAPP pathway for co-stimulatory signaling (genMAPP: Mm-Std_20060628.gdb). Each colored box represents the estimated change in transcript abundance for a given gene after normalization and data summarization. Biological replicates for the SOD1G93A transgenic mice are n = 5. Age-matched, non-transgenic mice are biological replicates of n = 5. The key details the relative increase in transcript expression levels, with blue intensity representing decreasing levels and pink intensity representing increasing levels. () Gastrocnemius. () Spinal cord. () Sciatic nerve. () A heat-map visualization of the normalized expression data for genes of the human T cell co-stimulatory pathway from 27 non-ALS and 63! ALS blood samples. We normalized Affymetrix gene chip data using robust multi-array averaging and clustered samples using self-organizing maps. Gene expression intensity is represented colorimetrically, with low expression represented as blue rectangles and high expression as pink rectangles. * Figure 2: Macrophages accumulate in peripheral nerves throughout the disease course. Shown is a time course of immunofluorescence staining for CD68+ macrophage (green) and DAPI-counterstained nuclei (blue) in sciatic nerve. () Day 50. () Day 60. () Day 80. () Day 100. () Day 110. Scale bars in –, 17 μm. () Quantification of accumulated CD68+ macrophages in the S100b+ nerves of the gastrocnemius. WT, wild type. * Figure 3: Blocking CD40L with a monoclonal antibody to CD40L improves body-weight maintenance, delays disease onset and extends survival in SOD1 mice. SOD1G93A mice received a loading dose (5.22 mg per kg body weight for females, 6.75 mg per kg for males) followed by weekly maintenance doses (1 mg per kg for females, 1.34 mg per kg for males) given intraperitoneally beginning at 50 days of age and continuing until death. () Kaplan-Meier time-to-event analysis for time required to attain peak body weight. Time to peak was not significantly (P = 0.35) changed by anti-CD40L treatment. Ctrl., control; Drug, anti-CD40L. () Time-to-event analysis for the time from peak body weight until death. Body-weight maintenance was significantly (P = 0.0413) improved by anti-CD40L treatment. () Time-to-event analysis for disease onset, the age at which mice first showed signs of definitive neurological disease (neurological severity score of 2). Disease onset was significantly (P = 0.0038) delayed by anti-CD40L treatment. () Time-to-event analysis for survival, the age at which mice died. Survival was significantly (P = 0.0043) prolonged b! y anti-CD40L treatment. Results of statistical analyses are presented in Table 1. * Figure 4: Meta-analysis of anti-CD40L treatment compared with riluzole, apocynin and historical controls. () Monte Carlo analysis of historical control SOD1 animals to assess the probability of randomly detecting a 9-d lengthening of survival. We randomly assigned 44 untreated SOD1G93A animals to either a mock control group or a mock treatment group and performed Kaplan-Meier survival analysis. We performed 1,000 iterations and plotted the frequency distribution as a function of percent change in survival. () The Kaplan-Meier survival data from historical control groups compared with a group treated with weekly intraperitoneal injection of 1 mg per kg (body weight) anti-CD40L. () Outlier analysis shows that anti-CD40L results do not fall within the distribution of results from other drugs tested in the SOD1G93A model. The jackknife outlier distance for each observation is calculated using estimates of the mean, s.d. and correlation matrix that do not include the observation itself. Extreme multivariate outliers are identified as points that exceed the upper distance value limit ! (dotted line). Results are tabulated by drug in Supplementary Table 4. * Figure 5: MR1 treatment lowers the frequency of CD68+ cells in sciatic nerve and CD8+ T cells in sciatic lymph node. () CD68+ macrophage (green) in S100b+ sciatic nerve (red), 100-day-old controls. () CD68+ macrophage (green) in S100b+ sciatic nerve (red), 100-day-old anti-CD40L–treated mice. () Quantification of reduction of CD68+ macrophage by anti-CD40L treatment, day 100. White bar, control; gray bar, anti-CD40L–treated; black bar, untreated age-matched non-transgenic mice. WT, wild type. (–) FACS analysis of CD4 and CD8 expression in CD3+ lymphocytes isolated from sciatic lymph node in age-matched (day 80) non-transgenic SOD1G93A (), untreated control (), and SOD1G93A anti-CD40L–treated mice (). Full flow cytometry details and machine settings are described in the Online Methods. * Figure 6: Anti-CD40L treatment decreases astrocytosis and microgliosis while reducing motor neuron loss in the spinal cord of SOD1G93A mice. () Gfap staining (green; DAPI staining is blue) in reactive astrocytes in the lumbar spinal cord of untreated SOD1G93A mice. () Gfap staining (green; DAPI, blue) in the lumbar spinal cord of anti-CD40L–treated mice. () Mac-2 staining (red; DAPI, blue) in microglia in the lumbar spinal cord of untreated SOD1G93A mice. Inset, Mac-2+ cell from vehicle control. () Mac-2 staining (red; DAPI, blue) in the lumbar spinal cord of anti-CD40L–treated mice. Inset, Mac-2+ cell from treated mouse. (,) Representative field of Nissl-stained lumbar motor neurons in untreated SOD1G93A mice () and anti-CD40L SOD1G93A mice (). () Quantitative comparison of lumbar spinal cord motor neuron counts per mm2 in control (n = 4) versus anti-CD40L–treated mice (n = 8). * Figure 7: Treatment of SOD1G93A mice with anti-CD40L decreases the expression of genes in the co-stimulatory pathway in the spinal cord. We used Affymetrix gene expression profiling to analyze spinal cords from non-transgenic animals (non Tg), SOD1G93A animals treated for 40 d with 1 mg per kg (body weight) per week of anti-CD40L (aCD40L) and SOD1G93A untreated animals (G93A). Plot shows fold differences in the expression of genes in the co-stimulatory pathway, comparing non-transgenic animals to untreated and treated SOD1G93A animals. Genes are noted on the x axis, sorted by difference in gene expression between treated and untreated groups. Accession codes * Abstract * Accession codes * Author information * Supplementary information Referenced accessions ArrayExpress * E-TABM-940 Author information * Abstract * Accession codes * Author information * Supplementary information Primary authors * These authors contributed equally to this work. * John M Lincecum & * Fernando G Vieira Affiliations * ALS Therapy Development Institute, Cambridge, Massachusetts, USA. * John M Lincecum, * Fernando G Vieira, * Monica Z Wang, * Kenneth Thompson, * Gerald S De Zutter, * Joshua Kidd, * Andrew Moreno, * Ricardo Sanchez, * Isarelis J Carrion, * Beth A Levine, * Bashar M Al-Nakhala, * Shawn M Sullivan, * Alan Gill & * Steven Perrin Contributions J.M.L., F.G.V., A.G. and S.P. designed the experiments. M.Z.W. performed the immunohistochemistry and FACS experiments. R.S. and I.J.C. performed the motor neuron histology. B.A.L. oversaw and consulted on the human blood sample study. K.T., J.K. and A.M. performed all the animal studies. G.S.D.Z. consulted on the interpretation of the results. B.M.A. and S.M.S. wrote the simulation and LIMS software. A.G. performed all pharmacological statistical analysis. S.P., J.M.L., A.G. and F.G.V. wrote the paper. All authors discussed the results and commented on the manuscript. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Steven Perrin (sperrin@als.net) Supplementary information * Abstract * Accession codes * Author information * Supplementary information Excel files * Supplementary Table 1 (28K) Calculated Q scores of significantly different pathways in SOD1G93A mice compared to non-transgenic littermates. * Supplementary Table 2 (736K) RMA normalized gene expression data of all genes in five significantly changing pathways in SOD1G93A mice compared to non-transgenic littermates. * Supplementary Table 3 (108K) Calculated fold-change data of all genes in five significantly changing pathways in SOD1G93A mice compared to non-transgenic littermates derived from RMA normalized data. * Supplementary Table 5 (212K) Relative normalized transcript expression of costimulatory genes in human clinical blood samples. * Supplementary Note (72K) Clinical annotation of human clinical blood samples PDF files * Supplementary Text and Figures (3.5M) Supplementary Figures 1–3 and Supplementary Table 4 Additional data
• Discovery of common Asian copy number variants using integrated high-resolution array CGH and massively parallel DNA sequencing
  Park H Kim JI Ju YS Gokcumen O Mills RE Kim S Lee S Suh D Hong D Kang HP Yoo YJ Shin JY Kim HJ Yavartanoo M Chang YW Ha JS Chong W Hwang GR Darvishi K Kim H Yang SJ Yang KS Kim H Hurles ME Scherer SW Carter NP Tyler-Smith C Lee C Seo JS - Nature Genetics 42(5):400-405 (2010)
  Nature Genetics | Letter Discovery of common Asian copy number variants using integrated high-resolution array CGH and massively parallel DNA sequencing * Hansoo Park1, 2, 3, 4, 11 Search for this author in: * NPG journals * PubMed * Google Scholar * Jong-Il Kim1, 4, 5, 11 Search for this author in: * NPG journals * PubMed * Google Scholar * Young Seok Ju1, 5, 11 Search for this author in: * NPG journals * PubMed * Google Scholar * Omer Gokcumen2, 3 Search for this author in: * NPG journals * PubMed * Google Scholar * Ryan E Mills2, 3 Search for this author in: * NPG journals * PubMed * Google Scholar * Sheehyun Kim1, 6 Search for this author in: * NPG journals * PubMed * Google Scholar * Seungbok Lee1, 7 Search for this author in: * NPG journals * PubMed * Google Scholar * Dongwhan Suh1, 7 Search for this author in: * NPG journals * PubMed * Google Scholar * Dongwan Hong1 Search for this author in: * NPG journals * PubMed * Google Scholar * Hyunseok Peter Kang1 Search for this author in: * NPG journals * PubMed * Google Scholar * Yun Joo Yoo1 Search for this author in: * NPG journals * PubMed * Google Scholar * Jong-Yeon Shin1, 4 Search for this author in: * NPG journals * PubMed * Google Scholar * Hyun-Jin Kim1, 7 Search for this author in: * NPG journals * PubMed * Google Scholar * Maryam Yavartanoo1, 5 Search for this author in: * NPG journals * PubMed * Google Scholar * Young Wha Chang1 Search for this author in: * NPG journals * PubMed * Google Scholar * Jung-Sook Ha2, 3 Search for this author in: * NPG journals * PubMed * Google Scholar * Wilson Chong2 Search for this author in: * NPG journals * PubMed * Google Scholar * Ga-Ram Hwang2 Search for this author in: * NPG journals * PubMed * Google Scholar * Katayoon Darvishi2, 3 Search for this author in: * NPG journals * PubMed * Google Scholar * HyeRan Kim6 Search for this author in: * NPG journals * PubMed * Google Scholar * Song Ju Yang6 Search for this author in: * NPG journals * PubMed * Google Scholar * Kap-Seok Yang6 Search for this author in: * NPG journals * PubMed * Google Scholar * Hyungtae Kim6 Search for this author in: * NPG journals * PubMed * Google Scholar * Matthew E Hurles8 Search for this author in: * NPG journals * PubMed * Google Scholar * Stephen W Scherer9, 10 Search for this author in: * NPG journals * PubMed * Google Scholar * Nigel P Carter8 Search for this author in: * NPG journals * PubMed * Google Scholar * Chris Tyler-Smith8 Search for this author in: * NPG journals * PubMed * Google Scholar * Charles Lee2, 3, 12 Search for this author in: * NPG journals * PubMed * Google Scholar * Jeong-Sun Seo1, 4, 5, 6, 7, 12 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorsJournal name:Nature GeneticsVolume:42,Pages:400–405Year published:(2010)DOI:doi:10.1038/ng.555Received30 November 2009Accepted22 February 2010Published online04 April 2010 Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Copy number variants (CNVs) account for the majority of human genomic diversity in terms of base coverage. Here, we have developed and applied a new method to combine high-resolution array comparative genomic hybridization (CGH) data with whole-genome DNA sequencing data to obtain a comprehensive catalog of common CNVs in Asian individuals. The genomes of 30 individuals from three Asian populations (Korean, Chinese and Japanese) were interrogated with an ultra-high-resolution array CGH platform containing 24 million probes. Whole-genome sequencing data from a reference genome (NA10851, with 28.3× coverage) and two Asian genomes (AK1, with 27.8× coverage and AK2, with 32.0× coverage) were used to transform the relative copy number information obtained from array CGH experiments into absolute copy number values. We discovered 5,177 CNVs, of which 3,547 were putative Asian-specific CNVs. These common CNVs in Asian populations will be a useful resource for subsequent genetic ! studies in these populations, and the new method of calling absolute CNVs will be essential for applying CNV data to personalized medicine. View full text Figures at a glance * Figure 1: Overview of the CNV discovery project for Asian populations. The genomic DNA from ten Altaic Korean individuals, ten CHB HapMap individuals of Chinese ancestry, ten JPT HapMap individuals with Japanese ancestry and three platform-control comparison resource individuals (AK1, NA12878 and NA19240) were used for aCGH experiments. Genome sequence data from three subjects (AK1, AK2 and NA10851) were used to filter out false positive CNV calls and to obtain absolute CNV calls. * Figure 2: Original approach for calling absolute copy number status. () Right: The top, panel shows aCGH data for a genomic region on chromosome 3 in AK1 as compared to the reference sample, NA10851. The second panel down shows read-depth information for the same genomic region, derived from whole-genome sequencing data of NA10851. The third panel down is a 'corrected' absolute copy number result for this genomic region in AK1 using the absolute copy number algorithm analysis method described in this study. The bottom panel displays the same genomic region for AK1 using read-depth information derived from whole-genome sequencing data. () Comparison between relative copy number states and absolute copy number values for CNV segments, before and after corrections for NA10851 copy number states. Out of the total 21,905 CNVs identified in the 30 Asian individuals by aCGH (that is, by relative copy number states), the relative copy number values of 10,925 were not affected by CNVs in the NA10851 reference. Among 10,980 'obscure' CNVs, 4,970 were d! etermined to be non-CNVs by absolute calls and were removed from the final list of CNVs. An additional 3,164 CNVs, which were considered 'covert' CNVs and were initially missed by the aCGH experiments, were also identified by the absolute copy number state calling algorithm. * Figure 3: Frequency of copy number gains and losses among 33 individuals. () Distribution of absolute copy number gains (copy number >2) and losses (copy number <2) in 33 individuals. () Distribution of relative and absolute copy number gains and losses by CNV size. The x and y axes represent size and number of CNV segments, respectively. * Figure 4: Putative Asian population–specific copy number variants. () Venn diagram showing validated putative Asian-specific CNVEs. The lower part of the figure (blue) indicates the ethnic distribution of 4,959 CNVEs that were discovered by a 42M NimbleGen aCGH platform and validated with a genotyping microarray in the same study2. The upper part of the figure indicates that 3,547 out of 5,177 CNVEs found among the 30 Asian individuals in this study do not reach a 1-bp overlap with CNVEs recently found by the Genome Structural Variation Consortium2. The Genome Structural Variation Consortium reported that they found 4,978 validated CNVEs, but we show only 4,959 of them in this Venn diagram because 19 were nonpolymorphic. () Distribution of gene ontology categories for genes in which coding sequences overlap with common copy number–gain regions (outer circle) and copy number–loss regions (inner circle) identified from 30 Asian subjects. () CNVE location and number of Asian individuals involved (bar graph, right). Red, copy number gain; g! reen, copy number loss. Selected genes and miRNAs are also shown on the left. * Figure 5: Effect of aCGH platforms in the CNV discovery. Absolute CNVs found from two HapMap individuals (NA12878 and NA19240) in this study using the Agilent 24M aCGH array were compared with CNVs found by genotyping microarray in the Genomic Structural Variation Consortium data. We also compared CNVs from AK1 obtained by Agilent 24M and Nimblegen 42M microarrays. Accession codes * Accession codes * Author information * Supplementary information Referenced accessions GenBank * SRA008370 * SRA010321 * SRA010320 Gene Expression Omnibus * GSE19651 Author information * Accession codes * Author information * Supplementary information Primary authors * These authors contributed equally to this work. * Hansoo Park, * Jong-Il Kim & * Young Seok Ju Affiliations * Genomic Medicine Institute, Medical Research Center, Seoul National University, Seoul, Korea. * Hansoo Park, * Jong-Il Kim, * Young Seok Ju, * Sheehyun Kim, * Seungbok Lee, * Dongwhan Suh, * Dongwan Hong, * Hyunseok Peter Kang, * Yun Joo Yoo, * Jong-Yeon Shin, * Hyun-Jin Kim, * Maryam Yavartanoo, * Young Wha Chang & * Jeong-Sun Seo * Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA. * Hansoo Park, * Omer Gokcumen, * Ryan E Mills, * Jung-Sook Ha, * Wilson Chong, * Ga-Ram Hwang, * Katayoon Darvishi & * Charles Lee * Harvard Medical School, Boston, Massachusetts, USA. * Hansoo Park, * Omer Gokcumen, * Ryan E Mills, * Jung-Sook Ha, * Katayoon Darvishi & * Charles Lee * Psoma Therapeutics Inc., Seoul, Korea. * Hansoo Park, * Jong-Il Kim, * Jong-Yeon Shin & * Jeong-Sun Seo * Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul, Korea. * Jong-Il Kim, * Young Seok Ju, * Maryam Yavartanoo & * Jeong-Sun Seo * Macrogen Inc., Seoul, Korea. * Sheehyun Kim, * HyeRan Kim, * Song Ju Yang, * Kap-Seok Yang, * Hyungtae Kim & * Jeong-Sun Seo * Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Korea. * Seungbok Lee, * Dongwhan Suh, * Hyun-Jin Kim & * Jeong-Sun Seo * Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK. * Matthew E Hurles, * Nigel P Carter & * Chris Tyler-Smith * The Centre for Applied Genomics and Program in Genetics and Genomic Biology, The Hospital for Sick Children, Toronto, Ontario, Canada. * Stephen W Scherer * Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada. * Stephen W Scherer * These authors jointly directed the project. * Charles Lee & * Jeong-Sun Seo Contributions J.-S.S. and C.L. planned and managed the project. H.P., J.-I.K., Y.S.J., O.G., R.E.M., Y.J.Y., J.-Y.S., J.-S.H., W.C., G.-R.H. and K.D. executed and analyzed aCGH experiments. J.-I.K., Y.S.J., S.K., D.H., H.-J.K. and D.H. executed sequencing of the genome and analyzed sequence data. D.S., S.L., M.Y., Y.W.C., HyeRan Kim, S.J.Y., K.-S.Y. and Hyungtae Kim performed validation experiments; M.E.H., S.W.S., N.P.C. and C.T.-S. assisted in data analyses; J.-S.S., C.L., H.P., J.-I.K., Y.S.J. and H.P.K. wrote the manuscript. Competing financial interests The authors declare no competing financial interests. Corresponding authors Correspondence to: * Jeong-Sun Seo (jeongsun@snu.ac.kr) or * Charles Lee (clee@rics.bwh.harvard.edu) Supplementary information * Accession codes * Author information * Supplementary information Excel files * Supplementary Table 3 (2M) Absolute CNVs of 30 Asians * Supplementary Table 5 (40K) List of primers for qPCR and breakpoint sequencing experiments * Supplementary Table 7 (1M) List of 5,177 CNVE identified in the 30 Asians studied * Supplementary Table 8 (348K) List of OMIM genes in identified CNVs * Supplementary Table 9 (40K) List of microRNAs overlapping the personal CNVs identified in the study * Supplementary Table 10 (52K) List of fusion gene overlapping the personal CNVs identified in this study * Supplementary Table 11 (116K) Modified PANTHER ontology analysis PDF files * Supplementary Text and Figures (3M) Supplementary Figures 1–11, Supplementary Tables 1–12 and Supplementary Note * Supplementary Figure 3 (23M) Read-depth information for 721 validated CNVs in AK1 using data for AK1 and NA10851 Additional data
• Mutation of the RAD51C gene in a Fanconi anemia–like disorder
  - Nature Genetics 42(5):406-409 (2010)
  Nature Genetics | Letter Mutation of the RAD51C gene in a Fanconi anemia–like disorder * Fiona Vaz1, 10 Search for this author in: * NPG journals * PubMed * Google Scholar * Helmut Hanenberg2, 3, 10 Search for this author in: * NPG journals * PubMed * Google Scholar * Beatrice Schuster4 Search for this author in: * NPG journals * PubMed * Google Scholar * Karen Barker5 Search for this author in: * NPG journals * PubMed * Google Scholar * Constanze Wiek2 Search for this author in: * NPG journals * PubMed * Google Scholar * Verena Erven2 Search for this author in: * NPG journals * PubMed * Google Scholar * Kornelia Neveling4 Search for this author in: * NPG journals * PubMed * Google Scholar * Daniela Endt4 Search for this author in: * NPG journals * PubMed * Google Scholar * Ian Kesterton6 Search for this author in: * NPG journals * PubMed * Google Scholar * Flavia Autore7 Search for this author in: * NPG journals * PubMed * Google Scholar * Franca Fraternali7 Search for this author in: * NPG journals * PubMed * Google Scholar * Marcel Freund2 Search for this author in: * NPG journals * PubMed * Google Scholar * Linda Hartmann8 Search for this author in: * NPG journals * PubMed * Google Scholar * David Grimwade1 Search for this author in: * NPG journals * PubMed * Google Scholar * Roland G Roberts1 Search for this author in: * NPG journals * PubMed * Google Scholar * Heiner Schaal8 Search for this author in: * NPG journals * PubMed * Google Scholar * Shehla Mohammed9 Search for this author in: * NPG journals * PubMed * Google Scholar * Nazneen Rahman5 Search for this author in: * NPG journals * PubMed * Google Scholar * Detlev Schindler4, 11 Search for this author in: * NPG journals * PubMed * Google Scholar * Christopher G Mathew1, 11 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorsJournal name:Nature GeneticsVolume:42,Pages:406–409Year published:(2010)DOI:doi:10.1038/ng.570Received09 November 2009Accepted22 March 2010Published online18 April 2010 Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Fanconi anemia (FA) is a rare chromosomal-instability disorder associated with a variety of developmental abnormalities, bone marrow failure and predisposition to leukemia and other cancers1. We have identified a homozygous missense mutation in the RAD51C gene in a consanguineous family with multiple severe congenital abnormalities characteristic of FA. RAD51C is a member of the RAD51-like gene family involved in homologous recombination–mediated DNA repair. The mutation results in loss of RAD51 focus formation in response to DNA damage and in increased cellular sensitivity to the DNA interstrand cross-linking agent mitomycin C and the topoisomerase-1 inhibitor camptothecin. Thus, biallelic germline mutations in a RAD51 paralog are associated with an FA-like syndrome. View full text Figures at a glance * Figure 1: Genetic analysis of the family carrying an FA-like disorder. () Pedigree of the family. () Protein blot of fibroblasts from subject IV-5 and of other FA cell lines (FA-D2, FA-J, FA-D1, FA-N and FA-A denote lines with mutations in FANCD2, BRIP1, BRCA2, PALB2 and FANCA, respectively); ubiquitinated FANCD2 (FANCD2-L) and nonubiquitinated FANCD2 (FANCD2-S) and other downstream FANC proteins are present in cells from IV-5. CON, unaffected control; loading control is RAD50. () Linkage analysis with SNPs on chromosome 17q23. M, megabases. The first fully informative SNP rs203024 is distal to EME1. () Sequencing of the mutation in RAD51C (G773A) in family members. * Figure 2: Functional analysis of the RAD51C alleles. () Fibroblast metaphase after exposure of the culture to 10 ng/ml MMC shows chromatid-type breakage and a radial rejoining figure (arrows). () Cell cycle distribution of peripheral blood lymphocyte culture from subject IV-5 shows increased G2 arrest (37.4% of cells in G2) in response to 45 nM MMC (AFF, light gray) compared to an unaffected control (18.4%; CON, dark gray overlay). () Untransduced (not shown) or pac (mock)-transduced fibroblasts from subject IV-5 (SH2038-F) show elevated G2 phase arrest (47.3 ± 8.5%, n = 4 experiments) after exposure to 36 nM MMC. () Transduction of SH2038-F cells with wild-type (WT) RAD51C rescues G2 arrest (22.6 ± 0.6%, n = 4, P < 0.005) under the same conditions as in . () Transduction with mutant RAD51CG773A leads to a marginal decrease in G2 arrest (41.5 ± 2.3%, n = 4, not significant compared to mock transduction, P = 0.24). () Untransduced (not shown) or pac-transduced Rad51c-deficient hamster irs3 cells show elevated G2 phase arrest! (42.5 ± 3.5%, n = 3) after exposure to 36 nM MMC. () Transduction of irs3 cells with human wild-type RAD51C rescues G2 arrest (16.4 ± 0.6%, n = 3, P < 0.001) under the same conditions as in . () Transduction with mutant RAD51CG773A leads to a moderate decrease in G2 arrest (30.5 ± 2.7%, n = 3, P < 0.005) compared to mock transduction. () Increased survival rates indicate successful complementation of ΔRAD51C-DT40 chicken cells by human wild-type RAD51C (dashed line) but not by the mutant RAD51CG773A (dotted line); the solid line is from uncorrected cells transduced with control vector. Error bars are s.d. from three experiments. () SH-2038 fibroblasts from subject IV-5 are defective in the formation of RAD51 nuclear foci after exposure to MMC (2.8 ± 2.2% positive cells, n = 4). Transduction with wild-type RAD51C rescued their proficiency (25.9 ± 4.0% positive cells, n = 4, P < 0.001) to a degree that was similar to unaffected control (CON) fibroblasts (31.6 ± 6.9% p! ositive cells). Error bars, s.d. * Figure 3: Camptothecin (CPT) sensitivity of lymphoblasts from subject IV-5. SH2038-L cells were tested for CPT sensitivity before transduction (no virus) or after transduction with control virus (no RAD51C insert), RAD51C with the R258H mutation, or wild-type RAD51C. Results for CPT-sensitive FA lymphoblastoid cell lines from FA groups FA-D1 and FA-N, and from a normal control line, are shown for comparison. The CPT sensitivity of SH2038-L is complemented by wild-type but not by mutant RAD51C (data shown is the mean plus or minus the one-sided s.d. from four experiments). Author information * Author information * Supplementary information Primary authors * These authors contributed equally to this work. * Fiona Vaz & * Helmut Hanenberg * These authors contributed equally to the direction of this work. * Detlev Schindler & * Christopher G Mathew Affiliations * Department of Medical and Molecular Genetics, King's College London School of Medicine, Guy's Hospital, London, UK. * Fiona Vaz, * David Grimwade, * Roland G Roberts & * Christopher G Mathew * Department of Pediatric Hematology, Oncology and Clinical Immunology, Children's Hospital, Heinrich Heine University, Düsseldorf, Germany. * Helmut Hanenberg, * Constanze Wiek, * Verena Erven & * Marcel Freund * Department of Pediatrics, Wells Center for Pediatric Research, Riley Hospital, Indiana University School of Medicine, Indianapolis, Indiana, USA. * Helmut Hanenberg * Department of Human Genetics, University of Würzburg, Würzburg, Germany. * Beatrice Schuster, * Kornelia Neveling, * Daniela Endt & * Detlev Schindler * Section of Cancer Genetics, Institute of Cancer Research, Sutton, Surrey, UK. * Karen Barker & * Nazneen Rahman * Cytogenetics Laboratory, Genetics Centre, Guy's and St. Thomas' NHS Foundation Trust, Guy's Hospital, London, UK. * Ian Kesterton * Randall Division of Cell and Molecular Biophysics, King's College London, New Hunt's House, Guy's Hospital, London, UK. * Flavia Autore & * Franca Fraternali * Institute of Virology, Heinrich Heine University, Düsseldorf, Germany. * Linda Hartmann & * Heiner Schaal * Department of Clinical Genetics, Guy's and St. Thomas' NHS Foundation Trust, Guy's Hospital, London, UK. * Shehla Mohammed Contributions The study was designed by C.G.M., D.S. and H.H. Phenotypic assessment, sample collection and characterization of FA subgroups were performed by S.M., H.H., D.S., F.V., C.G.M., I.K., C.W., B.S., V.E., K.N. and D.E. Genetic mapping, mutation analysis and functional studies were carried out by F.V., K.B., C.W., B.S., V.E., K.N., D.E., M.F. and L.H. under the supervision of H.H., H.S., D.G., D.S., N.R. and C.G.M. Bioinformatic and structural studies were done by R.G.R., F.A. and F.F. The manuscript was written by C.G.M., D.S. and H.H., with help from the other authors. Competing financial interests The authors declare no competing financial interests. Corresponding authors Correspondence to: * Christopher G Mathew (christopher.mathew@genetics.kcl.ac.uk) or * Helmut Hanenberg (helmut.hanenberg@uni-duesseldorf.de) or * Detlev Schindler (schindler@biozentrum.uni-wuerzburg.de) Supplementary information * Author information * Supplementary information PDF files * Supplementary Text and Figures (3M) Supplementary Figures 1–3 and Supplementary Tables 1–3 Additional data
• Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility gene
  - Nature Genetics 42(5):410-414 (2010)
  Nature Genetics | Letter Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility gene * Alfons Meindl1 Search for this author in: * NPG journals * PubMed * Google Scholar * Heide Hellebrand1, 16 Search for this author in: * NPG journals * PubMed * Google Scholar * Constanze Wiek2, 16 Search for this author in: * NPG journals * PubMed * Google Scholar * Verena Erven2 Search for this author in: * NPG journals * PubMed * Google Scholar * Barbara Wappenschmidt3 Search for this author in: * NPG journals * PubMed * Google Scholar * Dieter Niederacher4 Search for this author in: * NPG journals * PubMed * Google Scholar * Marcel Freund2 Search for this author in: * NPG journals * PubMed * Google Scholar * Peter Lichtner5 Search for this author in: * NPG journals * PubMed * Google Scholar * Linda Hartmann6 Search for this author in: * NPG journals * PubMed * Google Scholar * Heiner Schaal6 Search for this author in: * NPG journals * PubMed * Google Scholar * Juliane Ramser1 Search for this author in: * NPG journals * PubMed * Google Scholar * Ellen Honisch4 Search for this author in: * NPG journals * PubMed * Google Scholar * Christian Kubisch7 Search for this author in: * NPG journals * PubMed * Google Scholar * Hans E Wichmann8 Search for this author in: * NPG journals * PubMed * Google Scholar * Karin Kast9 Search for this author in: * NPG journals * PubMed * Google Scholar * Helmut Deißler10 Search for this author in: * NPG journals * PubMed * Google Scholar * Christoph Engel11 Search for this author in: * NPG journals * PubMed * Google Scholar * Bertram Müller-Myhsok12 Search for this author in: * NPG journals * PubMed * Google Scholar * Kornelia Neveling13 Search for this author in: * NPG journals * PubMed * Google Scholar * Marion Kiechle1 Search for this author in: * NPG journals * PubMed * Google Scholar * Christopher G Mathew14 Search for this author in: * NPG journals * PubMed * Google Scholar * Detlev Schindler13 Search for this author in: * NPG journals * PubMed * Google Scholar * Rita K Schmutzler3, 17 Search for this author in: * NPG journals * PubMed * Google Scholar * Helmut Hanenberg2, 15, 17 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorsJournal name:Nature GeneticsVolume:42,Pages:410–414Year published:(2010)DOI:doi:10.1038/ng.569Received05 November 2009Accepted22 March 2010Published online18 April 2010 Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Germline mutations in a number of genes involved in the recombinational repair of DNA double-strand breaks are associated with predisposition to breast and ovarian cancer. RAD51C is essential for homologous recombination repair, and a biallelic missense mutation can cause a Fanconi anemia–like phenotype. In index cases from 1,100 German families with gynecological malignancies, we identified six monoallelic pathogenic mutations in RAD51C that confer an increased risk for breast and ovarian cancer. These include two frameshift-causing insertions, two splice-site mutations and two nonfunctional missense mutations. The mutations were found exclusively within 480 pedigrees with the occurrence of both breast and ovarian tumors (BC/OC; 1.3%) and not in 620 pedigrees with breast cancer only or in 2,912 healthy German controls. These results provide the first unambiguous evidence of highly penetrant mutations associated with human cancer in a RAD51 paralog and support the 'common ! disease, rare allele' hypothesis. View full text Figures at a glance * Figure 1: RAD51C mutations in familial breast and ovarian cancer pedigrees. (–) Individuals with breast cancer (BC) are shown as filled circles, females with ovarian cancer (OC) as streaked circles; OP, surgery. Disease and age in years (y) at first diagnosis is given underneath the symbol, current age or age at death (+) above it. Other cancers diagnosed in the pedigrees are also shown (LC, lung cancer; KidC, kidney cancer; PanC, pancreatic cancer; CC, colon cancer; LAT, lower abdominal tumor; NHL, non-Hodgkin lymphoma; bil., bilateral). All affected individuals with breast or ovarian cancer not tested for germline mutations in RAD51C were deceased or refused testing. Carriers of RAD51C mutations are shown with their specific RAD51C mutation (as listed in Table 1), whereas individuals who tested negative for the mutation in the specific pedigree are depicted as wild-type (WT). In addition, LOH data (+ for loss of the WT allele, − for a retained WT allele) is shown for the individuals for whom formalin-fixed, paraffin-embedded (FFPE) tissue samp! les of the tumor(s) could be analyzed. * Figure 2: Functional analysis of the splice donor mutations 145+1G>T and 904+5G>T. () Structure of RAD51C transcript 001 (Ensembl ID OTTHUMT00000280540) and the primers for RT-PCR. () Using primers located in exon 1 and exon 3, we performed RT-PCR analysis of RNA from PB mononuclear cells of two affected individuals with breast or ovarian cancer (subj. 1, subj. 2) harboring the 145+1G>T splice donor mutation. This revealed three alternative transcripts from exon 1: RAD51C-001 and the two nonfunctional alternatively spliced transcript isoforms RAD51C-008 (Ensembl ID OTTHUMT00000280547) and RAD51C-009 (Ensembl ID OTTHUMT00000280548), as predicted by the HBond splice donor algorithm and confirmed by sequencing of the PCR products (Supplementary Fig. 1a). () Schematic drawing of the splice donor sites (GT) in RAD51C exon 1 used in transcripts RAD51C-001, RAD51C-008 and RAD51C-009, respectively. () RT-PCR analysis of HeLa cells transfected with RAD51C minigene splicing constructs carrying either the wild-type or the 145+1G>T mutant 5′ splice site showed compl! ete inactivation of this mutated 5′ splice site and confirmed the differences in splicing pattern between heterozygous mutation carriers and normal controls shown in . The cells were co-transfected with growth hormone-1 (GH1) as a control. () RT-PCR analysis of RNA extracted from tumor samples from two carriers of the 905+5G>T mutation. Sequencing of the PCR products showed that these splice donor mutations led to exon 6 skipping (Supplementary Fig. 1b). () Schematic drawing of a three-exon splicing reporter containing RAD51C exon 6 with adjacent intronic sequences. () RT-PCR analysis of RNA from HeLa cells transfected with the minigene constructs revealed exclusion of exon 6 in the presence of the 905+5G>T mutation compared to the wild-type 5′ splice site. * Figure 3: Function of RAD51C missense mutations in Rad51c-deficient DT40 cells. () Examining the survival of Rad51c-deficient DT40 cells with the mutant RAD51C proteins allowed us to distinguish mutants with normal function (G3R, A126T, V169A and G264V) from nonfunctional true null mutants (G125V and L138F). Also depicted are the survival curves for nontransduced (no virus) cells as well as cells transduced with either the control virus (vector control) or the wild-type RAD51C cDNA (wild-type or WT). Data shown are means ± s.d. from four different experiments. () Survival of Rad51c-deficient DT40 cells with the human RAD51C proteins having intermediate activity (D159N, G264S, T287A and R366Q; n = 4). Controls are as in . Data shown are means ± s.d. from four different experiments. () Protein blot on puromycin-resistant Rad51c-deficient DT40 cells expressing the wild-type and the missense proteins of the retroviral long terminal repeat promoter shows equal expression of the mutant proteins. * Figure 4: Function of RAD51C missense mutations in human RAD51C-mutated fibroblasts. We analyzed formation of RAD51 foci by immunofluorescent antibody staining in human RAD51C-mutated cells transduced with retroviral vectors that expressed each of the ten RAD51C missense alterations or the wild-type RAD51C cDNA. Shown are the percentages of cells (mean ± s.e.m.) with more than ten RAD51 foci after incubation for 24 h in 150 nM MMC, from three different experiments counted by two different people blinded for each condition. We assessed statistical significance by Student's t-test, applying SPSS software version 17.0; significance is indicated for G125V and L138F compared to the wild-type control. Accession codes * Accession codes * Author information * Supplementary information Referenced accessions EMBL Nucleotide Sequence Database * OTTHUMT00000280540 * OTTHUMT00000280547 * OTTHUMT00000280548 Author information * Accession codes * Author information * Supplementary information Primary authors * These authors contributed equally to the work. * Heide Hellebrand & * Constanze Wiek * These authors contributed equally to the direction of the work. * Rita K Schmutzler & * Helmut Hanenberg Affiliations * Department of Obstetrics and Gynecology, Division of Tumor Genetics, Klinikum rechts der Isar der Technischen Universitaet Muenchen, Munich, Germany. * Alfons Meindl, * Heide Hellebrand, * Juliane Ramser & * Marion Kiechle * Department of Pediatric Hematology, Oncology and Clinical Immunology, Children's Hospital, Heinrich-Heine-University, Düsseldorf, Germany. * Constanze Wiek, * Verena Erven, * Marcel Freund & * Helmut Hanenberg * Center for Familial Breast and Ovarian Cancer and Center for Integrated Oncology, University Hospital, Cologne, Germany. * Barbara Wappenschmidt & * Rita K Schmutzler * Department of Obstetrics and Gynecology, Heinrich-Heine-University, Düsseldorf, Germany. * Dieter Niederacher & * Ellen Honisch * Institute of Human Genetics, Helmholtz Zentrum Muenchen, Neuherberg, Germany. * Peter Lichtner * Institute of Virology, Heinrich-Heine-University, Düsseldorf, Germany. * Linda Hartmann & * Heiner Schaal * Institute of Human Genetics, Center for Molecular Medicine Cologne and Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases, University of Cologne, Cologne, Germany. * Christian Kubisch * Institute of Epidemiology, Helmholtz Zentrum Muenchen, Neuherberg, Germany. * Hans E Wichmann * Department of Obstetrics and Gynecology, Carl Gustav Carus University, Dresden, Germany. * Karin Kast * Department of Obstetrics and Gynecology, Ulm University, Ulm, Germany. * Helmut Deißler * Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany. * Christoph Engel * Max-Planck-Institute of Psychiatry, Munich, Germany. * Bertram Müller-Myhsok * Department of Human Genetics, University of Würzburg, Würzburg, Germany. * Kornelia Neveling & * Detlev Schindler * Department of Medical and Molecular Genetics, Kings College, Guy's Hospital, London, UK. * Christopher G Mathew * Department of Pediatrics, Wells Center for Pediatric Research, Riley Hospital, Indiana University School of Medicine, Indianapolis, Indiana, USA. * Helmut Hanenberg Contributions The study was designed by A.M., R.K.S. and H. Hanenberg. The screening experiments were performed by H. Hellebrand, D.N., B.W., K.K., H.D. and E.H. under the direction of A.M. Cloning, virus production, transductions and functional complementation tests were set up by C.W., V.E., K.N. and M.F. under the direction of H. Hanenberg and D.S. L.H. and H.S. performed splicing experiments. MALDI-TOF experiments were performed by P.L. under the direction of H.E.W. The statistical analyses were done by B.M.-M., R.K.S. and C.E. C.E. also provided clinical and histopathological data. Control samples were collected by C.K. and H.E.W. The search for families was initiated by M.K. and R.K.S., and families were provided by the GC-HBOC. J.R. and C.G.M. participated in discussing and revising the manuscript. The manuscript was written by A.M., R.K.S., D.N. and H. Hanenberg. Competing financial interests The authors declare no competing financial interests. Corresponding authors Correspondence to: * Alfons Meindl (alfons.meindl@lrz.tu-muenchen.de) or * Helmut Hanenberg (helmut.hanenberg@uni-duesseldorf.de) Supplementary information * Accession codes * Author information * Supplementary information PDF files * Supplementary Text and Figures (336K) Supplementary Figures 1–4 and Supplementary Table 1 Additional data
• A sequence variant at 4p16.3 confers susceptibility to urinary bladder cancer
  Kiemeney LA Sulem P Besenbacher S Vermeulen SH Sigurdsson A Thorleifsson G Gudbjartsson DF Stacey SN Gudmundsson J Zanon C Kostic J Masson G Bjarnason H Palsson ST Skarphedinsson OB Gudjonsson SA Witjes JA Grotenhuis AJ Verhaegh GW Bishop DT Sak SC Choudhury A Elliott F Barrett JH Hurst CD de Verdier PJ Ryk C Rudnai P Gurzau E Koppova K Vineis P Polidoro S Guarrera S Sacerdote C Campagna M Placidi D Arici C Zeegers MP Kellen E Gutierrez BS Sanz-Velez JI Sanchez-Zalabardo M Valdivia G Garcia-Prats MD Hengstler JG Blaszkewicz M Dietrich H Ophoff RA van den Berg LH Alexiusdottir K Kristjansson K Geirsson G Nikulasson S Petursdottir V Kong A Thorgeirsson T Mungan NA Lindblom A van Es MA Porru S Buntinx F Golka K Mayordomo JI Kumar R Matullo G Steineck G Kiltie AE Aben KK Jonsson E Thorsteinsdottir U Knowles MA Rafnar T Stefansson K - Nature Genetics 42(5):415-419 (2010)
  Nature Genetics | Letter A sequence variant at 4p16.3 confers susceptibility to urinary bladder cancer * Lambertus A Kiemeney1, 2, 3, 44, 45 Search for this author in: * NPG journals * PubMed * Google Scholar * Patrick Sulem4, 44 Search for this author in: * NPG journals * PubMed * Google Scholar * Soren Besenbacher4 Search for this author in: * NPG journals * PubMed * Google Scholar * Sita H Vermeulen1 Search for this author in: * NPG journals * PubMed * Google Scholar * Asgeir Sigurdsson4 Search for this author in: * NPG journals * PubMed * Google Scholar * Gudmar Thorleifsson4 Search for this author in: * NPG journals * PubMed * Google Scholar * Daniel F Gudbjartsson4 Search for this author in: * NPG journals * PubMed * Google Scholar * Simon N Stacey4 Search for this author in: * NPG journals * PubMed * Google Scholar * Julius Gudmundsson4 Search for this author in: * NPG journals * PubMed * Google Scholar * Carlo Zanon4 Search for this author in: * NPG journals * PubMed * Google Scholar * Jelena Kostic4 Search for this author in: * NPG journals * PubMed * Google Scholar * Gisli Masson4 Search for this author in: * NPG journals * PubMed * Google Scholar * Hjordis Bjarnason4 Search for this author in: * NPG journals * PubMed * Google Scholar * Stefan T Palsson4 Search for this author in: * NPG journals * PubMed * Google Scholar * Oskar B Skarphedinsson4 Search for this author in: * NPG journals * PubMed * Google Scholar * Sigurjon A Gudjonsson4 Search for this author in: * NPG journals * PubMed * Google Scholar * J Alfred Witjes2 Search for this author in: * NPG journals * PubMed * Google Scholar * Anne J Grotenhuis1 Search for this author in: * NPG journals * PubMed * Google Scholar * Gerald W Verhaegh2 Search for this author in: * NPG journals * PubMed * Google Scholar * D Timothy Bishop5 Search for this author in: * NPG journals * PubMed * Google Scholar * Sei Chung Sak6 Search for this author in: * NPG journals * PubMed * Google Scholar * Ananya Choudhury7 Search for this author in: * NPG journals * PubMed * Google Scholar * Faye Elliott5 Search for this author in: * NPG journals * PubMed * Google Scholar * Jennifer H Barrett5 Search for this author in: * NPG journals * PubMed * Google Scholar * Carolyn D Hurst6 Search for this author in: * NPG journals * PubMed * Google Scholar * Petra J de Verdier8 Search for this author in: * NPG journals * PubMed * Google Scholar * Charlotta Ryk8 Search for this author in: * NPG journals * PubMed * Google Scholar * Peter Rudnai9 Search for this author in: * NPG journals * PubMed * Google Scholar * Eugene Gurzau10 Search for this author in: * NPG journals * PubMed * Google Scholar * Kvetoslava Koppova11 Search for this author in: * NPG journals * PubMed * Google Scholar * Paolo Vineis12, 13 Search for this author in: * NPG journals * PubMed * Google Scholar * Silvia Polidoro12, 14 Search for this author in: * NPG journals * PubMed * Google Scholar * Simonetta Guarrera12, 14 Search for this author in: * NPG journals * PubMed * Google Scholar * Carlotta Sacerdote15, 16 Search for this author in: * NPG journals * PubMed * Google Scholar * Marcello Campagna17 Search for this author in: * NPG journals * PubMed * Google Scholar * Donatella Placidi17 Search for this author in: * NPG journals * PubMed * Google Scholar * Cecilia Arici17 Search for this author in: * NPG journals * PubMed * Google Scholar * Maurice P Zeegers18, 19 Search for this author in: * NPG journals * PubMed * Google Scholar * Eliane Kellen20 Search for this author in: * NPG journals * PubMed * Google Scholar * Berta Saez Gutierrez21 Search for this author in: * NPG journals * PubMed * Google Scholar * José I Sanz-Velez22 Search for this author in: * NPG journals * PubMed * Google Scholar * Manuel Sanchez-Zalabardo23 Search for this author in: * NPG journals * PubMed * Google Scholar * Gabriel Valdivia24 Search for this author in: * NPG journals * PubMed * Google Scholar * Maria D Garcia-Prats25 Search for this author in: * NPG journals * PubMed * Google Scholar * Jan G Hengstler26 Search for this author in: * NPG journals * PubMed * Google Scholar * Meinolf Blaszkewicz26 Search for this author in: * NPG journals * PubMed * Google Scholar * Holger Dietrich27 Search for this author in: * NPG journals * PubMed * Google Scholar * Roel A Ophoff28, 29 Search for this author in: * NPG journals * PubMed * Google Scholar * Leonard H van den Berg30 Search for this author in: * NPG journals * PubMed * Google Scholar * Kristin Alexiusdottir31 Search for this author in: * NPG journals * PubMed * Google Scholar * Kristleifur Kristjansson4 Search for this author in: * NPG journals * PubMed * Google Scholar * Gudmundur Geirsson32 Search for this author in: * NPG journals * PubMed * Google Scholar * Sigfus Nikulasson33 Search for this author in: * NPG journals * PubMed * Google Scholar * Vigdis Petursdottir33 Search for this author in: * NPG journals * PubMed * Google Scholar * Augustine Kong4 Search for this author in: * NPG journals * PubMed * Google Scholar * Thorgeir Thorgeirsson4 Search for this author in: * NPG journals * PubMed * Google Scholar * N Aydin Mungan34 Search for this author in: * NPG journals * PubMed * Google Scholar * Annika Lindblom35 Search for this author in: * NPG journals * PubMed * Google Scholar * Michael A van Es30 Search for this author in: * NPG journals * PubMed * Google Scholar * Stefano Porru17 Search for this author in: * NPG journals * PubMed * Google Scholar * Frank Buntinx36, 37 Search for this author in: * NPG journals * PubMed * Google Scholar * Klaus Golka26 Search for this author in: * NPG journals * PubMed * Google Scholar * José I Mayordomo38 Search for this author in: * NPG journals * PubMed * Google Scholar * Rajiv Kumar39 Search for this author in: * NPG journals * PubMed * Google Scholar * Giuseppe Matullo12, 14 Search for this author in: * NPG journals * PubMed * Google Scholar * Gunnar Steineck40, 41 Search for this author in: * NPG journals * PubMed * Google Scholar * Anne E Kiltie42 Search for this author in: * NPG journals * PubMed * Google Scholar * Katja K H Aben1, 3 Search for this author in: * NPG journals * PubMed * Google Scholar * Eirikur Jonsson32 Search for this author in: * NPG journals * PubMed * Google Scholar * Unnur Thorsteinsdottir4, 43 Search for this author in: * NPG journals * PubMed * Google Scholar * Margaret A Knowles6 Search for this author in: * NPG journals * PubMed * Google Scholar * Thorunn Rafnar4 Search for this author in: * NPG journals * PubMed * Google Scholar * Kari Stefansson4, 43 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorsJournal name:Nature GeneticsVolume:42,Pages:415–419Year published:(2010)DOI:doi:10.1038/ng.558Received30 December 2009Accepted03 March 2010Published online28 March 2010 Abstract * Abstract * Author information * Supplementary information Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Previously, we reported germline DNA variants associated with risk of urinary bladder cancer (UBC) in Dutch and Icelandic subjects. Here we expanded the Icelandic sample set and tested the top 20 markers from the combined analysis in several European case-control sample sets, with a total of 4,739 cases and 45,549 controls. The T allele of rs798766 on 4p16.3 was found to associate with UBC (odds ratio = 1.24, P = 9.9 × 10−12). rs798766 is located in an intron of TACC3, 70 kb from FGFR3, which often harbors activating somatic mutations in low-grade, noninvasive UBC. Notably, rs798766[T] shows stronger association with low-grade and low-stage UBC than with more aggressive forms of the disease and is associated with higher risk of recurrence in low-grade stage Ta tumors. The frequency of rs798766[T] is higher in Ta tumors that carry an activating mutation in FGFR3 than in Ta tumors with wild-type FGFR3. Our results show a link between germline variants, somatic mutations of ! FGFR3 and risk of UBC. View full text Figures at a glance * Figure 1: Schematic view of the structure and association results in the UBC-associated region on chromosome 4p16.3. () Pairwise correlation structure in an 800-kb interval (1.3–2.1 Mb, NCBI B35) on chromosome 4p16.3. The upper plot shows pairwise D′ for 292 common SNPs (with minor allele frequency > 5%) from the HapMap (v21) CEU dataset. The lower plot shows the corresponding r2 values. () Estimated recombination rates (saRR) in cM per Mb from the HapMap (v21) Phase II data. () Location of known genes in the region. () Schematic view of the association with bladder cancer for all SNPs tested in the region for the initial scan (Iceland and The Netherlands). The y axis shows the −log10P value. * Figure 2: Correlation between genotypes of rs798766 and the expression of FGFR3 and TACC3 in adipose tissue from 604 individuals. () Expression of FGFR3. () Expression of TACC3. Expression is shown as 10(average MLR), where MLR is the mean log10 expression ratio and the average is taken over individuals with a particular genotype. Regression of the MLR values on the number of copies of the UBC risk variant rs798766[T] shows that the expression of FGFR3 is increased by an estimated 22.4% with each T allele carried, whereas the expression of TACC3 is increased by an estimated 9.1% with each allele. The effect of age and sex is taken into account in the regression by including the variables age, sex and the interaction of age × sex among the explanatory variables. Author information * Abstract * Author information * Supplementary information Primary authors * These authors contributed equally to this work. * Lambertus A Kiemeney & * Patrick Sulem Affiliations * Department of Epidemiology, Biostatistics and Health Technology Assessment, Nijmegen, The Netherlands. * Lambertus A Kiemeney, * Sita H Vermeulen, * Anne J Grotenhuis & * Katja K H Aben * Department of Urology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. * Lambertus A Kiemeney, * J Alfred Witjes & * Gerald W Verhaegh * Comprehensive Cancer Center East, Nijmegen, The Netherlands. * Lambertus A Kiemeney & * Katja K H Aben * deCODE Genetics, Reykjavik, Iceland. * Patrick Sulem, * Soren Besenbacher, * Asgeir Sigurdsson, * Gudmar Thorleifsson, * Daniel F Gudbjartsson, * Simon N Stacey, * Julius Gudmundsson, * Carlo Zanon, * Jelena Kostic, * Gisli Masson, * Hjordis Bjarnason, * Stefan T Palsson, * Oskar B Skarphedinsson, * Sigurjon A Gudjonsson, * Kristleifur Kristjansson, * Augustine Kong, * Thorgeir Thorgeirsson, * Unnur Thorsteinsdottir, * Thorunn Rafnar & * Kari Stefansson * Section of Epidemiology and Biostatistics, Leeds Institute of Molecular Medicine, St. James's University Hospital, Leeds, UK. * D Timothy Bishop, * Faye Elliott & * Jennifer H Barrett * Section of Experimental Oncology, Leeds Institute of Molecular Medicine, St. James's University Hospital, Leeds, UK. * Sei Chung Sak, * Carolyn D Hurst & * Margaret A Knowles * Christie Hospital National Health Service Foundation Trust, Manchester, UK. * Ananya Choudhury * Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden. * Petra J de Verdier & * Charlotta Ryk * National Institute of Environmental Health, Budapest, Hungary. * Peter Rudnai * Environmental Health Centre, Cluj-Napoca, Romania. * Eugene Gurzau * State Health Institute, Banska Bystrica, Slovakia. * Kvetoslava Koppova * Institute for Scientific Interchange (ISI) Foundation, Torino, Italy. * Paolo Vineis, * Silvia Polidoro, * Simonetta Guarrera & * Giuseppe Matullo * Department of Epidemiology and Public Health, Imperial College, London, UK. * Paolo Vineis * Department of Genetics, Biology and Biochemistry, University of Torino, Torino, Italy. * Silvia Polidoro, * Simonetta Guarrera & * Giuseppe Matullo * Unit of Cancer Epidemiology, University of Torino, Torino, Italy. * Carlotta Sacerdote * Centre for Cancer Epidemiology and Prevention (CPO Piemonte), Torino, Italy. * Carlotta Sacerdote * Department of Experimental and Applied Medicine, Section of Occupational Medicine and Industrial Hygiene, University of Brescia, Brescia, Italy. * Marcello Campagna, * Donatella Placidi, * Cecilia Arici & * Stefano Porru * Unit of Genetic Epidemiology, Department of Public Health and Epidemiology, University of Birmingham, Birmingham, UK. * Maurice P Zeegers * Department of Complex Genetics, Cluster of Genetics and Cell Biology, Nutrition and Toxicology Research Institute, Maastricht University, Maastricht, The Netherlands. * Maurice P Zeegers * Leuven University Centre for Cancer Prevention (LUCK), Leuven, Belgium. * Eliane Kellen * Department of Medicine, University of Zaragoza, Zaragoza, Spain. * Berta Saez Gutierrez * Division of Urology, San Jorge Hospital, Huesca, Spain. * José I Sanz-Velez * Division of Urology, Hospital Clinico, Zaragoza, Spain. * Manuel Sanchez-Zalabardo * Department of Urology, University of Zaragoza School of Medicine, Zaragoza, Spain. * Gabriel Valdivia * Division of Surgical Pathology, San Jorge Hospital, Huesca, Spain. * Maria D Garcia-Prats * Leibniz Research Centre for Working Environment and Human Factors, Dortmund, Germany. * Jan G Hengstler, * Meinolf Blaszkewicz & * Klaus Golka * Department of Urology, Paul Gerhardt Foundation, Lutherstadt Wittenberg, Germany. * Holger Dietrich * Department of Medical Genetics, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands. * Roel A Ophoff * University of California Los Angeles Center for Neurobehavioral Genetics, Los Angeles, USA. * Roel A Ophoff * Department of Neurology, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands. * Leonard H van den Berg & * Michael A van Es * Department of Medical Oncology, Landspitali–University Hospital, Reykjavik, Iceland. * Kristin Alexiusdottir * Department of Urology, Landspitali–University Hospital, Reykjavik, Iceland. * Gudmundur Geirsson & * Eirikur Jonsson * Department of Pathology, Landspitali–University Hospital, Reykjavik, Iceland. * Sigfus Nikulasson & * Vigdis Petursdottir * Department of Urology, Zonguldak Karaelmas University, Zonguldak, Turkey. * N Aydin Mungan * Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden. * Annika Lindblom * Department of General Practice, Catholic University of Leuven, Leuven, Belgium. * Frank Buntinx * Department of General Practice, Maastricht University, Maastricht, The Netherlands. * Frank Buntinx * Division of Medical Oncology, University of Zaragoza, Zaragoza, Spain. * José I Mayordomo * Division of Molecular Genetic Epidemiology, German Cancer Research Centre, Heidelberg, Germany. * Rajiv Kumar * Section of Clinical Cancer Epidemiology, Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden. * Gunnar Steineck * Division of Clinical Cancer Epidemiology, Department of Oncology, Institute of Clinical Sciences, The Sahlgrenska Academy, Gothenburg, Sweden. * Gunnar Steineck * Gray Institute for Radiation Oncology and Biology, University of Oxford, Oxford, UK. * Anne E Kiltie * Faculty of Medicine, University of Iceland, Reykjavik, Iceland. * Unnur Thorsteinsdottir & * Kari Stefansson * A full list of author affiliations appears at the end of the paper. * Lambertus A Kiemeney Contributions The study was designed and results were interpreted by L.A.K., P.S., U.T., M.A.K., T.R. and K.S. Statistical analysis was carried out by L.A.K., P.S., S.B., G.T., D.F.G., G. Masson and A.K. Subject ascertainment, recruitment, biological material collection and collection of clinical and lifestyle information was organized and carried out by S.H.V., J.A.W., A.J.G., G.W.V., D.T.B., S.C.S., A.C., F.E., J.H.B., C.D.H., P.J.d.V., C.R., P.R., E.G., K. Koppova, P.V., S. Polidoro, S.G., C.S., M.C., D.P., C.A., M.P.Z., E.K., B.S.G., J.I.S.-V., M.S.-Z., G.V., M.D.G.-P., J.G.H., M.B., H.D., R.A.O., L.H.v.d.B., K.A., K. Kristjansson, G.G., S.N., V.P., N.A.M., A.L., M.A.v.E., S. Porru, F.B., K.G., J.I.M., R.K., G. Matullo, G.S., A.E.K., K.K.H.A., T.T., E.J. and M.A.K. Principal investigators for the UBC follow-up populations were A.E.K. (UK), G. Matullo and P.V. (Torino), S. Porru (Brescia), M.P.Z. and F.B. (Belgium), R.K. (Eastern Europe), J.I.M. (Spain), G.S. (Sweden), K.G. (Germany) a! nd L.A.K. (The Netherlands, group 2). Genotyping and laboratory experiments were carried out by A.S., S.N.S., J.G., J.K., H.B., S.T.P., O.B.S. and C.D.H. Bioinformatics analysis was carried out by P.S., A.S., G.T., C.Z. and S.A.G. L.A.K., P.S., U.T., M.A.K., T.R. and K.S. drafted the manuscript. All authors contributed to the final version of the paper. Competing financial interests The authors from deCODE genetics are shareholders in deCODE Genetics Inc. Corresponding authors Correspondence to: * Lambertus A Kiemeney (b.kiemeney@ebh.umcn.nl) or * Kari Stefansson (kstefans@decode.is) Supplementary information * Abstract * Author information * Supplementary information PDF files * Supplementary Text and Figures (2M) Supplementary Note, Supplementary Tables 1–12 and Supplementary Figures 1 and 2 Additional data
• Genome-wide association study of intracranial aneurysm identifies three new risk loci
  Yasuno K Bilguvar K Bijlenga P Low SK Krischek B Auburger G Simon M Krex D Arlier Z Nayak N Ruigrok YM Niemelä M Tajima A von Und Zu Fraunberg M Dóczi T Wirjatijasa F Hata A Blasco J Oszvald A Kasuya H Zilani G Schoch B Singh P Stüer C Risselada R Beck J Sola T Ricciardi F Aromaa A Illig T Schreiber S van Duijn CM van den Berg LH Perret C Proust C Roder C Ozturk AK Gaál E Berg D Geisen C Friedrich CM Summers P Frangi AF State MW Wichmann HE Breteler MM Wijmenga C Mane S Peltonen L Elio V Sturkenboom MC Lawford P Byrne J Macho J Sandalcioglu EI Meyer B Raabe A Steinmetz H Rüfenacht D Jääskeläinen JE Hernesniemi J Rinkel GJ Zembutsu H Inoue I Palotie A Cambien F Nakamura Y Lifton RP Günel M - Nature Genetics 42(5):420-425 (2010)
  Nature Genetics | Letter Genome-wide association study of intracranial aneurysm identifies three new risk loci * Katsuhito Yasuno1, 2, 3 Search for this author in: * NPG journals * PubMed * Google Scholar * Kaya Bilguvar1, 2, 3 Search for this author in: * NPG journals * PubMed * Google Scholar * Philippe Bijlenga4 Search for this author in: * NPG journals * PubMed * Google Scholar * Siew-Kee Low5 Search for this author in: * NPG journals * PubMed * Google Scholar * Boris Krischek6 Search for this author in: * NPG journals * PubMed * Google Scholar * Georg Auburger7 Search for this author in: * NPG journals * PubMed * Google Scholar * Matthias Simon8 Search for this author in: * NPG journals * PubMed * Google Scholar * Dietmar Krex9 Search for this author in: * NPG journals * PubMed * Google Scholar * Zulfikar Arlier1, 2, 3 Search for this author in: * NPG journals * PubMed * Google Scholar * Nikhil Nayak1, 2, 3 Search for this author in: * NPG journals * PubMed * Google Scholar * Ynte M Ruigrok10 Search for this author in: * NPG journals * PubMed * Google Scholar * Mika Niemelä11 Search for this author in: * NPG journals * PubMed * Google Scholar * Atsushi Tajima12 Search for this author in: * NPG journals * PubMed * Google Scholar * Mikael von und zu Fraunberg13 Search for this author in: * NPG journals * PubMed * Google Scholar * Tamás Dóczi14 Search for this author in: * NPG journals * PubMed * Google Scholar * Florentina Wirjatijasa7 Search for this author in: * NPG journals * PubMed * Google Scholar * Akira Hata15 Search for this author in: * NPG journals * PubMed * Google Scholar * Jordi Blasco16 Search for this author in: * NPG journals * PubMed * Google Scholar * Agi Oszvald17 Search for this author in: * NPG journals * PubMed * Google Scholar * Hidetoshi Kasuya18 Search for this author in: * NPG journals * PubMed * Google Scholar * Gulam Zilani19 Search for this author in: * NPG journals * PubMed * Google Scholar * Beate Schoch20 Search for this author in: * NPG journals * PubMed * Google Scholar * Pankaj Singh21, 22 Search for this author in: * NPG journals * PubMed * Google Scholar * Carsten Stüer23 Search for this author in: * NPG journals * PubMed * Google Scholar * Roelof Risselada24 Search for this author in: * NPG journals * PubMed * Google Scholar * Jürgen Beck17 Search for this author in: * NPG journals * PubMed * Google Scholar * Teresa Sola25 Search for this author in: * NPG journals * PubMed * Google Scholar * Filomena Ricciardi7 Search for this author in: * NPG journals * PubMed * Google Scholar * Arpo Aromaa26 Search for this author in: * NPG journals * PubMed * Google Scholar * Thomas Illig27 Search for this author in: * NPG journals * PubMed * Google Scholar * Stefan Schreiber28 Search for this author in: * NPG journals * PubMed * Google Scholar * Cornelia M van Duijn29, 30 Search for this author in: * NPG journals * PubMed * Google Scholar * Leonard H van den Berg10 Search for this author in: * NPG journals * PubMed * Google Scholar * Claire Perret31 Search for this author in: * NPG journals * PubMed * Google Scholar * Carole Proust31 Search for this author in: * NPG journals * PubMed * Google Scholar * Constantin Roder6 Search for this author in: * NPG journals * PubMed * Google Scholar * Ali K Ozturk1, 2, 3 Search for this author in: * NPG journals * PubMed * Google Scholar * Emília Gaál1, 2, 3, 11 Search for this author in: * NPG journals * PubMed * Google Scholar * Daniela Berg32 Search for this author in: * NPG journals * PubMed * Google Scholar * Christof Geisen33 Search for this author in: * NPG journals * PubMed * Google Scholar * Christoph M Friedrich34 Search for this author in: * NPG journals * PubMed * Google Scholar * Paul Summers19 Search for this author in: * NPG journals * PubMed * Google Scholar * Alejandro F Frangi35, 36, 37 Search for this author in: * NPG journals * PubMed * Google Scholar * Matthew W State3, 38, 39 Search for this author in: * NPG journals * PubMed * Google Scholar * H Erich Wichmann27 Search for this author in: * NPG journals * PubMed * Google Scholar * Monique M B Breteler29, 30 Search for this author in: * NPG journals * PubMed * Google Scholar * Cisca Wijmenga40 Search for this author in: * NPG journals * PubMed * Google Scholar * Shrikant Mane41 Search for this author in: * NPG journals * PubMed * Google Scholar * Leena Peltonen42, 43 Search for this author in: * NPG journals * PubMed * Google Scholar * Vivas Elio25 Search for this author in: * NPG journals * PubMed * Google Scholar * Miriam C J M Sturkenboom24 Search for this author in: * NPG journals * PubMed * Google Scholar * Patricia Lawford21 Search for this author in: * NPG journals * PubMed * Google Scholar * James Byrne19 Search for this author in: * NPG journals * PubMed * Google Scholar * Juan Macho16 Search for this author in: * NPG journals * PubMed * Google Scholar * Erol I Sandalcioglu20 Search for this author in: * NPG journals * PubMed * Google Scholar * Bernhard Meyer23 Search for this author in: * NPG journals * PubMed * Google Scholar * Andreas Raabe17 Search for this author in: * NPG journals * PubMed * Google Scholar * Helmuth Steinmetz7 Search for this author in: * NPG journals * PubMed * Google Scholar * Daniel Rüfenacht4, 44 Search for this author in: * NPG journals * PubMed * Google Scholar * Juha E Jääskeläinen13 Search for this author in: * NPG journals * PubMed * Google Scholar * Juha Hernesniemi11 Search for this author in: * NPG journals * PubMed * Google Scholar * Gabriel J E Rinkel10 Search for this author in: * NPG journals * PubMed * Google Scholar * Hitoshi Zembutsu5 Search for this author in: * NPG journals * PubMed * Google Scholar * Ituro Inoue12 Search for this author in: * NPG journals * PubMed * Google Scholar * Aarno Palotie42, 43 Search for this author in: * NPG journals * PubMed * Google Scholar * François Cambien31 Search for this author in: * NPG journals * PubMed * Google Scholar * Yusuke Nakamura5 Search for this author in: * NPG journals * PubMed * Google Scholar * Richard P Lifton3, 45, 46 Search for this author in: * NPG journals * PubMed * Google Scholar * Murat Günel1, 2, 3 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorsJournal name:Nature GeneticsVolume:42,Pages:420–425Year published:(2010)DOI:doi:10.1038/ng.563Received10 December 2009Accepted09 March 2010Published online04 April 2010 Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Saccular intracranial aneurysms are balloon-like dilations of the intracranial arterial wall; their hemorrhage commonly results in severe neurologic impairment and death. We report a second genome-wide association study with discovery and replication cohorts from Europe and Japan comprising 5,891 cases and 14,181 controls with ~832,000 genotyped and imputed SNPs across discovery cohorts. We identified three new loci showing strong evidence for association with intracranial aneurysms in the combined dataset, including intervals near RBBP8 on 18q11.2 (odds ratio (OR) = 1.22, P = 1.1 × 10−12), STARD13-KL on 13q13.1 (OR = 1.20, P = 2.5 × 10−9) and a gene-rich region on 10q24.32 (OR = 1.29, P = 1.2 × 10−9). We also confirmed prior associations near SOX17 (8q11.23–q12.1; OR = 1.28, P = 1.3 × 10−12) and CDKN2A-CDKN2B (9p21.3; OR = 1.31, P = 1.5 × 10−22). It is noteworthy that several putative risk genes play a role in cell-cycle progression, potentially affecting t! he proliferation and senescence of progenitor-cell populations that are responsible for vascular formation and repair. View full text Figures at a glance * Figure 1: Genome-wide association analysis results in the discovery cohort. () The PPAs for 831,532 quality control–passed SNPs that were analyzed specifying a prior probability of association of 1/10,000 are plotted against genomic locations of SNPs. A gray horizontal line at PPA = 0.5 indicates the cutoff value for follow-up genotyping. () Quantile-quantile plots of P values (−log10 scale) are shown for all the SNPs analyzed (black; n = 831,532); for SNPs after excluding those within previously identified regions (red; n = 830,907); and for SNPs after excluding all within the final associated intervals (blue; n = 830,158). () A scatter plot of −log10P versus log10 Bayes factors is shown with color for each point indicating the range of PPA values. There are very close relationships among the P values for association, the Bayes factor and the PPA value. Note that, given a uniform prior probability of association, the PPA increases as the Bayes factor increases. A vertical line indicates the minimum PPA threshold at 0.5 (Bayes factor = 1.0 × ! 104) for follow-up. * Figure 2: Regional plots for associated regions. For each chromosomal interval, −log10P values for association are plotted against the genomic coordinates (NCBI build 36) in the panel above; the recombination rates obtained from the HapMap database and the RefSeq genes (hg18) within the regions are shown in the panel below. Above, rs identifiers of SNPs listed in Table 2 are shown and their positions are indicated by gray vertical lines. Gray dashed lines indicate locations of other SNPs genotyped in the replication cohorts. Dark blue and light blue dots represent results of genotyped and imputed SNPs for the discovery cohort, respectively; orange and light orange squares represent association results for the replication cohort using JP1 combined with JP2 and also JP2-only, respectively; combined results for SNPs genotyped both in the discovery and the replication cohort using JP1 plus JP2 and JP2-only are shown by red and light red diamonds, respectively. * Figure 3: Consistency of association across cohorts. Forest plots are shown for meta-analysis of the SNPs listed in Table 2. Squares and horizontal segments represent estimated per-allele ORs and 95% CIs for individual cohorts. Diamonds represent the summary OR estimates and 95% CIs for the meta-analyses of six cohorts (using fixed- and random-effects models). Log10 (Bayes factor) > 0 supports association with intracranial aneurysm, whereas log10 (Bayes factor) < 0 supports no association with intracranial aneurysm. Analyzing the results here as six distinct cohorts rather than four cohorts (as in the primary analysis) resulted in only minor differences due to different weights given to sub-cohorts of the combined European cohort. Author information * Author information * Supplementary information Affiliations * Department of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut, USA. * Katsuhito Yasuno, * Kaya Bilguvar, * Zulfikar Arlier, * Nikhil Nayak, * Ali K Ozturk, * Emília Gaál & * Murat Günel * Department of Neurobiology, Yale University School of Medicine, New Haven, Connecticut, USA. * Katsuhito Yasuno, * Kaya Bilguvar, * Zulfikar Arlier, * Nikhil Nayak, * Ali K Ozturk, * Emília Gaál & * Murat Günel * Department of Genetics, Yale Program on Neurogenetics, Yale Center for Human Genetics and Genomics, Yale University School of Medicine, New Haven, Connecticut, USA. * Katsuhito Yasuno, * Kaya Bilguvar, * Zulfikar Arlier, * Nikhil Nayak, * Ali K Ozturk, * Emília Gaál, * Matthew W State, * Richard P Lifton & * Murat Günel * Department of Clinical Neurosciences, Service de Neurochirurgie, Geneva University Hospital, Geneva, Switzerland. * Philippe Bijlenga & * Daniel Rüfenacht * Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan. * Siew-Kee Low, * Hitoshi Zembutsu & * Yusuke Nakamura * Department of Neurosurgery, University of Tuebingen, Tuebingen, Germany. * Boris Krischek & * Constantin Roder * Department of Neurology, Goethe University, Frankfurt am Main, Germany. * Georg Auburger, * Florentina Wirjatijasa, * Filomena Ricciardi & * Helmuth Steinmetz * Department of Neurosurgery, University of Bonn, Bonn, Germany. * Matthias Simon * Department of Neurosurgery, Carl Gustav Carus University Hospital of Dresden, University of Technology, Dresden, Germany. * Dietmar Krex * Department of Neurology, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands. * Ynte M Ruigrok, * Leonard H van den Berg & * Gabriel J E Rinkel * Department of Neurosurgery, Helsinki University Central Hospital, Helsinki, Finland. * Mika Niemelä, * Emília Gaál & * Juha Hernesniemi * Division of Molecular Life Science, School of Medicine, Tokai University, Isehara, Kanagawa, Japan. * Atsushi Tajima & * Ituro Inoue * Department of Neurosurgery, Kuopio University Hospital, Kuopio, Finland. * Mikael von und zu Fraunberg & * Juha E Jääskeläinen * Neurosurgery, University of Pècs Medical School, Pècs, Hungary. * Tamás Dóczi * Department of Public Health, School of Medicine, Chiba University, Chiba, Japan. * Akira Hata * Department of Vascular Radiology, Hospital Clinic, Barcelona, Spain. * Jordi Blasco & * Juan Macho * Department of Neurosurgery, Goethe University, Frankfurt am Main, Germany. * Agi Oszvald, * Jürgen Beck & * Andreas Raabe * Department of Neurosurgery, Medical Center East, Tokyo Women's University, Tokyo, Japan. * Hidetoshi Kasuya * Nuffield Department of Surgery, John Radcliffe Hospital, University of Oxford, Oxford, UK. * Gulam Zilani, * Paul Summers & * James Byrne * Department of Neurosurgery, University Hospital, Essen, Germany. * Beate Schoch & * Erol I Sandalcioglu * Medical Physics Group, Department of Cardiovascular Science, University of Sheffield, Sheffield, UK. * Pankaj Singh & * Patricia Lawford * Department of Neurosurgery, Royal Hallamshire Hospital, Sheffield, UK. * Pankaj Singh * Department of Neurosurgery, Technical University of Munich, Munich, Germany. * Carsten Stüer & * Bernhard Meyer * Department of Medical Informatics, Erasmus University Medical Center, Rotterdam, The Netherlands. * Roelof Risselada & * Miriam C J M Sturkenboom * Therapeutic Neuroangiography, Hospital General de Catalunya, San Cugat del Valles, Spain. * Teresa Sola & * Vivas Elio * Department of Health and Functional Capacity, National Public Health Institute, Helsinki, Finland. * Arpo Aromaa * Institute of Epidemiology, German Research Center for Environmental Health, Helmholtz Zentrum München, Munich, Germany. * Thomas Illig & * H Erich Wichmann * Institute for Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany. * Stefan Schreiber * Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands. * Cornelia M van Duijn & * Monique M B Breteler * Netherlands Consortium for Health Aging, Rotterdam, The Netherlands. * Cornelia M van Duijn & * Monique M B Breteler * Unité Mixte de Recherche (UMR S937) and Pitié-Salpêtrière Post-Genomic Platform (P3S), Institut National de la Santé et de la Recherche Médicale (INSERM), University Pierre and Marie Curie (UPMC), Paris, France. * Claire Perret, * Carole Proust & * François Cambien * Center of Neurology, Department of Neurodegeneration and Hertie Institute for Clinical Brain Research, University of Tuebingen, Tuebingen, Germany. * Daniela Berg * Institute of Transfusion Medicine and Immunohaematology, Department of Molecular Haemostasis, Deutsches Rotes Kreuz Blood Donor Service Baden Wuerttemberg and Hessen, Frankfurt am Main, Germany. * Christof Geisen * Fraunhofer-Institut for Algorithms and Scientific Computing, Sankt Augustin, Germany. * Christoph M Friedrich * Computational Imaging and Simulation Technologies in Biomedicine (CISTIB), Universitat Pompeu Fabra, Barcelona, Spain. * Alejandro F Frangi * Networking Biomedical Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Barcelona, Spain. * Alejandro F Frangi * Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain. * Alejandro F Frangi * Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut. * Matthew W State * Child Study Center, Yale University School of Medicine, New Haven, Connecticut, USA. * Matthew W State * Department of Genetics, University Medical Center Groningen and University of Groningen, Groningen, The Netherlands. * Cisca Wijmenga * Keck Foundation Biotechnology Resource Laboratory, Yale University, New Haven, Connecticut, USA. * Shrikant Mane * Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK. * Leena Peltonen & * Aarno Palotie * The Finnish Institute for Molecular Medicine, University of Helsinki, Helsinki, Finland. * Leena Peltonen & * Aarno Palotie * Department of Neuroradiology, Swiss Neuro Institute, Clinic Hirslanden, Zürich, Switzerland. * Daniel Rüfenacht * Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut, USA. * Richard P Lifton * Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA. * Richard P Lifton Contributions M.N., M.v.u.z.F., E.G., J.E.J., J.H. and A.P. (Finnish case-control); Y.M.R. and G.J.E.R. (NL cases); P.B., T.D., J. Blasco, G.Z., P.S., R.R., T.S., C.M.F., P.S., A.F.F., V.E., M.C.J.M.S., P.L., J. Byrne, J.M. and D.R. (@neurIST case series); B.K., G.A., M.S., D.K., F.W., A.O., B.S., C.S., J. Beck, F.R., C.R., D.B., C.G., E.I.S., B.M., A.R. and H.S. (DE case series); A.T., A.H., H.K. and I.I. (JP1); S.-K.L., H.Z. and Y.N. (JP2). A.A., L.P. and A.P. (Health2000); A.A., L.P. and A.P. (NFBC1966); C.M.v.D. and M.M.B.B. (Rotterdam Study); L.H.v.d.B. and C.W. (Utrecht); T.I. and H.E.W. (KORA-gen); S.S. (PopGen). K.B., Z.A., N.N., A.K.O., E.G., S.M., R.P.L. and M.G. (Yale); C. Perret, C. Proust and F.C. (Aneurist); S.-K.L., H.Z. and Y.N. (JP2). K.Y., K.B., Z.A., N.N. and M.G. (Yale); S.-K.L., H.Z. and Y.N. (JP2 cohort); K.Y. and M.G. K.Y., K.B., M.W.S., R.P.L. and M.G. K.Y., R.P.L. and M.G. Competing financial interests The authors have a provisional patent application under consideration based on the findings of this work. Corresponding authors Correspondence to: * Richard P Lifton (richard.lifton@yale.edu) or * Murat Günel (murat.gunel@yale.edu) Supplementary information * Author information * Supplementary information PDF files * Supplementary Text and Figures (492K) Supplementary Note, Supplementary Tables 1–5 and Supplementary Figures 1 and 2 Additional data
• Genome-wide association study of systemic sclerosis identifies CD247 as a new susceptibility locus
  Radstake TR Gorlova O Rueda B Martin JE Alizadeh BZ Palomino-Morales R Coenen MJ Vonk MC Voskuyl AE Scheurwegh AJ Broen JC van Riel PL van 't Slot R Italiaander A Ophoff RA Riemekasten G Hunzelmann N Simeon CP Ortego-Centeno N González-Gay MA González-Escribano MF Spanish Scleroderma Group Airo P van Laar J Herrick A Worthington J Hesselstrand R Smith V de Keyser F Houssiau F Chee MM Madhok R Shiels P Westhovens R Kreuter A Kiener H de Baere E Witte T Padykov L Klareskog L Beretta L Scorza R Lie BA Hoffmann-Vold AM Carreira P Varga J Hinchcliff M Gregersen PK Lee AT Ying J Han Y Weng SF Amos CI Wigley FM Hummers L Nelson JL Agarwal SK Assassi S Gourh P Tan FK Koeleman BP Arnett FC Martin J Mayes MD - Nature Genetics 42(5):426-429 (2010)
  Nature Genetics | Letter Genome-wide association study of systemic sclerosis identifies CD247 as a new susceptibility locus * Timothy R D J Radstake1, 38 Search for this author in: * NPG journals * PubMed * Google Scholar * Olga Gorlova2, 38 Search for this author in: * NPG journals * PubMed * Google Scholar * Blanca Rueda3, 38 Search for this author in: * NPG journals * PubMed * Google Scholar * Jose-Ezequiel Martin3, 38 Search for this author in: * NPG journals * PubMed * Google Scholar * Behrooz Z Alizadeh4 Search for this author in: * NPG journals * PubMed * Google Scholar * Rogelio Palomino-Morales3 Search for this author in: * NPG journals * PubMed * Google Scholar * Marieke J Coenen5 Search for this author in: * NPG journals * PubMed * Google Scholar * Madelon C Vonk1 Search for this author in: * NPG journals * PubMed * Google Scholar * Alexandre E Voskuyl6 Search for this author in: * NPG journals * PubMed * Google Scholar * Annemie J Schuerwegh7 Search for this author in: * NPG journals * PubMed * Google Scholar * Jasper C Broen1 Search for this author in: * NPG journals * PubMed * Google Scholar * Piet L C M van Riel1 Search for this author in: * NPG journals * PubMed * Google Scholar * Ruben van 't Slot4 Search for this author in: * NPG journals * PubMed * Google Scholar * Annet Italiaander4 Search for this author in: * NPG journals * PubMed * Google Scholar * Roel A Ophoff4, 8 Search for this author in: * NPG journals * PubMed * Google Scholar * Gabriela Riemekasten9 Search for this author in: * NPG journals * PubMed * Google Scholar * Nico Hunzelmann10 Search for this author in: * NPG journals * PubMed * Google Scholar * Carmen P Simeon11 Search for this author in: * NPG journals * PubMed * Google Scholar * Norberto Ortego-Centeno12 Search for this author in: * NPG journals * PubMed * Google Scholar * Miguel A González-Gay13 Search for this author in: * NPG journals * PubMed * Google Scholar * María F González-Escribano14 Search for this author in: * NPG journals * PubMed * Google Scholar * Spanish Scleroderma Group37 * Paolo Airo15 Search for this author in: * NPG journals * PubMed * Google Scholar * Jaap van Laar16 Search for this author in: * NPG journals * PubMed * Google Scholar * Ariane Herrick17 Search for this author in: * NPG journals * PubMed * Google Scholar * Jane Worthington17 Search for this author in: * NPG journals * PubMed * Google Scholar * Roger Hesselstrand18 Search for this author in: * NPG journals * PubMed * Google Scholar * Vanessa Smith19 Search for this author in: * NPG journals * PubMed * Google Scholar * Filip de Keyser19 Search for this author in: * NPG journals * PubMed * Google Scholar * Fredric Houssiau20 Search for this author in: * NPG journals * PubMed * Google Scholar * Meng May Chee21 Search for this author in: * NPG journals * PubMed * Google Scholar * Rajan Madhok21 Search for this author in: * NPG journals * PubMed * Google Scholar * Paul Shiels21 Search for this author in: * NPG journals * PubMed * Google Scholar * Rene Westhovens22 Search for this author in: * NPG journals * PubMed * Google Scholar * Alexander Kreuter23 Search for this author in: * NPG journals * PubMed * Google Scholar * Hans Kiener24 Search for this author in: * NPG journals * PubMed * Google Scholar * Elfride de Baere25 Search for this author in: * NPG journals * PubMed * Google Scholar * Torsten Witte26 Search for this author in: * NPG journals * PubMed * Google Scholar * Leonid Padykov27 Search for this author in: * NPG journals * PubMed * Google Scholar * Lars Klareskog27 Search for this author in: * NPG journals * PubMed * Google Scholar * Lorenzo Beretta28 Search for this author in: * NPG journals * PubMed * Google Scholar * Rafaella Scorza28 Search for this author in: * NPG journals * PubMed * Google Scholar * Benedicte A Lie29 Search for this author in: * NPG journals * PubMed * Google Scholar * Anna-Maria Hoffmann-Vold30 Search for this author in: * NPG journals * PubMed * Google Scholar * Patricia Carreira13, 31 Search for this author in: * NPG journals * PubMed * Google Scholar * John Varga32 Search for this author in: * NPG journals * PubMed * Google Scholar * Monique Hinchcliff32 Search for this author in: * NPG journals * PubMed * Google Scholar * Peter K Gregersen33 Search for this author in: * NPG journals * PubMed * Google Scholar * Annette T Lee33 Search for this author in: * NPG journals * PubMed * Google Scholar * Jun Ying2 Search for this author in: * NPG journals * PubMed * Google Scholar * Younghun Han2 Search for this author in: * NPG journals * PubMed * Google Scholar * Shih-Feng Weng2 Search for this author in: * NPG journals * PubMed * Google Scholar * Christopher I Amos2 Search for this author in: * NPG journals * PubMed * Google Scholar * Fredrick M Wigley34 Search for this author in: * NPG journals * PubMed * Google Scholar * Laura Hummers34 Search for this author in: * NPG journals * PubMed * Google Scholar * J Lee Nelson35 Search for this author in: * NPG journals * PubMed * Google Scholar * Sandeep K Agarwal36 Search for this author in: * NPG journals * PubMed * Google Scholar * Shervin Assassi36 Search for this author in: * NPG journals * PubMed * Google Scholar * Pravitt Gourh36 Search for this author in: * NPG journals * PubMed * Google Scholar * Filemon K Tan36 Search for this author in: * NPG journals * PubMed * Google Scholar * Bobby P C Koeleman4, 38 Search for this author in: * NPG journals * PubMed * Google Scholar * Frank C Arnett36, 38 Search for this author in: * NPG journals * PubMed * Google Scholar * Javier Martin3, 38 Search for this author in: * NPG journals * PubMed * Google Scholar * Maureen D Mayes36, 38 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorsJournal name:Nature GeneticsVolume:42,Pages:426–429Year published:(2010)DOI:doi:10.1038/ng.565Received04 January 2010Accepted04 March 2010Published online11 April 2010Corrected online16 April 2010 Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of the skin and internal organs that leads to profound disability and premature death. To identify new SSc susceptibility loci, we conducted the first genome-wide association study in a population of European ancestry including a total of 2,296 individuals with SSc and 5,171 controls. Analysis of 279,621 autosomal SNPs followed by replication testing in an independent case-control set of European ancestry (2,753 individuals with SSc (cases) and 4,569 controls) identified a new susceptibility locus for systemic sclerosis at CD247 (1q22–23, rs2056626, P = 2.09 × 10−7 in the discovery samples, P = 3.39 × 10−9 in the combined analysis). Additionally, we confirm and firmly establish the role of the MHC (P = 2.31 × 10−18), IRF5 (P = 1.86 × 10−13) and STAT4 (P = 3.37 × 10−9) gene regions as SSc genetic risk factors. View full text Figures at a glance * Figure 1: Manhattan plot of the GWAS of the discovery cohort comprising 2,346 SSc cases and 5,193 healthy controls. The −log10 of the Mantel-Haenszel test P value of 279,621 SNPs after correction by λ is plotted against its physical chromosomal position. Chromosomes are shown in alternate colors. SNPs above the red line represent those with a P value <5 × 10−7. Plot corresponds to the combined analysis of the study cohorts. * Figure 2: Forest plot showing the odds ratios and confidence intervals of the CD247 association in the various populations studied in the discovery and replication cohorts. Change history * Change history * Author information * Supplementary informationCorrected online 16 April 2010In the version of this article initially published online, the name of author Annemie J. Schuerwegh was misspelled. The error has been corrected for the print, PDF, and HTML versions of this article. Author information * Change history * Author information * Supplementary information Primary authors * These authors contributed equally to this work. * Timothy R D J Radstake, * Olga Gorlova, * Blanca Rueda, * Jose-Ezequiel Martin, * Bobby P C Koeleman, * Frank C Arnett, * Javier Martin & * Maureen D Mayes Affiliations * Department of Rheumatology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands. * Timothy R D J Radstake, * Madelon C Vonk, * Jasper C Broen & * Piet L C M van Riel * Department of Epidemiology, M.D. Anderson Cancer Center, Houston, Texas, USA. * Olga Gorlova, * Jun Ying, * Younghun Han, * Shih-Feng Weng & * Christopher I Amos * Instituto de Parasitología y Biomedicina López-Neyra, Consejo Superior de Investigaciones Científicas, Granada, Spain. * Blanca Rueda, * Jose-Ezequiel Martin, * Rogelio Palomino-Morales & * Javier Martin * Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands. * Behrooz Z Alizadeh, * Ruben van 't Slot, * Annet Italiaander, * Roel A Ophoff & * Bobby P C Koeleman * Department of Human Genetics, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands. * Marieke J Coenen * Department of Rheumatology, Vrije Universiteit (VU) Medical Centre, Nijmegen, The Netherlands. * Alexandre E Voskuyl * Department of Rheumatology, University of Leiden, Nijmegen, The Netherlands. * Annemie J Schuerwegh * University of California Los Angeles Center for Neurobehavioral Genetics, Los Angeles, California. * Roel A Ophoff * Department of Rheumatology and Clinical Immunology, Charité University Hospital, Berlin, Germany. * Gabriela Riemekasten * Department of Dermatology, University of Cologne, Cologne, Germany. * Nico Hunzelmann * Servicio de Medicina Interna, Hospital Valle de Hebron, Barcelona, Spain. * Carmen P Simeon * Servicio de Medicina Interna, Hospital Clínico Universitario, Granada, Spain. * Norberto Ortego-Centeno * Servicio de Reumatología, Hospital Marqués de Valdecilla, Santander, Spain. * Miguel A González-Gay & * Patricia Carreira * Servicio de Inmunología, Hospital Virgen del Rocío, Sevilla, Spain. * María F González-Escribano * University of Brescia, Brescia, Italy. * Paolo Airo * University of Newcastle, Newcastle Upon Tyne, UK. * Jaap van Laar * Department of Rheumatology and Epidemiology, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK. * Ariane Herrick & * Jane Worthington * University of Lund, Lund, Sweden. * Roger Hesselstrand * University of Ghent, Ghent, Belgium. * Vanessa Smith & * Filip de Keyser * University of Leuven, Leuven, Belgium. * Fredric Houssiau * University of Glasgow, Glasgow, UK. * Meng May Chee, * Rajan Madhok & * Paul Shiels * University of Antwerpen, Antwerpen, Belgium. * Rene Westhovens * Ruhr University of Bochum, Bochum, Germany. * Alexander Kreuter * University of Vienna, Vienna, Austria. * Hans Kiener * Department of Genetics, University of Ghent, Ghent, Belgium. * Elfride de Baere * University of Hannover, Hannover, Germany. * Torsten Witte * Karolinska Institute, Stockholm, Sweden. * Leonid Padykov & * Lars Klareskog * University of Milan, Milan, Italy. * Lorenzo Beretta & * Rafaella Scorza * Institute of Immunology, Oslo University Hospital, Oslo, Norway. * Benedicte A Lie * Department of Rheumatology, Rikshospitalet, Oslo University Hospital, Oslo, Norway. * Anna-Maria Hoffmann-Vold * Hospital 12 de Octubre, Madrid, Spain. * Patricia Carreira * Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA. * John Varga & * Monique Hinchcliff * Feinstein Institute of Medical Research, Manhasset, New York, USA. * Peter K Gregersen & * Annette T Lee * Johns Hopkins University Medical Center, Baltimore, Maryland, USA. * Fredrick M Wigley & * Laura Hummers * Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. * J Lee Nelson * The University of Texas Health Science Center–Houston, Houston, Texas, USA. * Sandeep K Agarwal, * Shervin Assassi, * Pravitt Gourh, * Filemon K Tan, * Frank C Arnett & * Maureen D Mayes * A full list of members is provided in the Supplementary Note. * Spanish Scleroderma Group Consortia * Spanish Scleroderma Group Contributions T.R.D.J.R., O.G., B.R., J.-E.M., B.P.C.K., F.C.A., J.M., M.D.M. T.R.D.J.R., M.J.C., M.C.V., A.E.V., A.J.S., J.C.B., B.A.L., A.-M.H.-V., R.A.O., G.R., N.H., C.P.S., N.O.-C., M.A.G.-G., M.F.G.-E., P.A., J.v.L., A.H., J.W., R.H., V.S., F.d.K., F.H., M.M.C., R.M., P.S., R.W., A.K., H.K., E.d.B., T.W., L.P., L.K., L.B., R.S., J.V., M.H., P.G., J.L.N., F.M.W., L.H., P.C., S.A. T.R.D.J.R., O.G., B.R., J.-E.M., B.Z.A., R.P.-M., J.Y., Y.H., S.-F.W., R.v.'t.S., P.G., A.T.L., C.I.A., S.K.A., B.P.C.K., J.M., M.D.M., A.I., P.C., S.A., P.K.G. T.R.D.J.R., O.G., B.R., J.-E.M., B.Z.A., J.Y., M.J.C., M.C.V., A.E.V., A.J.S., J.C.B., P.L.C.M.v.R., R.v.S., B.A.L., A.-M.H.-V., G.R., N.H., C.P.S., N.O.-C., M.A.G.-G., M.F.G.-E., P.A., J.v.L., A.H., J.W., R.H., V.S., F.d.K., F.H., M.M.C., R.M., P.S., R.W., A.K., H.K., E.d.B., T.W., L.P., L.B., R.S., J.V., M.H., P.G., C.I.A., J.L.N., F.M.W., L.H., S.K.A., P.G., F.K.T., B.P.C.K., F.C.A., J.M., M.D.M., P.K.G. T.R.D.J.R., B.P.C.K., F.C.A., J.M., M.D.M. Competing financial interests The authors declare no competing financial interests. Corresponding authors Correspondence to: * Timothy R D J Radstake (tradstake73@gmail.com) or * Maureen D Mayes (maureen.d.mayes@uth.tmc.edu) Supplementary information * Change history * Author information * Supplementary information PDF files * Supplementary Text and Figures (2M) Supplementary Tables 1–5, Supplementary Figures 1–4 and Supplementary Note Additional data
• Variants in ADCY5 and near CCNL1 are associated with fetal growth and birth weight
  Freathy RM Mook-Kanamori DO Sovio U Prokopenko I Timpson NJ Berry DJ Warrington NM Widen E Hottenga JJ Kaakinen M Lange LA Bradfield JP Kerkhof M Marsh JA Mägi R Chen CM Lyon HN Kirin M Adair LS Aulchenko YS Bennett AJ Borja JB Bouatia-Naji N Charoen P Coin LJ Cousminer DL de Geus EJ Deloukas P Elliott P Evans DM Froguel P The Genetic Investigation of ANthropometric Traits (GIANT) Consortium Glaser B Groves CJ Hartikainen AL Hassanali N Hirschhorn JN Hofman A Holly JM Hyppönen E Kanoni S Knight BA Laitinen J Lindgren CM The Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) McArdle WL O'Reilly PF Pennell CE Postma DS Pouta A Ramasamy A Rayner NW Ring SM Rivadeneira F Shields BM Strachan DP Surakka I Taanila A Tiesler C Uitterlinden AG van Duijn CM The Wellcome Trust Case Control Consortium (WTCCC) Wijga AH Willemsen G Zhang H Zhao J Wilson JF Steegers EA Hattersley AT Eriksson JG Peltonen L Mohlke KL Grant SF Hakonarson H Koppelman GH Dedoussis GV Heinrich J Gillman MW Palmer LJ Frayling TM Boomsma DI Smith GD Power C Jaddoe VW Jarvelin MR McCarthy MI - Nature Genetics 42(5):430-435 (2010)
  Nature Genetics | Letter Variants in ADCY5 and near CCNL1 are associated with fetal growth and birth weight * Rachel M Freathy1, 60 Search for this author in: * NPG journals * PubMed * Google Scholar * Dennis O Mook-Kanamori2, 3, 4, 60 Search for this author in: * NPG journals * PubMed * Google Scholar * Ulla Sovio5, 60 Search for this author in: * NPG journals * PubMed * Google Scholar * Inga Prokopenko6, 7, 60 Search for this author in: * NPG journals * PubMed * Google Scholar * Nicholas J Timpson8, 60 Search for this author in: * NPG journals * PubMed * Google Scholar * Diane J Berry9, 60 Search for this author in: * NPG journals * PubMed * Google Scholar * Nicole M Warrington10, 60 Search for this author in: * NPG journals * PubMed * Google Scholar * Elisabeth Widen11 Search for this author in: * NPG journals * PubMed * Google Scholar * Jouke Jan Hottenga12 Search for this author in: * NPG journals * PubMed * Google Scholar * Marika Kaakinen13, 14 Search for this author in: * NPG journals * PubMed * Google Scholar * Leslie A Lange15 Search for this author in: * NPG journals * PubMed * Google Scholar * Jonathan P Bradfield16 Search for this author in: * NPG journals * PubMed * Google Scholar * Marjan Kerkhof17 Search for this author in: * NPG journals * PubMed * Google Scholar * Julie A Marsh10 Search for this author in: * NPG journals * PubMed * Google Scholar * Reedik Mägi6, 7 Search for this author in: * NPG journals * PubMed * Google Scholar * Chih-Mei Chen18, 19 Search for this author in: * NPG journals * PubMed * Google Scholar * Helen N Lyon20, 21 Search for this author in: * NPG journals * PubMed * Google Scholar * Mirna Kirin22 Search for this author in: * NPG journals * PubMed * Google Scholar * Linda S Adair23 Search for this author in: * NPG journals * PubMed * Google Scholar * Yurii S Aulchenko3 Search for this author in: * NPG journals * PubMed * Google Scholar * Amanda J Bennett6 Search for this author in: * NPG journals * PubMed * Google Scholar * Judith B Borja24 Search for this author in: * NPG journals * PubMed * Google Scholar * Nabila Bouatia-Naji25, 26 Search for this author in: * NPG journals * PubMed * Google Scholar * Pimphen Charoen5, 27 Search for this author in: * NPG journals * PubMed * Google Scholar * Lachlan J M Coin5 Search for this author in: * NPG journals * PubMed * Google Scholar * Diana L Cousminer11 Search for this author in: * NPG journals * PubMed * Google Scholar * Eco J C de Geus12 Search for this author in: * NPG journals * PubMed * Google Scholar * Panos Deloukas28 Search for this author in: * NPG journals * PubMed * Google Scholar * Paul Elliott5 Search for this author in: * NPG journals * PubMed * Google Scholar * David M Evans8 Search for this author in: * NPG journals * PubMed * Google Scholar * Philippe Froguel25, 29 Search for this author in: * NPG journals * PubMed * Google Scholar * The Genetic Investigation of ANthropometric Traits (GIANT) Consortium58 * Beate Glaser8, 30 Search for this author in: * NPG journals * PubMed * Google Scholar * Christopher J Groves6 Search for this author in: * NPG journals * PubMed * Google Scholar * Anna-Liisa Hartikainen31 Search for this author in: * NPG journals * PubMed * Google Scholar * Neelam Hassanali6 Search for this author in: * NPG journals * PubMed * Google Scholar * Joel N Hirschhorn20, 32, 33, 34 Search for this author in: * NPG journals * PubMed * Google Scholar * Albert Hofman3 Search for this author in: * NPG journals * PubMed * Google Scholar * Jeff M P Holly35 Search for this author in: * NPG journals * PubMed * Google Scholar * Elina Hyppönen9 Search for this author in: * NPG journals * PubMed * Google Scholar * Stavroula Kanoni36 Search for this author in: * NPG journals * PubMed * Google Scholar * Bridget A Knight37 Search for this author in: * NPG journals * PubMed * Google Scholar * Jaana Laitinen38 Search for this author in: * NPG journals * PubMed * Google Scholar * Cecilia M Lindgren6, 7 Search for this author in: * NPG journals * PubMed * Google Scholar * The Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC)58 * Wendy L McArdle39 Search for this author in: * NPG journals * PubMed * Google Scholar * Paul F O'Reilly5 Search for this author in: * NPG journals * PubMed * Google Scholar * Craig E Pennell40 Search for this author in: * NPG journals * PubMed * Google Scholar * Dirkje S Postma41 Search for this author in: * NPG journals * PubMed * Google Scholar * Anneli Pouta42 Search for this author in: * NPG journals * PubMed * Google Scholar * Adaikalavan Ramasamy5, 43 Search for this author in: * NPG journals * PubMed * Google Scholar * Nigel W Rayner6, 7 Search for this author in: * NPG journals * PubMed * Google Scholar * Susan M Ring39 Search for this author in: * NPG journals * PubMed * Google Scholar * Fernando Rivadeneira3, 44 Search for this author in: * NPG journals * PubMed * Google Scholar * Beverley M Shields37 Search for this author in: * NPG journals * PubMed * Google Scholar * David P Strachan45 Search for this author in: * NPG journals * PubMed * Google Scholar * Ida Surakka11 Search for this author in: * NPG journals * PubMed * Google Scholar * Anja Taanila13 Search for this author in: * NPG journals * PubMed * Google Scholar * Carla Tiesler18, 19 Search for this author in: * NPG journals * PubMed * Google Scholar * Andre G Uitterlinden3, 44 Search for this author in: * NPG journals * PubMed * Google Scholar * Cornelia M van Duijn3 Search for this author in: * NPG journals * PubMed * Google Scholar * The Wellcome Trust Case Control Consortium (WTCCC)58 * Alet H Wijga46 Search for this author in: * NPG journals * PubMed * Google Scholar * Gonneke Willemsen12 Search for this author in: * NPG journals * PubMed * Google Scholar * Haitao Zhang16 Search for this author in: * NPG journals * PubMed * Google Scholar * Jianhua Zhao47 Search for this author in: * NPG journals * PubMed * Google Scholar * James F Wilson22 Search for this author in: * NPG journals * PubMed * Google Scholar * Eric A P Steegers48 Search for this author in: * NPG journals * PubMed * Google Scholar * Andrew T Hattersley37 Search for this author in: * NPG journals * PubMed * Google Scholar * Johan G Eriksson49, 50, 51, 52 Search for this author in: * NPG journals * PubMed * Google Scholar * Leena Peltonen11, 28, 53, 59 Search for this author in: * NPG journals * PubMed * Google Scholar * Karen L Mohlke15 Search for this author in: * NPG journals * PubMed * Google Scholar * Struan F A Grant16, 47, 54 Search for this author in: * NPG journals * PubMed * Google Scholar * Hakon Hakonarson16, 47, 54 Search for this author in: * NPG journals * PubMed * Google Scholar * Gerard H Koppelman55 Search for this author in: * NPG journals * PubMed * Google Scholar * George V Dedoussis36 Search for this author in: * NPG journals * PubMed * Google Scholar * Joachim Heinrich18 Search for this author in: * NPG journals * PubMed * Google Scholar * Matthew W Gillman56 Search for this author in: * NPG journals * PubMed * Google Scholar * Lyle J Palmer10 Search for this author in: * NPG journals * PubMed * Google Scholar * Timothy M Frayling1 Search for this author in: * NPG journals * PubMed * Google Scholar * Dorret I Boomsma12, 61 Search for this author in: * NPG journals * PubMed * Google Scholar * George Davey Smith8, 61 Search for this author in: * NPG journals * PubMed * Google Scholar * Chris Power9, 61 Search for this author in: * NPG journals * PubMed * Google Scholar * Vincent W V Jaddoe2, 3, 61 Search for this author in: * NPG journals * PubMed * Google Scholar * Marjo-Riitta Jarvelin5, 13, 14, 42, 61 Search for this author in: * NPG journals * PubMed * Google Scholar * Mark I McCarthy6, 7, 57, 61 Search for this author in: * NPG journals * PubMed * Google Scholar * for the Early Growth Genetics (EGG) Consortium * Affiliations * Contributions * Corresponding authorsJournal name:Nature GeneticsVolume:42,Pages:430–435Year published:(2010)DOI:doi:10.1038/ng.567Received21 October 2009Accepted17 March 2010Published online06 April 2010 Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg To identify genetic variants associated with birth weight, we meta-analyzed six genome-wide association (GWA) studies (n = 10,623 Europeans from pregnancy/birth cohorts) and followed up two lead signals in 13 replication studies (n = 27,591). rs900400 near LEKR1 and CCNL1 (P = 2 × 10−35) and rs9883204 in ADCY5 (P = 7 × 10−15) were robustly associated with birth weight. Correlated SNPs in ADCY5 were recently implicated in regulation of glucose levels and susceptibility to type 2 diabetes1, providing evidence that the well-described association between lower birth weight and subsequent type 2 diabetes2, 3 has a genetic component, distinct from the proposed role of programming by maternal nutrition. Using data from both SNPs, we found that the 9% of Europeans carrying four birth weight–lowering alleles were, on average, 113 g (95% CI 89–137 g) lighter at birth than the 24% with zero or one alleles (Ptrend = 7 × 10−30). The impact on birth weight is similar to that ! of a mother smoking 4–5 cigarettes per day in the third trimester of pregnancy4. View full text Figures at a glance * Figure 1: Regional plots of two previously unknown associations with birth weight. () For each of the two regions, 3q25 () and 3q21 (), directly genotyped and imputed SNPs are plotted using filled circles with their meta-analysis P values (as −log10 values) as a function of genomic position (NCBI Build 35). In each plot, the discovery-stage SNP taken forward to replication stage is represented by a blue diamond (defining a global meta-analysis P value), with its discovery meta-analysis P value denoted by a red diamond. Local LD structure is reflected by the plotted estimated recombination rates (taken from HapMap) in the region around the associated SNPs and their correlated proxies. Each analyzed SNP is represented by a circle. The color scheme of the circles respects LD patterns (HapMap CEU pairwise r2 correlation coefficients) between top discovery SNP and surrounding variants: white, r2 < 0.2; gray, 0.5 > r2 ≥ 0.2; orange, 0.8 > r2 ≥ 0.5; red, r2 ≥ 0.8. Gene annotations were taken from the University of California Santa Cruz genome browser. * Figure 2: Forest plots of the association between birth weight and genotype at each locus. () Index SNP rs900400 at 3q25 () and index SNP rs9883204 at 3q21 (). If the index SNP was unavailable, a closely correlated proxy (HapMap r2 > 0.9) was used. Author information * Author information * Supplementary information Primary authors * These authors contributed equally to this work. * Rachel M Freathy, * Dennis O Mook-Kanamori, * Ulla Sovio, * Inga Prokopenko, * Nicholas J Timpson, * Diane J Berry & * Nicole M Warrington Affiliations * Genetics of Complex Traits, Peninsula College of Medicine and Dentistry, University of Exeter, Exeter, UK. * Rachel M Freathy & * Timothy M Frayling * Department of Pediatrics, Erasmus Medical Center, Rotterdam, The Netherlands. * Dennis O Mook-Kanamori & * Vincent W V Jaddoe * Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands. * Dennis O Mook-Kanamori, * Yurii S Aulchenko, * Albert Hofman, * Fernando Rivadeneira, * Andre G Uitterlinden, * Cornelia M van Duijn & * Vincent W V Jaddoe * The Generation R Study, Erasmus Medical Center, Rotterdam, The Netherlands. * Dennis O Mook-Kanamori * Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK. * Ulla Sovio, * Pimphen Charoen, * Lachlan J M Coin, * Paul Elliott, * Paul F O'Reilly, * Adaikalavan Ramasamy & * Marjo-Riitta Jarvelin * Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, UK. * Inga Prokopenko, * Reedik Mägi, * Amanda J Bennett, * Christopher J Groves, * Neelam Hassanali, * Cecilia M Lindgren, * Nigel W Rayner & * Mark I McCarthy * Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. * Inga Prokopenko, * Reedik Mägi, * Cecilia M Lindgren, * Nigel W Rayner & * Mark I McCarthy * The Medical Research Council (MRC) Centre for Causal Analyses in Translational Epidemiology, Department of Social Medicine, University of Bristol, Oakfield House, Bristol, UK. * Nicholas J Timpson, * David M Evans, * Beate Glaser & * George Davey Smith * Centre for Paediatric Epidemiology and Biostatistics, MRC Centre of Epidemiology for Child Health, University College of London Institute of Child Health, London, UK. * Diane J Berry, * Elina Hyppönen & * Chris Power * Centre for Genetic Epidemiology and Biostatistics, The University of Western Australia, Perth, Western Australia, Australia. * Nicole M Warrington, * Julie A Marsh & * Lyle J Palmer * Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland. * Elisabeth Widen, * Diana L Cousminer, * Ida Surakka & * Leena Peltonen * Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands. * Jouke Jan Hottenga, * Eco J C de Geus, * Gonneke Willemsen & * Dorret I Boomsma * Institute of Health Sciences, University of Oulu, Oulu, Finland. * Marika Kaakinen, * Anja Taanila & * Marjo-Riitta Jarvelin * Biocenter Oulu, University of Oulu, Oulu, Finland. * Marika Kaakinen & * Marjo-Riitta Jarvelin * Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA. * Leslie A Lange & * Karen L Mohlke * Center for Applied Genomics, The Children's Hospital of Philadelphia, Pennsylvania, USA. * Jonathan P Bradfield, * Haitao Zhang, * Struan F A Grant & * Hakon Hakonarson * Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. * Marjan Kerkhof * Helmholtz Zentrum Muenchen, German Research Centre for Environmental Health, Institute of Epidemiology, Neuherberg, Germany. * Chih-Mei Chen, * Carla Tiesler & * Joachim Heinrich * Ludwig-Maximilians University of Munich, Dr. von Hauner Children's Hospital, Munich, Germany. * Chih-Mei Chen & * Carla Tiesler * Division of Genetics, Program in Genomics, Children's Hospital, Boston, Massachusetts, USA. * Helen N Lyon & * Joel N Hirschhorn * Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA. * Helen N Lyon * Centre for Population Health Sciences, University of Edinburgh, Edinburgh, Scotland, UK. * Mirna Kirin & * James F Wilson * Department of Nutrition, University of North Carolina, Chapel Hill, North Carolina, USA. * Linda S Adair * Office of Population Studies Foundation, University of San Carlos, Cebu City, Philippines. * Judith B Borja * Centre National de la Recherche Scientifique, UMR 8199, Institute of Biology, Pasteur Institute of Lille, Lille, France. * Nabila Bouatia-Naji & * Philippe Froguel * Lille Nord de France University, Lille, France. * Nabila Bouatia-Naji * Department of Tropical Hygiene, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. * Pimphen Charoen * Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK. * Panos Deloukas & * Leena Peltonen * Genomic Medicine, Hammersmith Hospital, Imperial College London, London, UK. * Philippe Froguel * Children of the Nineties, Department of Social Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol, UK. * Beate Glaser * Institute of Clinical Medicine, University of Oulu, Oulu, Finland. * Anna-Liisa Hartikainen * Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts, USA. * Joel N Hirschhorn * Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA. * Joel N Hirschhorn * Division of Endocrinology, Children's Hospital, Boston, Massachusetts, USA. * Joel N Hirschhorn * Department of Clinical Science at North Bristol, University of Bristol, Paul O'Gorman Lifeline Centre, Southmead Hospital, Bristol, UK. * Jeff M P Holly * Department of Dietetics-Nutrition, Harokopio University, Greece. * Stavroula Kanoni & * George V Dedoussis * Peninsula National Institute for Health Research (NIHR) Clinical Research Facility, Peninsula College of Medicine and Dentistry, University of Exeter, Barrack Road, Exeter, UK. * Bridget A Knight, * Beverley M Shields & * Andrew T Hattersley * Oulu Regional Institute of Occupational Health, Oulu, Finland. * Jaana Laitinen * Department of Social Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol, UK. * Wendy L McArdle & * Susan M Ring * School of Women's and Infants' Health, The University of Western Australia, Perth, Western Australia, Australia. * Craig E Pennell * Department of Pulmonology, University Medical Center, University of Groningen, Groningen, The Netherlands. * Dirkje S Postma * National Institute of Health and Welfare, Oulu, Finland. * Anneli Pouta & * Marjo-Riitta Jarvelin * Respiratory Epidemiology and Public Health Group, National Heart and Lung Institute, Imperial College London, London, UK. * Adaikalavan Ramasamy * Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands. * Fernando Rivadeneira & * Andre G Uitterlinden * Division of Community Health Sciences, St. George's, University of London, London, UK. * David P Strachan * Centre for Prevention and Health Services Research, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands. * Alet H Wijga * Division of Human Genetics, The Children's Hospital of Philadelphia, Pennsylvania, USA. * Jianhua Zhao, * Struan F A Grant & * Hakon Hakonarson * Department of Obstetrics and Gynecology, Erasmus Medical Center, Rotterdam, The Netherlands. * Eric A P Steegers * Helsinki University Central Hospital, Unit of General Practice, Helsinki, Finland. * Johan G Eriksson * Department of General Practice, University of Helsinki, Helsinki, Finland. * Johan G Eriksson * Folkhälsan Research Centre, Helsinki, Finland. * Johan G Eriksson * National Institute for Health and Welfare, Helsinki, Finland. * Johan G Eriksson * Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA. * Leena Peltonen * Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA. * Struan F A Grant & * Hakon Hakonarson * Pediatric Pulmonology and Pediatric Allergology, Beatrix Children's Hospital, University Medical Center, University of Groningen, Groningen, The Netherlands. * Gerard H Koppelman * Obesity Prevention Program, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, Massachusetts, USA. * Matthew W Gillman * Oxford NIHR Biomedical Research Centre, Churchill Hospital, Oxford, UK. * Mark I McCarthy * A complete list of members is available in a Supplementary Note. * The Genetic Investigation of ANthropometric Traits (GIANT) Consortium, * The Meta-Analyses of Glucose and Insulin-related traits Consortium & * The Wellcome Trust Case Control Consortium * Deceased. * Leena Peltonen * These authors jointly directed this work. * Dorret I Boomsma, * George Davey Smith, * Chris Power, * Vincent W V Jaddoe, * Marjo-Riitta Jarvelin & * Mark I McCarthy Consortia * The Genetic Investigation of ANthropometric Traits (GIANT) Consortium * The Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) * The Wellcome Trust Case Control Consortium (WTCCC) * the Early Growth Genetics (EGG) Consortium * Mark I McCarthy Contributions R.M.F., U.S., N.J.T., E.W., M. Kerkhof, H.N.L., L.S.A., J.B.B., E.J.C.d.G., A.-L.H., J.N.H., A.H., E.H., J.L., D.S.P., A.P., A.T., A.H.W., G.W., J.F.W., E.A.P.S., A.T.H., L.P., K.L.M., S.F.A.G., H.H., G.H.K., G.V.D., J.H., M.W.G., L.J.P., T.M.F., D.I.B., G.D.S., C.P., V.W.V.J., M.-R.J., M.I.M. D.O.M.-K., U.S., D.J.B., M. Kaakinen, M. Kerkhof, L.S.A., A.J.B., J.B.B., P.E., A.-L.H., E.H., S.K., B.A.K., J.L., W.L.M., C.E.P., D.S.P., A.P., F.R., B.M.S., D.P.S., A.T., A.G.U., A.H.W., G.W., J.F.W., A.T.H., J.G.E., S.F.A.G., H.H., G.H.K., G.V.D., J.H., M.W.G., L.J.P., G.D.S., C.P., V.W.V.J., M.-R.J. R.M.F., J.J.H., M. Kerkhof, H.N.L., A.J.B., N.B.-N., E.J.C.d.G., P.D., P.E., P.F., C.J.G., N.H., J.N.H., W.L.M., D.S.P., S.M.R., F.R., A.G.U., A.H.W., J.F.W., L.P., S.F.A.G., H.H., G.H.K., D.I.B., M.-R.J. R.M.F., D.O.M.K., U.S., I.P., N.J.T., D.J.B., N.M.W., E.W., J.J.H., M. Kaakinen, L.A.L., J.P.B., M. Kerkhof, J.A.M., R.M., C.-M.C., H.N.L., M. Kirin, Y.S.A., P.C., L.J.M.C., D.L.C., D.M.E., B.G., C.M.L., P.F.O., D.S.P., A.R., N.W.R, B.M.S., I.S., C.T., C.M.v.D., A.H.W., J.Z., H.Z., G.H.K., M.W.G., L.J.P. R.M.F., D.O.M.K., U.S., I.P., N.J.T., D.J.B., J.M.P.H., A.T.H., L.J.P., T.M.F., V.W.V.J., M.-R.J., M.I.M. Competing financial interests The authors declare no competing financial interests. Corresponding authors Correspondence to: * Dorret I Boomsma (dorret@psy.vu.nl) or * George Davey Smith (George.Davey-Smith@bristol.ac.uk) or * Chris Power (C.Power@ich.ucl.ac.uk) or * Vincent W V Jaddoe (v.jaddoe@erasmusmc.nl) or * Marjo-Riitta Jarvelin (m.jarvelin@imperial.ac.uk) or * Mark I McCarthy (mark.mccarthy@drl.ox.ac.uk) Supplementary information * Author information * Supplementary information Excel files * Supplementary Table 1 (100K) Basic characteristics, exclusions, genotyping, quality control and imputation in discovery studies * Supplementary Table 2 (116K) Basic characteristics, exclusions, genotyping, quality control and imputation in European replication studies and non-European/admixed studies PDF files * Supplementary Text and Figures (4M) Supplementary Tables 1–5, Supplementary Figures 1–5 and Supplementary Note. Additional data
• Meta-analysis and imputation refines the association of 15q25 with smoking quantity
  Liu JZ Tozzi F Waterworth DM Pillai SG Muglia P Middleton L Berrettini W Knouff CW Yuan X Waeber G Vollenweider P Preisig M Wareham NJ Zhao JH Loos RJ Barroso I Khaw KT Grundy S Barter P Mahley R Kesaniemi A McPherson R Vincent JB Strauss J Kennedy JL Farmer A McGuffin P Day R Matthews K Bakke P Gulsvik A Lucae S Ising M Brueckl T Horstmann S Wichmann HE Rawal R Dahmen N Lamina C Polasek O Zgaga L Huffman J Campbell S Kooner J Chambers JC Burnett MS Devaney JM Pichard AD Kent KM Satler L Lindsay JM Waksman R Epstein S Wilson JF Wild SH Campbell H Vitart V Reilly MP Li M Qu L Wilensky R Matthai W Hakonarson HH Rader DJ Franke A Wittig M Schäfer A Uda M Terracciano A Xiao X Busonero F Scheet P Schlessinger D Clair DS Rujescu D Abecasis GR Grabe HJ Teumer A Völzke H Petersmann A John U Rudan I Hayward C Wright AF Kolcic I Wright BJ Thompson JR Balmforth AJ Hall AS Samani NJ Anderson CA Ahmad T Mathew CG Parkes M Satsangi J Caulfield M Munroe PB Farrall M Dominiczak A Worthington J Thomson W Eyre S Barton A The Wellcome Trust Case Control Consortium Mooser V Francks C Marchini J - Nature Genetics 42(5):436-440 (2010)
  Nature Genetics | Letter Meta-analysis and imputation refines the association of 15q25 with smoking quantity * Jason Z Liu1 Search for this author in: * NPG journals * PubMed * Google Scholar * Federica Tozzi2 Search for this author in: * NPG journals * PubMed * Google Scholar * Dawn M Waterworth3 Search for this author in: * NPG journals * PubMed * Google Scholar * Sreekumar G Pillai3 Search for this author in: * NPG journals * PubMed * Google Scholar * Pierandrea Muglia2 Search for this author in: * NPG journals * PubMed * Google Scholar * Lefkos Middleton4 Search for this author in: * NPG journals * PubMed * Google Scholar * Wade Berrettini5 Search for this author in: * NPG journals * PubMed * Google Scholar * Christopher W Knouff6 Search for this author in: * NPG journals * PubMed * Google Scholar * Xin Yuan3 Search for this author in: * NPG journals * PubMed * Google Scholar * Gérard Waeber7, 8 Search for this author in: * NPG journals * PubMed * Google Scholar * Peter 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Anderson11 Search for this author in: * NPG journals * PubMed * Google Scholar * Tariq Ahmad56 Search for this author in: * NPG journals * PubMed * Google Scholar * Christopher G Mathew57 Search for this author in: * NPG journals * PubMed * Google Scholar * Miles Parkes58 Search for this author in: * NPG journals * PubMed * Google Scholar * Jack Satsangi59 Search for this author in: * NPG journals * PubMed * Google Scholar * Mark Caulfield60 Search for this author in: * NPG journals * PubMed * Google Scholar * Patricia B Munroe60 Search for this author in: * NPG journals * PubMed * Google Scholar * Martin Farrall61 Search for this author in: * NPG journals * PubMed * Google Scholar * Anna Dominiczak62 Search for this author in: * NPG journals * PubMed * Google Scholar * Jane Worthington63 Search for this author in: * NPG journals * PubMed * Google Scholar * Wendy Thomson63 Search for this author in: * NPG journals * PubMed * Google Scholar * Steve Eyre63 Search for this author in: * NPG journals * PubMed * Google Scholar * Anne Barton63 Search for this author in: * NPG journals * PubMed * Google Scholar * The Wellcome Trust Case Control Consortium65 * Vincent Mooser3 Search for this author in: * NPG journals * PubMed * Google Scholar * Clyde Francks2, 64 Search for this author in: * NPG journals * PubMed * Google Scholar * Jonathan Marchini1 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorsJournal name:Nature GeneticsVolume:42,Pages:436–440Year published:(2010)DOI:doi:10.1038/ng.572Received19 October 2009Accepted18 March 2010Published online25 April 2010 Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Smoking is a leading global cause of disease and mortality1. We established the Oxford-GlaxoSmithKline study (Ox-GSK) to perform a genome-wide meta-analysis of SNP association with smoking-related behavioral traits. Our final data set included 41,150 individuals drawn from 20 disease, population and control cohorts. Our analysis confirmed an effect on smoking quantity at a locus on 15q25 (P = 9.45 × 10−19) that includes CHRNA5, CHRNA3 and CHRNB4, three genes encoding neuronal nicotinic acetylcholine receptor subunits. We used data from the 1000 Genomes project to investigate the region using imputation, which allowed for analysis of virtually all common SNPs in the region and offered a fivefold increase in marker density over HapMap2 (ref. 2) as an imputation reference panel. Our fine-mapping approach identified a SNP showing the highest significance, rs55853698, located within the promoter region of CHRNA5. Conditional analysis also identified a secondary locus (rs649530! 8) in CHRNA3. View full text Figures at a glance * Figure 1: Plot showing the significance of association of all SNPs in the genome-wide smoking quantity meta-analysis. SNPs are plotted on the x axis according to their positions on each chromosome against association with smoking quantity on the y axis (−log10P value). SNPs with P values < 1.0 × 10−5 are highlighted in green. * Figure 2: Chromosome 15q25 signal plots. Signal plot based on the 1000 Genomes imputation and meta-analysis of smoking quantity association (top). SNPs are plotted by their positions on the chromosome against association with smoking quantity (−log10P value) on the left y axis. The five SNPs with the lowest P values from the HapMap imputation are highlighted in red. The five SNPs with the lowest P values from the 1000 Genomes imputation are highlighted in green (unless already colored red). The rs identities of highlighted SNPs are given in the box. Recombination rates across the region are shown by the red line plotted against the right y axis. Chromosome 15q25 signal plot based on the 1000 Genomes imputation and meta-analysis of smoking quantity association, conditional on rs55853698 (middle). The five SNPs with the lowest P values from the conditional analysis are highlighted in green. The five SNPs with the lowest P values from the unconditioned HapMap imputation analysis are highlighted in red. Genes and the! positions of exons using data from the UCSC genome browser (bottom; see URLs). Author information * Author information * Supplementary information Affiliations * Department of Statistics, University of Oxford, Oxford, UK. * Jason Z Liu & * Jonathan Marchini * Genetics Division, GlaxoSmithKline, Verona, Italy. * Federica Tozzi, * Pierandrea Muglia & * Clyde Francks * Genetics Division, GlaxoSmithKline, Upper Merion, Pennsylvania, USA. * Dawn M Waterworth, * Sreekumar G Pillai, * Xin Yuan & * Vincent Mooser * Division of Neurosciences and Mental Health, Imperial College London, UK. * Lefkos Middleton * Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA. * Wade Berrettini * Genetics Division, GlaxoSmithKline, Research Triangle Park, North Carolina, USA. * Christopher W Knouff * University Hospital Center, University of Lausanne, Lausanne, Switzerland. * Gérard Waeber, * Peter Vollenweider & * Martin Preisig * Department of Internal Medicine, University of Lausanne, Lausanne, Switzerland. * Gérard Waeber & * Peter Vollenweider * Department of Psychiatry, University of Lausanne, Lausanne, Switzerland. * Martin Preisig * Medical Research Council Epidemiology Unit, Institute of Metabolic Science, Cambridge, UK. * Nicholas J Wareham, * Jing Hua Zhao & * Ruth J F Loos * Wellcome Trust Sanger Institute, Hinxton, UK. * Inês Barroso & * Carl A Anderson * Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. * Kay-Tee Khaw * Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, Texas, USA. * Scott Grundy * The Heart Research Institute, Sydney, New South Wales, Australia. * Philip Barter * Gladstone Institute of Cardiovascular Disease, University of California, San Francisco, California, USA. * Robert Mahley * American Hospital, Istanbul, Turkey. * Robert Mahley * Department of Internal Medicine, University of Oulu, Oulu, Finland. * Antero Kesaniemi * Biocenter Oulu, University of Oulu, Oulu, Finland. * Antero Kesaniemi * Division of Cardiology, University of Ottawa Heart Institute, Ottawa, Ontario, Canada. * Ruth McPherson * Centre for Addiction and Mental Health, University of Toronto, Toronto, Ontario, Canada. * John B Vincent, * John Strauss & * James L Kennedy * Medical Research Council Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King′s College London, London, UK. * Anne Farmer & * Peter McGuffin * Center for Neuroscience, Division of Medical Sciences, University of Dundee, Dundee, UK. * Richard Day & * Keith Matthews * Institute of Medicine, University of Bergen, Bergen, Norway. * Per Bakke & * Amund Gulsvik * Max Planck Institute of Psychiatry, Munich, Germany. * Susanne Lucae, * Marcus Ising, * Tanja Brueckl & * Sonja Horstmann * Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany. * H-Erich Wichmann, * Rajesh Rawal & * Claudia Lamina * Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany. * Klinikum Grosshadern, Munich, Germany. * H-Erich Wichmann * Psychiatrische Klinik und Poliklinik University of Mainz, Mainz, Germany. * Norbert Dahmen * Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Innsbruck Medical University, Innsbruck, Austria. * Claudia Lamina * School of Public Health, School of Medicine, University of Zagreb, Croatia. * Ozren Polasek & * Ivana Kolcic * Centre for Population Health Sciences, University of Edinburgh, Edinburgh, UK. * Lina Zgaga, * James F Wilson, * Sarah H Wild, * Harry Campbell & * Igor Rudan * Institute of Genetics and Molecular Medicine, MRC Human Genetics Unit, Edinburgh, UK. * Jennifer Huffman, * Susan Campbell, * Veronique Vitart, * Caroline Hayward & * Alan F Wright * National Heart and Lung Institute, Imperial College London, London, UK. * Jaspal Kooner * Division of Epidemiology, Imperial College London, London, UK. * John C Chambers * Cardiovascular Research Institute, MedStar Research Institute, Washington Hospital Center, Washington DC, USA. * Mary Susan Burnett, * Joseph M Devaney, * Augusto D Pichard, * Kenneth M Kent, * Lowell Satler, * Joseph M Lindsay, * Ron Waksman & * Stephen Epstein * The Cardiovascular Institute, University of Pennsylvania, Philadelphia, Pennsylvania, USA. * Muredach P Reilly, * Robert Wilensky, * William Matthai & * Daniel J Rader * The Institute for Translational Medicine and Therapeutics, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. * Muredach P Reilly & * Daniel J Rader * Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA. * Mingyao Li & * Liming Qu * The Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA. * Hakon H Hakonarson * Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany. * Andre Franke, * Michael Wittig & * Arne Schäfer * Istituto di Neurogenetica e Neurofarmacologia, Consiglio Nazionale delle Ricerche, Monserrato, Cagliari, Italy. * Manuela Uda & * Fabio Busonero * National Institute on Aging, Baltimore, Maryland, USA. * Antonio Terracciano & * David Schlessinger * Department of Epidemiology, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA. * Xiangjun Xiao & * Paul Scheet * Department of Mental Health, University of Aberdeen, Aberdeen, UK. * David St Clair * Division of Molecular and Clinical Neurobiology, Department of Psychiatry, Ludwig-Maximilians-University, Munich, Germany. * Dan Rujescu * Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA. * Gonçalo R Abecasis * Department of Psychiatry and Psychotherapy, University of Greifswald, Greifswald, Germany. * Hans Jörgen Grabe * Interfacultary Institute for Genetics and Functional Genomics, University of Greifswald, Greifswald, Germany. * Alexander Teumer * Institute for Community Medicine, University of Greifswald, Greifswald, Germany. * Henry Völzke * Institute of Clinical Chemistry and Laboratory Medicine, University of Greifswald, Greifswald, Germany. * Astrid Petersmann * Department of Social Medicine and Epidemiology, University of Greifswald, Greifswald, Germany. * Ulrich John * Croatian Centre for Global Health, University of Split, Split, Croatia. * Igor Rudan * Department of Health Sciences, University of Leicester, Leicester, UK. * Benjamin J Wright & * John R Thompson * Mulitdisciplinary Cardiovascular Research Centre (MCRC), Leeds Institute of Genetics, Health and Therapeutics (LIGHT), University of Leeds, Leeds, UK. * Anthony J Balmforth & * Alistair S Hall * Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Leicester, UK. * Nilesh J Samani * Peninsula College of Medicine and Dentistry, Exeter, UK. * Tariq Ahmad * Department of Medical and Molecular Genetics, King's College London School of Medicine, Guy's Hospital, London, UK. * Christopher G Mathew * Gastroenterology Research Unit, Addenbrooke's Hospital, Cambridge, UK. * Miles Parkes * Gastrointestinal Unit, Molecular Medicine Centre, University of Edinburgh, Western General Hospital, Edinburgh, UK. * Jack Satsangi * Clinical Pharmacology and Barts and the London Genome Centre, William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, UK. * Mark Caulfield & * Patricia B Munroe * Department of Cardiovascular Medicine, University of Oxford, Wellcome Trust Centre for Human Genetics, Oxford, UK. * Martin Farrall * British Heart Foundation Glasgow Cardiovascular Research Centre, Division of Cardiovascular and Medical Sciences, University of Glasgow, Western Infirmary, Glasgow, UK. * Anna Dominiczak * arc Epidemiology Research Unit, School of Translational Medicine, Faculty of Medical and Human Sciences, University of Manchester, UK. * Jane Worthington, * Wendy Thomson, * Steve Eyre & * Anne Barton * Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. * Clyde Francks * A full list of members is provided in the Supplementary Note. * The Wellcome Trust Case Control Consortium Consortia * The Wellcome Trust Case Control Consortium Contributions J.Z.L. carried out most of the analysis for this study. J.M. and C.F. conceived and directed this study and wrote the manuscript. F.T., D.M.W. and V.M. were involved in study design and helped to coordinate the inclusion of many of the GSK cohorts. S.G.P., P. Muglia, L.M., W.B., C.W.K., X.Y., G.W., P.V., M. Preisig, N.J.W., J.H.Z., R.J.F.L., I.B., K.-T.K., S.G., P. Barter, R. Mahley, A.K., R. McPherson, J.B.V., J. Strauss, J.L.K., A. Farmer, P. McGuffin, R.D., K.M., P. Bakke, A.G., S.L., M.I., T.B., S.H., H.-E.W., R.R., N.D., C.L., O.P., L.Z., J.H., S.C., J.K., J.C.C., M.S.B., J.M.D., A.D.P., K.M.K.. L.S., J.M.L., R. Waksman, S. Epstein, J.F.W., S.H.W., H.C., V.V., M.P.R., M.L., L.Q., R. Wilensky, W.M., H.H.H., D.J.R., A. Franke, M.W., A.S., M.U., A. Terracciano, X.X., F.B., P.S., D.S., D.St.C., D.R., G.R.A., H.J.G., A. Teumer, H.V., A.P., U.J., I.R., C.H., A.F.W., I.K., B.J.W., J.R.T., A.J.B., A.S.H., N.J.S., C.A.A., T.A., C.G.M., M. Parkes, J. Satsangi, M.C., P.B.M., M.F.,! A.D., J.W., W.T., S. Eyre, A.B. and W.T.C.C.C. prepared and shared data sets and, in some cases, cohort-specific results from their own primary analysis. Competing financial interests F.T., C.F., D.M.W., V.M., P.M., S.G.P. and C.W.K either are or were full-time employees of the company GlaxoSmithKline (GSK). GSK also funded several aspects of the study as detailed in the ACKNOWLEDGMENTS section. Corresponding authors Correspondence to: * Jonathan Marchini (marchini@stats.ox.ac.uk) or * Clyde Francks (clyde.francks@well.ox.ac.uk) Supplementary information * Author information * Supplementary information PDF files * Supplementary Text and Figures (2M) Supplementary Figure 1–4, Supplementary Tables 1–3 and Supplementary Note Additional data
• Genome-wide meta-analyses identify multiple loci associated with smoking behavior
  The Tobacco and Genetics Consortium Furberg H Kim Y Dackor J Boerwinkle E Franceschini N Ardissino D Bernardinelli L Mannucci PM Mauri F Merlini PA Absher D Assimes TL Fortmann SP Iribarren C Knowles JW Quertermous T Ferrucci L Tanaka T Bis JC Furberg CD Haritunians T McKnight B Psaty BM Taylor KD Thacker EL Almgren P Groop L Ladenvall C Boehnke M Jackson AU Mohlke KL Stringham HM Tuomilehto J Benjamin EJ Hwang SJ Levy D Preis SR Vasan RS Duan J Gejman PV Levinson DF Sanders AR Shi J Lips EH McKay JD Agudo A Barzan L Bencko V Benhamou S Castellsagué X Canova C Conway DI Fabianova E Foretova L Janout V Healy CM Holcátová I Kjaerheim K Lagiou P Lissowska J Lowry R Macfarlane TV Mates D Richiardi L Rudnai P Szeszenia-Dabrowska N Zaridze D Znaor A Lathrop M Brennan P Bandinelli S Frayling TM Guralnik JM Milaneschi Y Perry JR Altshuler D Elosua R Kathiresan S Lucas G Melander O O'Donnell CJ Salomaa V Schwartz SM Voight BF Penninx BW Smit JH Vogelzangs N Boomsma DI de Geus EJ Vink JM Willemsen G Chanock SJ Gu F Hankinson SE Hunter DJ Hofman A Tiemeier H Uitterlinden AG van Duijn CM Walter S Chasman DI Everett BM Paré G Ridker PM Li MD Maes HH Audrain-McGovern J Posthuma D Thornton LM Lerman C Kaprio J Rose JE Ioannidis JP Kraft P Lin DY Sullivan PF - Nature Genetics 42(5):441-447 (2010)
  Nature Genetics | Letter Genome-wide meta-analyses identify multiple loci associated with smoking behavior * The Tobacco and Genetics Consortium * Affiliations * Contributions * Corresponding authorsJournal name:Nature GeneticsVolume:42,Pages:441–447Year published:(2010)DOI:doi:10.1038/ng.571Received19 October 2009Accepted18 March 2010Published online25 April 2010 Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Consistent but indirect evidence has implicated genetic factors in smoking behavior1, 2. We report meta-analyses of several smoking phenotypes within cohorts of the Tobacco and Genetics Consortium (n = 74,053). We also partnered with the European Network of Genetic and Genomic Epidemiology (ENGAGE) and Oxford-GlaxoSmithKline (Ox-GSK) consortia to follow up the 15 most significant regions (n > 140,000). We identified three loci associated with number of cigarettes smoked per day. The strongest association was a synonymous 15q25 SNP in the nicotinic receptor gene CHRNA3 (rs1051730[A], β = 1.03, standard error (s.e.) = 0.053, P = 2.8 × 10−73). Two 10q25 SNPs (rs1329650[G], β = 0.367, s.e. = 0.059, P = 5.7 × 10−10; and rs1028936[A], β = 0.446, s.e. = 0.074, P = 1.3 × 10−9) and one 9q13 SNP in EGLN2 (rs3733829[G], β = 0.333, s.e. = 0.058, P = 1.0 × 10−8) also exceeded genome-wide significance for cigarettes per day. For smoking initiation, eight SNPs exceeded geno! me-wide significance, with the strongest association at a nonsynonymous SNP in BDNF on chromosome 11 (rs6265[C], odds ratio (OR) = 1.06, 95% confidence interval (Cl) 1.04–1.08, P = 1.8 × 10−8). One SNP located near DBH on chromosome 9 (rs3025343[G], OR = 1.12, 95% Cl 1.08–1.18, P = 3.6 × 10−8) was significantly associated with smoking cessation. View full text Figures at a glance * Figure 1: Genome-wide association results for the TAG Consortium. Manhattan plots showing significance of association of all SNPs in the TAG Consortium meta-analyses for four smoking phenotypes. (–) Manhattan plots show SNPs plotted on the x axis according to their position on each chromosome against, on the y axis (shown as −log10P value), the association with CPD (), former versus current smoking (), ever versus never smoking () and age of smoking initiation (). * Figure 2: Forest and regional plots of significant associations for CPD from meta-analyses of the TAG, Ox-GSK and ENGAGE consortia. (–) Regional association plots show SNPs plotted by position on chromosome against −log10P value with each smoking phenotype. Estimated recombination rates (from HapMap-CEU) are plotted in light blue to reflect the local LD structure on a secondary y axis. The SNPs surrounding the most significant SNP (red diamond) are color coded to reflect their LD with this SNP (using pairwise r2 values from HapMap-CEU): blue, r2 ≥ 0.8–1.0; green, 0.5–0.8, orange, 0.2–0.5; gray, <0.2. The gray bars at the bottom of the plot represent the relative size and location of genes in the region. * Figure 3: Forest and regional plots of significant associations for smoking behavior. (–) Shown are plots for smoking initiation (,) and smoking cessation (,) from meta-analyses of the TAG, Ox-GSK and ENGAGE consortia. Regional association plots show SNPs plotted by position on the chromosome against −log10P value with each smoking phenotype. Estimated recombination rates (from HapMap-CEU) are plotted in light blue to reflect the local LD structure on a secondary y axis. The SNPs surrounding the most significant SNP (red diamond) are color coded to reflect their LD with this SNP (using pairwise r2 values from HapMap CEU): blue, r2 ≥ 0.8–1.0; green, 0.5–0.8; orange, 0.2–0.5; gray, <0.2. The gray bars at the bottom of the plot represent the relative size and location of genes in the region. Author information * Author information * Supplementary information Affiliations * Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA. * Helena Furberg, * YunJung Kim, * Jennifer Dackor, * Karen L Mohlke & * Patrick F Sullivan * University of North Carolina Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA. * Helena Furberg, * Karen L Mohlke & * Patrick F Sullivan * Human Genetics Center and Institute for Molecular Medicine, University of Texas Health Science Center, Houston, Texas, USA. * Eric Boerwinkle * Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, USA. * Nora Franceschini * Division of Cardiology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy. * Diego Ardissino * Statistical Laboratory, Centre for Mathematical Sciences, University of Cambridge, Cambridge, UK. * Luisa Bernardinelli * Department of Applied Health Sciences, University of Pavia, Pavia, Italy. * Luisa Bernardinelli * Department of Internal Medicine and Medical Specialties, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico, Ospedale Maggiore, Mangiagalli e Regina Elena, University of Milan, Milan, Italy. * Pier M Mannucci * Department of Cardiology, Azienda Ospedaliera Niguarda Ca' Granda, Milan, Italy. * Francesco Mauri & * Piera A Merlini * HudsonAlpha Institute for Biotechnology, Huntsville, Alabama, USA. * Devin Absher * Cardiovascular Medicine, Stanford University, Stanford, California, USA. * Themistocles L Assimes, * Joshua W Knowles & * Thomas Quertermous * Stanford Prevention Research Center, Stanford University, Stanford, California, USA. * Stephen P Fortmann * Kaiser Permanente Northern California Division of Research, Oakland, California, USA. * Carlos Iribarren * National Institute on Aging, Baltimore, Maryland, USA. * Luigi Ferrucci * Medstart Research Institute, National Institute on Aging, Baltimore, Maryland, USA. * Toshiko Tanaka * Cardiovascular Health Research Unit, University of Washington, Seattle, Washington, USA. * Joshua C Bis, * Barbara McKnight, * Bruce M Psaty, * Evan L Thacker & * Stephen M Schwartz * Department of Medicine, University of Washington, Seattle, Washington, USA. * Joshua C Bis & * Bruce M Psaty * Division of Public Health Sciences, Wake Forest University Health Sciences, Winston-Salem, North Carolina, USA. * Curt D Furberg * Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA. * Talin Haritunians & * Kent D Taylor * Department of Biostatistics, University of Washington, Seattle, Washington, USA. * Barbara McKnight * Department of Epidemiology and Health Services, University of Washington, Seattle, Washington, USA. * Bruce M Psaty * Group Health Research Institute, Seattle, Washington, USA. * Bruce M Psaty * Department of Epidemiology, University of Washington, Seattle, Washington, USA. * Evan L Thacker * Department of Clinical Sciences, Diabetes and Endocrinology Unit, Lund University, Malmö, Sweden. * Peter Almgren, * Leif Groop & * Claes Ladenvall * Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, Michigan, USA. * Michael Boehnke, * Anne U Jackson & * Heather M Stringham * Hjelt Institute, Department of Public Health, University of Helsinki, Helsinki, Finland. * Jaakko Tuomilehto & * Jaakko Kaprio * Diabetes Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland. * Jaakko Tuomilehto * Finland South Ostrobothnia Central Hospital, Seinäjoki, Finland. * Jaakko Tuomilehto * Boston University School of Medicine, Boston, Massachusetts, USA. * Emelia J Benjamin & * Ramachandran S Vasan * Boston University School of Public Health, Boston, Massachusetts, USA. * Emelia J Benjamin * Center for Population Studies, National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA. * Shih-Jen Hwang & * Sarah Rosner Preis * Department of Medicine, Sections of Preventive Medicine and Cardiology, Boston University School of Medicine, Boston, Massachusetts, USA. * Daniel Levy & * Ramachandran S Vasan * Center for Psychiatric Genetics, NorthShore University HealthSystem Research Institute, Evanston, Illinois, USA. * Jubao Duan, * Pablo V Gejman & * Alan R Sanders * Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, California, USA. * Douglas F Levinson * Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA. * Jianxin Shi * International Agency for Research on Cancer (IARC), Lyon, France. * Esther H Lips, * James D McKay & * Paul Brennan * Institut Català d'Oncologia, Barcelona, Spain. * Antonio Agudo & * Xavier Castellsagué * General Hospital, Pordenone, Italy. * Luigi Barzan * Institute of Hygiene and Epidemiology, First Faculty of Medicine, Charles University, Prague, Czech Republic. * Vladimir Bencko & * Ivana Holcátová * Institut National de la santé et de la Recherche Medicalé (INSERM) U794, Paris, France. * Simone Benhamou * Institut Gustave Roussy, Villejuif, France. * Simone Benhamou * Department of Environmental Medicine and Public Health, University of Padua, Padua, Italy. * Cristina Canova * University of Glasgow Medical Faculty Dental School, Glasgow, UK. * David I Conway * Specialized Institute of Hygiene and Epidemiology, Banska Bystrica, Slovakia. * Eleonora Fabianova * Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic. * Lenka Foretova * Palacky University, Olomouc, Czech Republic. * Vladimir Janout * Trinity College School of Dental Science, Dublin, Ireland. * Claire M Healy * Cancer Registry of Norway, Oslo, Norway. * Kristina Kjaerheim * University of Athens School of Medicine, Athens, Greece. * Pagona Lagiou * Department of Cancer Epidemiology and Prevention, Maria Sklodowska-Curie Cancer Center and Institute of Oncology, Warsaw, Poland. * Jolanta Lissowska * University of Newcastle Dental School, Newcastle, UK. * Ray Lowry * University of Aberdeen School of Medicine, Aberdeen, UK. * Tatiana V Macfarlane * Institute of Public Health, Bucharest, Romania. * Dana Mates * Center for Experimental Research and Medical Studies, University of Turin, Turin, Italy. * Lorenzo Richiardi * National Institute of Environmental Health, Budapest, Hungary. * Peter Rudnai * Department of Epidemiology, Institute of Occupational Medicine, Lodz, Poland. * Neonilia Szeszenia-Dabrowska * Institute of Carcinogenesis, Cancer Research Centre, Moscow, Russia. * David Zaridze * Croatian National Cancer Registry, Zagreb, Croatia. * Ariana Znaor * Centre National de Genotypage, Institut Genomique, Comissariat à l'énergie Atomique, Evry, France. * Mark Lathrop * Fondation Jean Dausset-Centre d'Étude du Polymorphisme Humain (CEPH), Paris, France. * Mark Lathrop * Geriatric Unit, Azienda Sanitaria di Firenze, Florence, Italy. * Stefania Bandinelli * Genetics of Complex Traits, Peninsula Medical School, The University of Exeter, Exeter, UK. * Timothy M Frayling & * John R B Perry * Laboratory of Epidemiology, Demography and Biometry, National Institute on Aging, Bethesda, Maryland, USA. * Jack M Guralnik * Tuscany Health Regional Agency, Florence, Italy. * Yuri Milaneschi * Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA. * David Altshuler & * Sek Kathiresan * Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts, USA. * David Altshuler * Diabetes Unit, Massachusetts General Hospital, Boston, Massachusetts, USA. * David Altshuler * Center for Human Genetics Research, Massachusetts General Hospital, Boston, Massachusetts, USA. * David Altshuler & * Sek Kathiresan * Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA. * David Altshuler * Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA. * David Altshuler * Cardiovascular Epidemiology and Genetics, Institut Municipal d'Investigacio Medica, Barcelona, Spain. * Roberto Elosua & * Gavin Lucas * Harvard Medical School, Boston, Massachusetts, USA. * Sek Kathiresan * Department of Clinical Sciences, Hypertension and Cardiovascular Diseases, University Hospital Malmö, Lund University, Malmö, Sweden. * Olle Melander * National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, USA. * Christopher J O'Donnell * National Institute for Health and Welfare (THL), Helsinki, Finland. * Veikko Salomaa & * Jaakko Kaprio * Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA. * Benjamin F Voight * EMGO Institute, Vrije Universiteit (VU) Medical Center, Amsterdam, The Netherlands. * Brenda W Penninx, * Johannes H Smit & * Nicole Vogelzangs * Department of Psychiatry, VU University Medical Center, Amsterdam, The Netherlands. * Brenda W Penninx, * Johannes H Smit & * Nicole Vogelzangs * Biological Psychology, VU University Amsterdam, Amsterdam, The Netherlands. * Dorret I Boomsma, * Eco J C de Geus, * Jacqueline M Vink & * Gonneke Willemsen * Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA. * Stephen J Chanock * Program in Molecular and Genetic Epidemiology, Department of Epidemiology, Harvard University, Boston, Massachusetts, USA. * Fangyi Gu, * David J Hunter & * Peter Kraft * Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. * Susan E Hankinson * Department of Epidemiology, Erasmus Medical Center, Member of the Netherlands Consortium on Healthy Aging, Rotterdam, The Netherlands. * Albert Hofman, * Henning Tiemeier, * Andre G Uitterlinden, * Cornelia M van Duijn & * Stefan Walter * Department of Child and Adolescent Psychiatry, Erasmus Medical Center, Rotterdam, The Netherlands. * Henning Tiemeier * Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands. * Andre G Uitterlinden * Centre for Medical Systems Biology, Erasmus Medical Center, Rotterdam, The Netherlands. * Cornelia M van Duijn * Department of Public Health, Erasmus Medical Center, Rotterdam, The Netherlands. * Stefan Walter * Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. * Daniel I Chasman, * Brendan M Everett, * Guillaume Paré & * Paul M Ridker * Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. * Brendan M Everett & * Paul M Ridker * Department of Psychiatry and Neurobehavioural Sciences, University of Virginia, Charlottesville, Virginia, USA. * Ming D Li * Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia, USA. * Hermine H Maes * Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia, USA. * Hermine H Maes * Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania, USA. * Janet Audrain-McGovern & * Caryn Lerman * Department of Functional Genomics, VU Amsterdam, Amsterdam, The Netherlands. * Danielle Posthuma * Department of Medical Genomics, VU University Medical Center Amsterdam, Amsterdam, The Netherlands. * Danielle Posthuma * Department of Psychiatry, University of North Carolina, Chapel Hill, North Carolina, USA. * Laura M Thornton * Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA. * Caryn Lerman * Institute for Molecular Medicine, University of Helsinki, Helsinki, Finland. * Jaakko Kaprio * Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina, USA. * Jed E Rose * Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece. * John P A Ioannidis * Tufts Clinical and Translational Science Institute, Tufts University School of Medicine, Boston, Massachusetts, USA. * John P A Ioannidis * Center for Genetic Epidemiology and Modeling, Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Boston, Massachusetts, USA. * John P A Ioannidis * Department of Biostatistics, University of North Carolina, Chapel Hill, North Carolina, USA. * Dan-Yu Lin Consortia * The Tobacco and Genetics Consortium * Helena Furberg, * YunJung Kim, * Jennifer Dackor, * Eric Boerwinkle, * Nora Franceschini, * Diego Ardissino, * Luisa Bernardinelli, * Pier M Mannucci, * Francesco Mauri, * Piera A Merlini, * Devin Absher, * Themistocles L Assimes, * Stephen P Fortmann, * Carlos Iribarren, * Joshua W Knowles, * Thomas Quertermous, * Luigi Ferrucci, * Toshiko Tanaka, * Joshua C Bis, * Curt D Furberg, * Talin Haritunians, * Barbara McKnight, * Bruce M Psaty, * Kent D Taylor, * Evan L Thacker, * Peter Almgren, * Leif Groop, * Claes Ladenvall, * Michael Boehnke, * Anne U Jackson, * Karen L Mohlke, * Heather M Stringham, * Jaakko Tuomilehto, * Emelia J Benjamin, * Shih-Jen Hwang, * Daniel Levy, * Sarah Rosner Preis, * Ramachandran S Vasan, * Jubao Duan, * Pablo V Gejman, * Douglas F Levinson, * Alan R Sanders, * Jianxin Shi, * Esther H Lips, * James D McKay, * Antonio Agudo, * Luigi Barzan, * Vladimir Bencko, * Simone Benhamou, * Xavier Castellsagué, * Cristina Canova, * David I Conway, * Eleonora Fabianova, * Lenka Foretova, * Vladimir Janout, * Claire M Healy, * Ivana Holcátová, * Kristina Kjaerheim, * Pagona Lagiou, * Jolanta Lissowska, * Ray Lowry, * Tatiana V Macfarlane, * Dana Mates, * Lorenzo Richiardi, * Peter Rudnai, * Neonilia Szeszenia-Dabrowska, * David Zaridze, * Ariana Znaor, * Mark Lathrop, * Paul Brennan, * Stefania Bandinelli, * Timothy M Frayling, * Jack M Guralnik, * Yuri Milaneschi, * John R B Perry, * David Altshuler, * Roberto Elosua, * Sek Kathiresan, * Gavin Lucas, * Olle Melander, * Christopher J O'Donnell, * Veikko Salomaa, * Stephen M Schwartz, * Benjamin F Voight, * Brenda W Penninx, * Johannes H Smit, * Nicole Vogelzangs, * Dorret I Boomsma, * Eco J C de Geus, * Jacqueline M Vink, * Gonneke Willemsen, * Stephen J Chanock, * Fangyi Gu, * Susan E Hankinson, * David J Hunter, * Albert Hofman, * Henning Tiemeier, * Andre G Uitterlinden, * Cornelia M van Duijn, * Stefan Walter, * Daniel I Chasman, * Brendan M Everett, * Guillaume Paré, * Paul M Ridker, * Ming D Li, * Hermine H Maes, * Janet Audrain-McGovern, * Danielle Posthuma, * Laura M Thornton, * Caryn Lerman, * Jaakko Kaprio, * Jed E Rose, * John P A Ioannidis, * Peter Kraft, * Dan-Yu Lin & * Patrick F Sullivan Contributions TAG: study conception, design, management: H.F., P.F.S., Y.K., J. Dackor; TAG Statistical Working Group: D.-Y.L., P.K., J.P.A.I., D.P., H.F., Y.K., J. Dackor, S.P.F., N.F., E.H.L., J.D.M., J.M.V., D.I.B., D.L., B.M.E., E.L.T., B. McKnight, P.F.S., D. Absher; TAG Phenotype Working Group: C. Lerman, J.K., H.H.M., L.M.T., J.A.-M., E.H.L., J.E.R., M.D.L., J.M.V., H.F., Y.K., J. Dackor, S.P.F., P.F.S., E.L.T.; data analysis: Y.K., D.M.A., F.G., E.H.L., J.D.M., J.M.V., A.U.J., L. Bernardinelli, S.R.P., S.-J.H., B.M.E., C. Ladenvall, J.R.B.P., T.T., E.L.T., J.C.B., G.L., S.W.; TAG Manuscript Writing Group: H.F., Y.K., J. Dackor, P.F.S., C. Lerman, M.D.L., J.K., J.A.-M., P.K. All authors reviewed and approved the final version of the manuscript. The corresponding authors had access to the full data set of summary results contributed by each study. ARIC: study conception, design, management: E.B.; phenotype collection, data management: N.F.; sample processing and genotyping: N.F.; data analysis: Y.K., N.F. Atherosclerosis Thrombosis and Vascular Biology Italian Study Group: study conception, design, management: L. Bernardinelli, P.M.M., P.A.M., D. Ardissino; phenotype collection, data management: F.M., L. Bernandinelli; data analysis: L. Bernandinelli. ADVANCE: study conception, design, management: S.P.F., D. Absher, T.Q., C.I., T.L.A., J.W.K.; phenotype collection, data management: S.P.F., T.Q., C.I., T.L.A., J.W.K.; sample processing and genotyping: D. Absher, T.Q.; data analysis: S.P.F., D. Absher, T.L.A., J.W.K. Baltimore Longitudinal Study of Aging: study conception, design, management: L. Ferrucci; phenotype collection, data management: L. Ferrucci; data analysis: T.T. CHS: study conception, design, management: B.M.P., J.C.B., C.D.F.; phenotype collection, data management: B.M.P.; sample processing and genotyping: T.H., K.D.T.; data analysis: B.M.P., E.L.T., J.C.B., B. McKnight. DGI: study conception, design, management: L.G.; phenotype collection, data management: P.A.; data analysis: P.A., C. Ladenvall. FUSION: study conception, design, management: K.L.M., M.B.; phenotype collection, data management: H.M.S., J.T.; data analysis: H.M.S., A.U.J. Framingham Heart Study: study conception, design, management: R.S.V., E.J.B., D.L.; phenotype collection, data management: S.R.P., R.S.V., S.-J.H., E.J.B., D.L.; data analysis: S.R.P., S.-J.H. GAIN: study conception, design, management: D.F.L., P.V.G.; phenotype collection, data management: A.R.S., D.F.L., J. Duan, J.S., P.V.G.; sample processing and genotyping: J. Duan, P.V.G.; data analysis: A.R.S., D.F.L., J. Duan, J.S., P.V.G. IARC/ARCAGE/Central European GWAS: phenotype collection, data management: D.Z., N.S.-D., J.L., P.R., E.F., D.M., V.B., L. Foretova, V.J., S. Benhamou, P.L., I.H., L.R., K.K., A.A., X.C., T.V.M., L. Barzan, C.C., R.L., D.I. Conway, A.Z., C.M.H., P.B.; sample processing and genotyping: J.D.M., M.L., P.B.; data analysis: E.H.L., J.D.M. InCHIANTI: study conception, design, management: T.M.F., J.M.G., S. Bandinelli; phenotype collection, data management: Y.M.; data analysis: J.R.B.P. MIGEN: study conception, design, management: R.E., V.S., O.M., C.J.O., D. Altshuler; phenotype collection, data management: G.L., S.M.S., R.E., V.S., B.F.V., O.M., S.K., C.J.O.; sample processing and genotyping: S.K., D. Altshuler; data analysis: G.L., B.F.V., D. Altshuler NESDA: study conception, design, management: B.W.P., J.H.S.; phenotype collection, data management: B.W.P., J.H.S., N.V.; sample processing and genotyping: B.W.P., J.H.S.; data analysis: N.V. NTR: study conception, design, management: D.I.B., G.W., E.J.C.d.G.; phenotype collection, data management: D.I.B., G.W., E.J.C.d.G., J.M.V.; sample processing and genotyping: D.I.B., G.W., E.J.C.d.G.; data analysis: J.M.V. NHS: phenotype collection, data management: S.E.H., D.J.H., P.K., F.G.; sample processing and genotyping: S.J.C., S.E.H., D.J.H., P.K.; data analysis: S.J.C., F.G., P.K. Rotterdam: study conception, design, management: A.H.; phenotype collection, data management: H.T., A.G.U.; sample processing and genotyping: H.T., A.G.U.; data analysis: H.T., A.G.U., S.W., C.M.v.D. WGHS: study conception, design, management: B.M.E., G.P., D.I. Chasman, P.M.R.; phenotype collection, data management: B.M.E., G.P., D.I. Chasman, P.M.R.; sample processing and genotyping: G.P., D.I. Chasman; data analysis: B.M.E., G.P., D.I. Chasman. Helena Furberg1,2, YunJung Kim1, Jennifer Dackor1, Eric Boerwinkle3, Nora Franceschini4, Diego Ardissino5, Luisa Bernardinelli6,7, Pier M Mannucci8, Francesco Mauri9, Piera A Merlini9, Devin Absher10, Themistocles L Assimes11, Stephen P Fortmann12, Carlos Iribarren13, Joshua W Knowles11, Thomas Quertermous11, Luigi Ferrucci14, Toshiko Tanaka15, Joshua C Bis16,17, Curt D Furberg18, Talin Haritunians19, Barbara McKnight16,20, Bruce M Psaty16,17,21,22, Kent D Taylor19, Evan L Thacker16,23, Peter Almgren24, Leif Groop24, Claes Ladenvall24, Michael Boehnke25, Anne U Jackson25, Karen L Mohlke1,2, Heather M Stringham25, Jaakko Tuomilehto26,27,28, Emelia J Benjamin29,30, Shih-Jen Hwang31, Daniel Levy32, Sarah Rosner Preis31, Ramachandran S Vasan29,32, Jubao Duan33, Pablo V Gejman33, Douglas F Levinson34, Alan R Sanders33, Jianxin Shi35, Esther H Lips36, James D McKay36, Antonio Agudo37, Luigi Barzan38, Vladimir Bencko39, Simone Benhamou40,41, Xavier Castellsagué37, Cristina Canova4! 2, David I Conway43, Eleonora Fabianova44, Lenka Foretova45, Vladimir Janout46, Claire M Healy47, Ivana Holcátová39, Kristina Kjaerheim48, Pagona Lagiou49, Jolanta Lissowska50, Ray Lowry51, Tatiana V Macfarlane52, Dana Mates53, Lorenzo Richiardi54, Peter Rudnai55, Neonilia Szeszenia-Dabrowska56, David Zaridze57, Ariana Znaor58, Mark Lathrop59,60, Paul Brennan36, Stefania Bandinelli61, Timothy M Frayling62, Jack M Guralnik63, Yuri Milaneschi64, John R B Perry62, David Altshuler65,66,67,68,69,70, Roberto Elosua71, Sek Kathiresan65,68,72, Gavin Lucas71, Olle Melander73, Christopher J O'Donnell74, Veikko Salomaa75, Stephen M Schwartz16, Benjamin F Voight76, Brenda W Penninx77,78, Johannes H Smit77,78, Nicole Vogelzangs77,78, Dorret I Boomsma79, Eco J C de Geus79, Jacqueline M Vink79, Gonneke Willemsen79, Stephen J Chanock80, Fangyi Gu81, Susan E Hankinson82, David J Hunter81, Albert Hofman83, Henning Tiemeier83,84, Andre G Uitterlinden83,85, Cornelia M van Duijn83,86, Stefan ! Walter83,87, Daniel I Chasman88, Brendan M Everett88,89, Guill! aume Paré88, Paul M Ridker88,89, Ming D Li90, Hermine H Maes91,92, Janet Audrain-McGovern93, Danielle Posthuma94,95, Laura M Thornton96, Caryn Lerman93,97, Jaakko Kaprio26,75,98, Jed E Rose99, John P A Ioannidis100,101,102, Peter Kraft81, Dan-Yu Lin103 & Patrick F Sullivan1,2 Competing financial interests The authors declare no competing financial interests. Corresponding authors Correspondence to: * Helena Furberg (helena_furberg@med.unc.edu) or * Patrick F Sullivan (pfsulliv@med.unc.edu) Supplementary information * Author information * Supplementary information Excel files * Supplementary Table 6 (48K) Association testing for CPD on chromosome 15, conditional on rs1051730 PDF files * Supplementary Text and Figures (656K) Supplementary Tables 1–5, Supplementary Figures 1 and 2 and Supplementary Note Additional data
• Sequence variants at CHRNB3–CHRNA6 and CYP2A6 affect smoking behavior
  Thorgeirsson TE Gudbjartsson DF Surakka I Vink JM Amin N Geller F Sulem P Rafnar T Esko T Walter S Gieger C Rawal R Mangino M Prokopenko I Mägi R Keskitalo K Gudjonsdottir IH Gretarsdottir S Stefansson H Thompson JR Aulchenko YS Nelis M Aben KK den Heijer M Dirksen A Ashraf H Soranzo N Valdes AM Steves C Uitterlinden AG Hofman A Tönjes A Kovacs P Hottenga JJ Willemsen G Vogelzangs N Döring A Dahmen N Nitz B Pergadia ML Saez B De Diego V Lezcano V Garcia-Prats MD Ripatti S Perola M Kettunen J Hartikainen AL Pouta A Laitinen J Isohanni M Huei-Yi S Allen M Krestyaninova M Hall AS Jones GT van Rij AM Mueller T Dieplinger B Haltmayer M Jonsson S Matthiasson SE Oskarsson H Tyrfingsson T Kiemeney LA Mayordomo JI Lindholt JS Pedersen JH Franklin WA Wolf H Montgomery GW Heath AC Martin NG Madden PA Giegling I Rujescu D Järvelin MR Salomaa V Stumvoll M Spector TD Wichmann HE Metspalu A Samani NJ Penninx BW Oostra BA Boomsma DI Tiemeier H van Duijn CM Kaprio J Gulcher JR The ENGAGE Consortium McCarthy MI Peltonen L Thorsteinsdottir U Stefansson K - Nature Genetics 42(5):448-453 (2010)
  Nature Genetics | Letter Sequence variants at CHRNB3–CHRNA6 and CYP2A6 affect smoking behavior * Thorgeir E Thorgeirsson1, 2 Search for this author in: * NPG journals * PubMed * Google Scholar * Daniel F Gudbjartsson1 Search for this author in: * NPG journals * PubMed * Google Scholar * Ida Surakka3, 4 Search for this author in: * NPG journals * PubMed * Google Scholar * Jacqueline M Vink5 Search for this author in: * NPG journals * PubMed * Google Scholar * Najaf Amin6 Search for this author in: * NPG journals * PubMed * Google Scholar * Frank Geller1 Search for this author in: * NPG journals * PubMed * Google Scholar * Patrick Sulem1 Search for this author in: * NPG journals * PubMed * Google Scholar * Thorunn Rafnar1 Search for this author in: * NPG journals * PubMed * Google Scholar * Tõnu Esko7, 8 Search for this author in: * NPG journals * PubMed * Google Scholar * Stefan Walter6 Search for this author in: * NPG journals * PubMed * Google Scholar * Christian Gieger9 Search for this author in: * NPG journals * PubMed * Google Scholar * Rajesh Rawal9 Search for this author in: * NPG journals * PubMed * Google Scholar * Massimo Mangino10 Search for this author in: * NPG journals * PubMed * Google Scholar * Inga Prokopenko11, 12 Search for this author in: * NPG journals * PubMed * Google Scholar * Reedik Mägi11, 12 Search for this author in: * NPG journals * PubMed * Google Scholar * Kaisu Keskitalo13 Search for this author in: * NPG journals * PubMed * Google Scholar * Iris H Gudjonsdottir1 Search for this author in: * NPG journals * PubMed * Google Scholar * Solveig Gretarsdottir1 Search for this author in: * NPG journals * PubMed * Google Scholar * Hreinn Stefansson1 Search for this author in: * NPG journals * PubMed * Google Scholar * John R Thompson14 Search for this author in: * NPG journals * PubMed * Google Scholar * Yurii S Aulchenko6 Search for this author in: * NPG journals * PubMed * Google Scholar * Mari Nelis7, 8 Search for this author in: * NPG 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PubMed * Google Scholar * Michael Stumvoll21 Search for this author in: * NPG journals * PubMed * Google Scholar * Tim D Spector10 Search for this author in: * NPG journals * PubMed * Google Scholar * H-Erich Wichmann9, 52, 53 Search for this author in: * NPG journals * PubMed * Google Scholar * Andres Metspalu7, 8 Search for this author in: * NPG journals * PubMed * Google Scholar * Nilesh J Samani54 Search for this author in: * NPG journals * PubMed * Google Scholar * Brenda W Penninx24 Search for this author in: * NPG journals * PubMed * Google Scholar * Ben A Oostra55 Search for this author in: * NPG journals * PubMed * Google Scholar * Dorret I Boomsma5 Search for this author in: * NPG journals * PubMed * Google Scholar * Henning Tiemeier6 Search for this author in: * NPG journals * PubMed * Google Scholar * Cornelia M van Duijn6 Search for this author in: * NPG journals * PubMed * Google Scholar * Jaakko Kaprio3, 13, 56 Search for this author in: * NPG journals * PubMed * Google Scholar * Jeffrey R Gulcher1 Search for this author in: * NPG journals * PubMed * Google Scholar * The ENGAGE Consortium57 * Mark I McCarthy11, 12 Search for this author in: * NPG journals * PubMed * Google Scholar * Leena Peltonen3, 19 Search for this author in: * NPG journals * PubMed * Google Scholar * Unnur Thorsteinsdottir1, 38 Search for this author in: * NPG journals * PubMed * Google Scholar * Kari Stefansson1, 38 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorsJournal name:Nature GeneticsVolume:42,Pages:448–453Year published:(2010)DOI:doi:10.1038/ng.573Received21 October 2009Accepted18 March 2010Published online25 April 2010 Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Smoking is a common risk factor for many diseases1. We conducted genome-wide association meta-analyses for the number of cigarettes smoked per day (CPD) in smokers (n = 31,266) and smoking initiation (n = 46,481) using samples from the ENGAGE Consortium. In a second stage, we tested selected SNPs with in silico replication in the Tobacco and Genetics (TAG) and Glaxo Smith Kline (Ox-GSK) consortia cohorts (n = 45,691 smokers) and assessed some of those in a third sample of European ancestry (n = 9,040). Variants in three genomic regions associated with CPD (P < 5 × 10−8), including previously identified SNPs at 15q25 represented by rs1051730[A] (effect size = 0.80 CPD, P = 2.4 × 10−69), and SNPs at 19q13 and 8p11, represented by rs4105144[C] (effect size = 0.39 CPD, P = 2.2 × 10−12) and rs6474412-T (effect size = 0.29 CPD, P = 1.4 × 10−8), respectively. Among the genes at the two newly associated loci are genes encoding nicotine-metabolizing enzymes (CYP2A6 and CY! P2B6) and nicotinic acetylcholine receptor subunits (CHRNB3 and CHRNA6), all of which have been highlighted in previous studies of smoking and nicotine dependence2, 3, 4. Nominal associations with lung cancer were observed at both 8p11 (rs6474412[T], odds ratio (OR) = 1.09, P = 0.04) and 19q13 (rs4105144[C], OR = 1.12, P = 0.0006). View full text Author information * Author information * Supplementary information Affiliations * deCODE Genetics, Reykjavik, Iceland. * Thorgeir E Thorgeirsson, * Daniel F Gudbjartsson, * Frank Geller, * Patrick Sulem, * Thorunn Rafnar, * Iris H Gudjonsdottir, * Solveig Gretarsdottir, * Hreinn Stefansson, * Jeffrey R Gulcher, * Unnur Thorsteinsdottir & * Kari Stefansson * Center for Biomolecular Science and Engineering, Jack Baskin School of Engineering, University of California, Santa Cruz, California, USA. * Thorgeir E Thorgeirsson * Institute for Molecular Medicine (FIMM), University of Helsinki, Finland. * Ida Surakka, * Samuli Ripatti, * Shen Huei-Yi, * Jaakko Kaprio & * Leena Peltonen * National Institute for Health and Welfare, Helsinki, Finland. * Ida Surakka, * Samuli Ripatti, * Markus Perola, * Shen Huei-Yi & * Veikko Salomaa * Department of Biological Psychology, Vrije Universiteit (VU) Amsterdam, Amsterdam, The Netherlands. * Jacqueline M Vink, * Jouke Jan Hottenga, * Gonneke Willemsen & * Dorret I Boomsma * Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands. * Najaf Amin, * Stefan Walter, * Yurii S Aulchenko, * André G Uitterlinden, * Albert Hofman, * Henning Tiemeier & * Cornelia M van Duijn * Estonian Genome Project of University of Tartu, Tartu, Estonia. * Tõnu Esko, * Mari Nelis & * Andres Metspalu * Estonian Biocentre, Tartu, Estonia. * Tõnu Esko, * Mari Nelis & * Andres Metspalu * Institute of Epidemiology, Helmholtz Zentrum München, Neuherberg, Germany. * Christian Gieger, * Rajesh Rawal, * Angela Döring, * Barbara Nitz & * H-Erich Wichmann * Department of Twin Research and Genetic Epidemiology, King's College London, St. Thomas' Hospital Campus, London, UK. * Massimo Mangino, * Nicole Soranzo, * Ana M Valdes, * Claire Steves & * Tim D Spector * Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK. * Inga Prokopenko, * Reedik Mägi, * Maxine Allen & * Mark I McCarthy * Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. * Inga Prokopenko, * Reedik Mägi & * Mark I McCarthy * Department of Public Health, University of Helsinki, Helsinki, Finland. * Kaisu Keskitalo & * Jaakko Kaprio * Department of Health Sciences and Genetics, University of Leicester, Leicester, UK. * John R Thompson * Radboud University Nijmegen Medical Centre, Department of Epidemiology, Biostatistics and Health Technology Assessment, Nijmegen, The Netherlands. * Katja K Aben, * Martin den Heijer & * Lambertus A Kiemeney * Comprehensive Cancer Centre East, Nijmegen, The Netherlands. * Katja K Aben & * Lambertus A Kiemeney * Radboud University Nijmegen Medical Centre, Department of Endocrinology, Nijmegen, The Netherlands. * Martin den Heijer * Department of Pulmonary Medicine, Gentofte University Hospital, Hellerup, Denmark. * Asger Dirksen & * Haseem Ashraf * Wellcome Trust Sanger Institute, Hinxton, UK. * Nicole Soranzo, * Johannes Kettunen & * Leena Peltonen * Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands. * André G Uitterlinden * Department of Medicine, University of Leipzig, Leipzig, Germany. * Anke Tönjes & * Michael Stumvoll * Coordination Centre for Clinical Trials, University of Leipzig, Leipzig, Germany. * Anke Tönjes * Interdisciplinary Centre for Clinical Research, University of Leipzig, Leipzig, Germany. * Peter Kovacs * Department of Psychiatry, VU University Medical Center, Amsterdam, The Netherlands. * Nicole Vogelzangs & * Brenda W Penninx * Department of Psychiatry, University of Mainz, Mainz, Germany. * Norbert Dahmen * Washington University School of Medicine, Department of Psychiatry, St. Louis, Missouri, USA. * Michele L Pergadia, * Andrew C Heath & * Pamela A F Madden * Instituto de Nanotecnología de Aragón, Zaragoza, Spain. * Berta Saez * Division of Dermatology, Hospital San Pedro, Logroño, Spain. * Veronica De Diego & * Victoria Lezcano * Division of Pathology, San Jorge Hospital, Huesca, Spain. * Maria D Garcia-Prats * Institute of Clinical Medicine, University of Oulu, Oulu, Finland. * Anna-Liisa Hartikainen & * Matti Isohanni * Lifecourse and Service Department, National Institute of Health and Welfare, Oulu, Finland. * Anneli Pouta & * Marjo-Riitta Järvelin * Finnish Institute of Occupational Health, Oulu, Finland. * Jaana Laitinen * European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK. * Maria Krestyaninova * Multidisciplinary Cardiovascular Research Centre (MCRC), Leeds Institute of Genetics, Health and Therapeutics (LIGHT), University of Leeds, Leeds, UK. * Alistair S Hall * Vascular Research Group, Otago Medical School, Dunedin, New Zealand. * Gregory T Jones & * Andre M van Rij * Department of Laboratory Medicine, Konventhospital Barmherzige Brueder Linz, Linz, Austria. * Thomas Mueller, * Benjamin Dieplinger & * Meinhard Haltmayer * Landspitali University Hospital, Department of Medicine, Reykjavik, Iceland. * Steinn Jonsson * University of Iceland, Faculty of Medicine, Reykjavik, Iceland. * Stefan E Matthiasson, * Unnur Thorsteinsdottir & * Kari Stefansson * Therapeia, Reykjavik, Iceland. * Hogni Oskarsson * National Center of Addiction Medicine, Vogur Hospital, Reykjavik, Iceland. * Thorarinn Tyrfingsson * Radboud University Nijmegen Medical Centre, Department of Urology, Nijmegen, The Netherlands. * Lambertus A Kiemeney * University of Zaragoza, Zaragoza, Spain. * Jose I Mayordomo * Vascular Research Unit, Viborg Hospital, Viborg, Denmark. * Jes S Lindholt * Department of Cardiothoracic Surgery, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. * Jesper Holst Pedersen * Department of Pathology, University of Colorado Denver, Aurora, Colorado, USA. * Wilbur A Franklin * Community and Behavioral Health, Colorado School of Public Health, University of Colorado Denver, Aurora, Colorado, USA. * Holly Wolf * Queensland Institute of Medical Research, Queensland, Australia. * Grant W Montgomery & * Nicholas G Martin * Department of Psychiatry, University of Munich (LMU), Munich, Germany. * Ina Giegling & * Dan Rujescu * Department of Epidemiology and Public Health, Imperial College, Faculty of Medicine, London, UK. * Marjo-Riitta Järvelin * Institute of Health Sciences, University of Oulu, Oulu, Finland. * Marjo-Riitta Järvelin * Biocenter Oulu, University of Oulu, Oulu, Finland. * Marjo-Riitta Järvelin * Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany. * H-Erich Wichmann * Klinikum Grosshadern, Munich, Germany. * H-Erich Wichmann * Department of Cardiovascular Sciences, University of Leicester, Clinical Sciences Wing, Glenfield Hospital, Leicester, UK. * Nilesh J Samani * Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands. * Ben A Oostra * Department of Mental Health and Alcohol Abuse Services, National Institute for Health and Welfare, Helsinki, Finland. * Jaakko Kaprio * A full list of members is provided in the Supplementary Note. * The ENGAGE Consortium Consortia * The ENGAGE Consortium Contributions The study was designed by and the results interpreted by T.E.T., D.F.G., F.G., J.R.G., U.T., K.S., L.P. and M.I.M. The meta-analysis was performed by D.F.G. and F.G., and D.F.G., F.G., I.S., J.M.V., P.S., N.A., T.E., S.W., C.G., R.R., M.M., I.P., R.M., J. Kettunen, Y.S.A., N.S. and J.J.H. were responsible for data analysis in each of the ENGAGE samples. Stage 3 and smoking-related disease samples were coordinated by I.H.G., H.S., S.G. and T.R. Those responsible for case and control ascertainment, recruitment and phenotypic information and project management at the study sites are: J.R.T., W.A.F., H.W., G.W.M., A.C.H., N.G.M., P.A.F.M., K.K.A., M.d.H., L.A.K., G.T.J., A.M.v.R., T.M., B.D., M.H., S.J., T.R., S.E.M., S.G., A.M.V., C.S., A.G.U., A.H., A.T., P.K., G.W., N.V., A. Dirksen, N.D., B.N., M.L.P., B.S., S.R., M.P., J. Kettunen, A.-L.H., A.P., J.L., M.I., A.S.H., T.E.T., H.O., T.T., V.D.D., V.L., M.D.G.-P., J.I.M., A. Döring, H.A., J.S.L., J.H.P., I.G., D.R., M.-R.J., V! .S., M.S., T.D.S., H.-E.W., A.M., M.N., N.J.S., B.W.P., B.A.O., D.I.B., H.T., C.M.v.D., J. Kaprio, J.R.G., M.I.M., L.P., U.T. and K.S. Data submission coordination was provided by S.H.-Y., M.A. and M.K. Authors T.E.T., D.F.G. and U.T. wrote the first draft of the paper. All authors contributed to the final version of the paper. Competing financial interests Authors whose affiliations are listed as deCODE genetics are employees of deCODE genetics, a biotechnology company. Corresponding authors Correspondence to: * Kari Stefansson (kstefans@decode.is) or * Unnur Thorsteinsdottir (unnur.thorsteinsdottir@decode.is) Supplementary information * Author information * Supplementary information PDF files * Supplementary Text and Figures (216K) Supplementary Figures 1–3, Supplementary Tables 1–4 and Supplementary Note Additional data
• Subtle variations in Pten dose determine cancer susceptibility
  - Nature Genetics 42(5):454-458 (2010)
  Nature Genetics | Letter Subtle variations in Pten dose determine cancer susceptibility * Andrea Alimonti1, 2, 3, 4 Search for this author in: * NPG journals * PubMed * Google Scholar * Arkaitz Carracedo1, 2, 3, 4, 8 Search for this author in: * NPG journals * PubMed * Google Scholar * John G Clohessy1, 2, 3, 4, 8 Search for this author in: * NPG journals * PubMed * Google Scholar * Lloyd C Trotman3, 7 Search for this author in: * NPG journals * PubMed * Google Scholar * Caterina Nardella1, 2, 3, 4 Search for this author in: * NPG journals * PubMed * Google Scholar * Ainara Egia1, 2, 3, 4 Search for this author in: * NPG journals * PubMed * Google Scholar * Leonardo Salmena1, 2, 3, 4 Search for this author in: * NPG journals * PubMed * Google Scholar * Katia Sampieri1, 2 Search for this author in: * NPG journals * PubMed * Google Scholar * William J Haveman1, 2, 3, 4 Search for this author in: * NPG journals * PubMed * Google Scholar * Edi Brogi4 Search for this author in: * NPG journals * PubMed * Google Scholar * Andrea L Richardson5 Search for this author in: * NPG journals * PubMed * Google Scholar * Jiangwen Zhang6 Search for this author in: * NPG journals * PubMed * Google Scholar * Pier Paolo Pandolfi1, 2, 3, 4 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorJournal name:Nature GeneticsVolume:42,Pages:454–458Year published:(2010)DOI:doi:10.1038/ng.556Received15 December 2009Accepted23 February 2010Published online18 April 2010 Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Cancer susceptibility has been attributed to at least one heterozygous genetic alteration in a tumor suppressor gene (TSG)1. It has been hypothesized that subtle variations in TSG expression can promote cancer development2, 3. However, this hypothesis has not yet been definitively supported in vivo. Pten is a TSG frequently lost in human cancer and mutated in inherited cancer-predisposition syndromes4. Here we analyze Pten hypermorphic mice (Ptenhy/+), expressing 80% normal levels of Pten. Ptenhy/+ mice develop a spectrum of tumors, with breast tumors occurring at the highest penetrance. All breast tumors analyzed here retained two intact copies of Pten and maintained Pten levels above heterozygosity. Notably, subtle downregulation of Pten altered the steady-state biology of the mammary tissues and the expression profiles of genes involved in cancer cell proliferation. We present an alterative working model for cancer development in which subtle reductions in the dose of TSG! s predispose to tumorigenesis in a tissue-specific manner. View full text Figures at a glance * Figure 1: A subtle reduction in the dose of Pten dictates overall survival in Ptenhy/+ mice and initiates mammary tumorigenesis. (–) Kaplan-Meier plots for overall survival in the general population () and in the male () and female () populations. hy/+, mice having a Pten hypomorphic and a wild-type (wt) allele; hy/−, mice having a Pten hypomorphic and null allele; +/−, mice having a Pten wt and null allele. OS, overall survival; n, number of mice analyzed; P, statistical significance. () Percentage of mice with mammary tumors according to age in the female population; n, number of animals analyzed; P, statistical significance. Inset is a representative image of a mammary tumor in Ptenhy/+ mice. () Top, H&E staining (×20) of a Ptenwt normal mammary gland and Ptenhy/+ and Pten+/− mammary tumors. Bottom, average size and Ki-67 proliferative index of the Ptenwt mammary glands and Ptenhy/+ and Pten+/− mammary tumors. () Immunohistochemical analysis for Pten and pAkt in Ptenhy/+ and Pten+/− mammary tumors (four tumors for each genotype were analyzed). The insets in Ptenhy/+ show a representati! ve image (×40) for Pten and pAkt staining in a control mammary gland. () Protein blot analysis for Pten and pAkt protein levels (above) in Ptenwt, Ptenhy/+ and Pten+/− mammary tumors showing the presence of Pten protein and the corresponding pAkt level. Bottom, quantification of Pten protein level in mammary tumors from Ptenwt, Ptenhy/+ and Pten+/− mice. Error bars, s.d. from three independent experiments. Asterisk indicates a nonspecific band observed when blotting protein extracted from mouse tissue. Numbers to the left of the blots represent molecular weight markers in kDa; those below the Pten blot indicate densitometrically quantified protein levels that have been normalized to β-actin. Presentation of cropped images is in accordance with Nature Publishing Group policy. * Figure 2: A subtle variation of Pten gene expression promotes hyper proliferation in a tissue-specific manner. () Representative images of mammary tissue (above) and quantification (below) of Ki-67 staining in tissues from 2-month-old Ptenwt and Ptenhy/+ littermate mice. P, statistical significance; error bars, s.d. () Growth curve analysis of Ptenwt and Ptenhy/+ mouse mammary epithelial cells. Error bars, s.d. () Analysis of the cell viability (at the indicated time points) of Ptenwt and Ptenhy/+ mouse mammary epithelial cells after treatment with ultraviolet irradiation (at 60 J/m2). () Protein blot analysis for Pten, pAkt and Cyclin D1 protein levels in Ptenwt and Ptenhy/+ MMECs. Asterisk indicates residual Pten signal that is present because the membrane was not stripped prior to blotting for pAkt. Numbers to the right of the blots represent molecular weight markers in kDa; those numbers below the blots indicate densitometrically quantified protein levels for Pten (normalized to β-actin) and pAkt (normalized to total Akt). Presentation of cropped images is in accordance with Nat! ure Publishing Group policy. * Figure 3: Graphic representation of the correlation between Pten dosage (showing percent of normal levels), Akt signaling intensity and the corresponding observed incidence for the indicated phenotypes. * Figure 4: Gene expression profiles of Ptenhy/+ MEFs, MMECs and human breast cancer samples with reduced PTEN levels. () A subtle decrease in Pten levels significantly modulates three gene expression signatures for cell cycle (GNF2_CSK1B, GNF2_CDC2 and GNF2_CDC20) in Ptenhy/+ MEFs. Genes are ranked by signal to noise ratio according to their differential expression between Ptenhy/+ MEFs and controls. Genes in the lineage-specific gene sets are marked with vertical bars, and the enrichment score is shown in green. () Quantitative RT-PCR analysis in Ptenwt and Ptenhy/+ MMECs for the indicated genes. P, statistical significance. Error bars, s.e.m. of four independent mice (two to four samples per MMEC culture and mouse). () Stratification of the gene datasets upregulated in Ptenhy/+ MEFs according to GO-BP. * Figure 5: Implications for tumorigenesis upon subtle reduction of TSG levels. () The 'no hits' model of cancer susceptibility. The rectangular green box represents a functional allele of a given TSG. The rectangular red box represents a nonfunctional allele inactivated by, for example, mutation or deletion. The rectangular green, yellow and red box represents an allele of a TSG whose expression is reduced below the normal levels. The black rectangle represents a genetic hit. Note that the model represented does not exclude the presence of additional hits on other loci. () A continuum model (left) for cancer initiation and promotion vis-à-vis a saltatory model (right). Note that in the continuum model, even subtle reductions in the dose of a TSG can initiate tumorigenesis in a tissue-specific manner. Phenotypes 1, 2 and 3 indicate that with the reduction of the TSG dose, the tumor phenotype can change in a tissue-specific manner, increasing incidence and aggressiveness of the disease. In the saltatory model, cancer arises from a stepwise genetic mutat! ion–driven allelic loss. Accession codes * Accession codes * Author information * Supplementary information Referenced accessions Entrez Nucleotide * NC_000085 Gene Expression Omnibus * GSE20316 * GSE3744 Author information * Accession codes * Author information * Supplementary information Primary authors * These authors contributed equally to this work. * Arkaitz Carracedo & * John G Clohessy Affiliations * Cancer Genetics Program, Department of Medicine, Beth Israel Deaconess Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA. * Andrea Alimonti, * Arkaitz Carracedo, * John G Clohessy, * Caterina Nardella, * Ainara Egia, * Leonardo Salmena, * Katia Sampieri, * William J Haveman & * Pier Paolo Pandolfi * Department of Pathology, Beth Israel Deaconess Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA. * Andrea Alimonti, * Arkaitz Carracedo, * John G Clohessy, * Caterina Nardella, * Ainara Egia, * Leonardo Salmena, * Katia Sampieri, * William J Haveman & * Pier Paolo Pandolfi * Cancer Biology and Genetics Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, New York, USA. * Andrea Alimonti, * Arkaitz Carracedo, * John G Clohessy, * Lloyd C Trotman, * Caterina Nardella, * Ainara Egia, * Leonardo Salmena, * William J Haveman & * Pier Paolo Pandolfi * Department of Pathology, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, New York, USA. * Andrea Alimonti, * Arkaitz Carracedo, * John G Clohessy, * Caterina Nardella, * Ainara Egia, * Leonardo Salmena, * William J Haveman, * Edi Brogi & * Pier Paolo Pandolfi * Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA. * Andrea L Richardson * Faculty of Arts and Sciences (FAS), Center for Systems Biology, Harvard University, Cambridge, Massachusetts, USA. * Jiangwen Zhang * Current address: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA. * Lloyd C Trotman Contributions A.A., L.C.T. and P.P.P. conceived and designed the experiments. A.A., A.C., J.G.C., C.N., A.E., L.S., K.S. and W.J.H. performed the experiments. A.A., A.C., J.G.C., C.N., L.S., E.B., A.L.R., J.Z. and P.P.P. analyzed the data. A.A., A.C., J.G.C. and P.P.P. wrote the paper. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Pier Paolo Pandolfi (ppandolf@bidmc.harvard.edu) Supplementary information * Accession codes * Author information * Supplementary information PDF files * Supplementary Text and Figures (6M) Supplementary Figures 1–8 and Supplementary Table 1 Additional data
• The flowering gene SINGLE FLOWER TRUSS drives heterosis for yield in tomato
  Krieger U Lippman ZB Zamir D - Nature Genetics 42(5):459-463 (2010)
  Nature Genetics | Letter The flowering gene SINGLE FLOWER TRUSS drives heterosis for yield in tomato * Uri Krieger1 Search for this author in: * NPG journals * PubMed * Google Scholar * Zachary B Lippman2 Search for this author in: * NPG journals * PubMed * Google Scholar * Dani Zamir1 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorsJournal name:Nature GeneticsVolume:42,Pages:459–463Year published:(2010)DOI:doi:10.1038/ng.550Received01 December 2009Accepted18 February 2010Published online28 March 2010 Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Intercrossing different varieties of plants frequently produces hybrid offspring with superior vigor and increased yields, in a poorly understood phenomenon known as heterosis1, 2. One classical unproven model for heterosis is overdominance, which posits in its simplest form that improved vigor can result from a single heterozygous gene3, 4, 5, 6, 7, 8. Here we report that heterozygosity for tomato loss-of-function alleles of SINGLE FLOWER TRUSS (SFT), which is the genetic originator of the flowering hormone florigen, increases yield by up to 60%. Yield overdominance from SFT heterozygosity is robust, occurring in distinct genetic backgrounds and environments. We show that several traits integrate pleiotropically to drive heterosis in a multiplicative manner9, and these effects derive from a suppression of growth termination mediated by SELF PRUNING (SP), an antagonist of SFT. Our findings provide the first example of a single overdominant gene for yield and suggest that sin! gle heterozygous mutations may improve productivity in other agricultural organisms. View full text Figures at a glance * Figure 1: Heterozygosity for loss-of-function mutations in SFT drives heterosis in tomato. () Representative plant and total fruit yield from a high-yielding M82 inbred control plant (left), a low-yielding homozygous loss-of-function mutant allele of SFT (sft-4537, right; Online Methods) and a highly heterotic sft-4537/+ heterozygote (middle). All genotypes are isogenic in the M82 background. () Statistical comparison of mean values (± s.e.m.) for total fruit yields between three independently derived sft/sft homozygous mutants (carrying the sft-4537 weak allele, sft-7187 strong allele and sft-stop strong allele, respectively; Online Methods), the inbred M82 control and the F1sft/+ hybrids of the sft/sft mutants with M82. Total fruit yields from all three sft/+ heterozygotes were heterotic over M82 controls, and sft-4537/+ and sft-7187/+ heterozygotes achieved the same yields as AB2, which is a leading commercial processing-tomato hybrid. () Statistical comparison of mean values (± s.e.m.) for fruit sugar content (Brix value) showing an intermediate effect for s! ft/+ heterozygotes relative to M82 controls (low sugar) and sft/sft homozygotes (high sugar). Lines marked with asterisks are significantly different from the M82 control according to the 'compare with control' (Dunnett's) method: *P < 0.05, **P < 0.01. Similar results were obtained using multiple comparison analysis (Tukey-Kramer test; **P < 0.05) for total fruit yield, which revealed a significant difference between AB2 and sft/+ heterozygotes compared to M82 plants and sft/sft homozygotes. For Brix values, all four groups of genotypes were significantly different from each other (Tukey-Kramer test; **P < 0.05). * Figure 2: sft/+ heterozygosity causes heterosis in distinct genetic backgrounds and growth conditions. In the tomato industry, genotypes with high yield and Brix value (that is, high values of Brix-yield, the multiplied output of Brix and total fruit yield measured in g/m2) are the most efficient for the production of various tomato concentrates. () Statistical comparison of Brix-yield between sft/+ heterozygotes in the background of a full-genome hybrid between M82 and the processing-tomato line E6203 (dark gray) (Online Methods), the homozygous inbred lines M82 and E6203 (white) and the hybrid (M82 × E6203) control (light gray). Experiments were performed in both wide- and dense-spacing conditions (Online Methods). () Statistical comparison of Brix-yield between sft/+ heterozygotes in the background of the large-fruited fresh market tomato line M99 (dark gray) (Online Methods), the homozygous inbred lines M82 and M99 (white) and the hybrid controls (M82 × M99) (light gray). The mean values (± s.e.m.) for each genotype marked by asterisks reflect a significant difference ! from the control hybrids according to the 'compare with control' (Dunnett's) method: *P < 0.05, **P < 0.01. Similar results were obtained using multiple-range means comparison (Tukey-Kramer test; **P < 0.05), which revealed a significant difference between sft/+ heterozygotes and their corresponding controls. * Figure 3: SFT-dependent heterosis arises from multiple phenotypic changes on component traits that integrate to improve yield. () Representative inflorescences from M82 plants (left), sft/sft homozygous mutants (right) and sft/+ heterozygotes (middle). The sft/sft homozygotes produce only a few inflorescences before reverting to indeterminate vegetative branches that infrequently produce single fertile flowers, which were counted. Because canonical multiflowered inflorescences almost never form, sft/sft mutant plants have the fewest inflorescences, flowers and fruits of any genotype. (–) Quantification and statistical comparison of three component traits for yield. () sft/+ heterozygotes (dark gray) produce more inflorescences compared to M82 plants. As canonical inflorescences almost never form in sft/sft homozygous mutants, no data was collected for this genotype. () sft/+ heterozygotes produce the most flowers per plant of all genotypes (are overdominant) and show an additive effect for fruit weight (), with a d/[a] value of 0.25. Mean values (± s.e.m.) were compared to the M82 isogenic line (! white) using the 'compare with control' (Dunnett's) method when three genotypes were present, and a t-test analysis was performed when two genotypes were present (total inflorescence). Significant differences compared to M82 plants are represented by asterisks: *P < 0.05, **P < 0.01. * Figure 4: Overdominance for inflorescence production is based on a dosage-dependent suppression of growth termination mediated by SP. () Temporal accumulation of inflorescences in M82 plants (red) and sft/+ heterozygotes (gray) throughout growth. Significant differences between mean values were calculated in each time point using t-test analyses and are represented by asterisks: *P < 0.05, **P < 0.01. () Diagrams showing the reiteration of modular sympodial units along individual shoots from M82-determinate (left), sft/sft homozygote (right) and sft/+ heterozygote plants (middle). Numbers indicate total number of leaves in each sympodial unit, which are indicated by brackets. Flattened gray and black ovals indicate sets of leaves in alternating sympodial units. Black and gray arrows represent axillary shoots preceding the inflorescence in each sympodial unit. Note that there are more sympodial units, inflorescences and leaves along each shoot of sft/+ heterozygotes compared to M82-determinate and sft/sft mutant plants (Supplementary Fig. 4). () Diagram of a shoot from an M82-indeterminate plant (left) and ! a yield comparison between sft/+ heterozygotes in an indeterminate background (sft/+, sp/+) and control M82-indeterminate plants (sft/+, sp/+). Total fruit yields of M82-determinate × M82-indeterminate (light gray) and sft/sft × M82-indeterminate (dark gray) do not differ significantly from each other, and both are lower yielding than the heterotic sft/+ M82-determinate plants, which are the highest yielding of all genotypes (Supplementary Fig. 5). () RT-PCR analysis of SFT and Sl-AP1 expression levels in young expanding leaves and shoot apices, respectively, showing no qualitative differences in transcript accumulation between M82 plants and heterozygote genotypes for either gene. EXP (EXPRESSED, SGN-U346908) is a published gene showing stable expression across diverse tissues, used here as real-time PCR control (Online Methods). Accession codes * Accession codes * Author information * Supplementary information Referenced accessions Entrez Nucleotide * AY186735 * LEU84140 Author information * Accession codes * Author information * Supplementary information Affiliations * The Hebrew University of Jerusalem Faculty of Agriculture, Institute of Plant Sciences, Rehovot, Israel. * Uri Krieger & * Dani Zamir * Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA. * Zachary B Lippman Contributions U.K., Z.B.L. and D.Z. planned and carried out all experiments, collected the data, performed the statistical analyses and wrote the paper. Competing financial interests D.Z. is a cofounder of Phenom Networks, a privately held company that is serving as a repository and online statistical analysis platform for the raw heterosis field data. Corresponding authors Correspondence to: * Dani Zamir (zamir@agri.huji.ac.il) or * Zachary B Lippman (lippman@cshl.edu) Supplementary information * Accession codes * Author information * Supplementary information PDF files * Supplementary Text and Figures (3M) Supplementary Figures 1–6 and Supplementary Tables 1–4 Additional data
• Erratum: New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk
  - Nature Genetics 42(5):464 (2010)
  Nature Genetics | Erratum Erratum: New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk * Josée Dupuis Search for this author in: * NPG journals * PubMed * Google Scholar * Claudia Langenberg Search for this author in: * NPG journals * PubMed * Google Scholar * Inga Prokopenko Search for this author in: * NPG journals * PubMed * Google Scholar * Richa Saxena Search for this author in: * NPG journals * PubMed * Google Scholar * Nicole Soranzo Search for this author in: * NPG journals * PubMed * Google Scholar * Anne U Jackson Search for this author in: * NPG journals * PubMed * Google Scholar * Eleanor Wheeler Search for this author in: * NPG journals * PubMed * Google Scholar * Nicole L Glazer Search for this author in: * NPG journals * PubMed * Google Scholar * Nabila Bouatia-Naji Search for this author in: * NPG journals * PubMed * Google Scholar * Anna L Gloyn Search for this author in: * NPG journals * PubMed * Google Scholar * 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journals * PubMed * Google Scholar * Laura Crisponi Search for this author in: * NPG journals * PubMed * Google Scholar * Ian N M Day Search for this author in: * NPG journals * PubMed * Google Scholar * Eco J C de Geus Search for this author in: * NPG journals * PubMed * Google Scholar * Jerome Delplanque Search for this author in: * NPG journals * PubMed * Google Scholar * Christian Dina Search for this author in: * NPG journals * PubMed * Google Scholar * Michael R Erdos Search for this author in: * NPG journals * PubMed * Google Scholar * Annette C Fedson Search for this author in: * NPG journals * PubMed * Google Scholar * Antje Fischer-Rosinsky Search for this author in: * NPG journals * PubMed * Google Scholar * Nita G Forouhi Search for this author in: * NPG journals * PubMed * Google Scholar * Caroline S Fox Search for this author in: * NPG journals * PubMed * Google Scholar * Rune Frants Search for this author in: * NPG journals * PubMed * Google Scholar * Maria Grazia 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Scholar * Anna-Liisa Hartikainen Search for this author in: * NPG journals * PubMed * Google Scholar * Neelam Hassanali Search for this author in: * NPG journals * PubMed * Google Scholar * Caroline Hayward Search for this author in: * NPG journals * PubMed * Google Scholar * Simon C Heath Search for this author in: * NPG journals * PubMed * Google Scholar * Serge Hercberg Search for this author in: * NPG journals * PubMed * Google Scholar * Christian Herder Search for this author in: * NPG journals * PubMed * Google Scholar * Andrew A Hicks Search for this author in: * NPG journals * PubMed * Google Scholar * David R Hillman Search for this author in: * NPG journals * PubMed * Google Scholar * Aroon D Hingorani Search for this author in: * NPG journals * PubMed * Google Scholar * Albert Hofman Search for this author in: * NPG journals * PubMed * Google Scholar * Jennie Hui Search for this author in: * NPG journals * PubMed * Google Scholar * Joe Hung Search for this author in: * NPG journals * PubMed * Google Scholar * Bo Isomaa Search for this author in: * NPG journals * PubMed * Google Scholar * Paul R V Johnson Search for this author in: * NPG journals * PubMed * Google Scholar * Torben Jørgensen Search for this author in: * NPG journals * PubMed * Google Scholar * Antti Jula Search for this author in: * NPG journals * PubMed * Google Scholar * Marika Kaakinen Search for this author in: * NPG journals * PubMed * Google Scholar * Jaakko Kaprio Search for this author in: * NPG journals * PubMed * Google Scholar * Y Antero Kesaniemi Search for this author in: * NPG journals * PubMed * Google Scholar * Mika Kivimaki Search for this author in: * NPG journals * PubMed * Google Scholar * Beatrice Knight Search for this author in: * NPG journals * PubMed * Google Scholar * Seppo Koskinen Search for this author in: * NPG journals * PubMed * Google Scholar * Peter Kovacs Search for this author in: * NPG journals * PubMed * Google Scholar * Kirsten Ohm Kyvik Search for this author in: * NPG journals * PubMed * Google Scholar * G Mark Lathrop Search for this author in: * NPG journals * PubMed * Google Scholar * Debbie A Lawlor Search for this author in: * NPG journals * PubMed * Google Scholar * Olivier Le Bacquer Search for this author in: * NPG journals * PubMed * Google Scholar * Cécile Lecoeur Search for this author in: * NPG journals * PubMed * Google Scholar * Yun Li Search for this author in: * NPG journals * PubMed * Google Scholar * Valeriya Lyssenko Search for this author in: * NPG journals * PubMed * Google Scholar * Robert Mahley Search for this author in: * NPG journals * PubMed * Google Scholar * Massimo Mangino Search for this author in: * NPG journals * PubMed * Google Scholar * Alisa K Manning Search for this author in: * NPG journals * PubMed * Google Scholar * María Teresa Martínez-Larrad Search for this author in: * NPG journals * PubMed * Google Scholar * Jarred B McAteer Search for this author in: * NPG journals * PubMed * Google Scholar * Laura J McCulloch Search for this author in: * NPG journals * PubMed * Google Scholar * Ruth McPherson Search for this author in: * NPG journals * PubMed * Google Scholar * Christa Meisinger Search for this author in: * NPG journals * PubMed * Google Scholar * David Melzer Search for this author in: * NPG journals * PubMed * Google Scholar * David Meyre Search for this author in: * NPG journals * PubMed * Google Scholar * Braxton D Mitchell Search for this author in: * NPG journals * PubMed * Google Scholar * Mario A Morken Search for this author in: * NPG journals * PubMed * Google Scholar * Sutapa Mukherjee Search for this author in: * NPG journals * PubMed * Google Scholar * Silvia Naitza Search for this author in: * NPG journals * PubMed * Google Scholar * Narisu Narisu Search for this author in: * NPG journals * PubMed * Google Scholar * Matthew J Neville Search for this author in: * NPG journals * PubMed * Google Scholar * Ben A Oostra Search for this author in: * NPG journals * PubMed * Google Scholar * Marco Orrù Search for this author in: * NPG journals * PubMed * Google Scholar * Ruth Pakyz Search for this author in: * NPG journals * PubMed * Google Scholar * Colin N A Palmer Search for this author in: * NPG journals * PubMed * Google Scholar * Giuseppe Paolisso Search for this author in: * NPG journals * PubMed * Google Scholar * Cristian Pattaro Search for this author in: * NPG journals * PubMed * Google Scholar * Daniel Pearson Search for this author in: * NPG journals * PubMed * Google Scholar * John F Peden Search for this author in: * NPG journals * PubMed * Google Scholar * Nancy L Pedersen Search for this author in: * NPG journals * PubMed * Google Scholar * Markus Perola Search for this author in: * NPG journals * PubMed * Google Scholar * Andreas F H Pfeiffer Search for this author in: * NPG journals * PubMed * Google Scholar * Irene Pichler Search for this author in: * NPG journals * PubMed * Google Scholar * Ozren Polasek Search for this author in: * NPG journals * PubMed * Google Scholar * Danielle Posthuma Search for this author in: * NPG journals * PubMed * Google Scholar * Simon C Potter Search for this author in: * NPG journals * PubMed * Google Scholar * Anneli Pouta Search for this author in: * NPG journals * PubMed * Google Scholar * Michael A Province Search for this author in: * NPG journals * PubMed * Google Scholar * Bruce M Psaty Search for this author in: * NPG journals * PubMed * Google Scholar * Wolfgang Rathmann Search for this author in: * NPG journals * PubMed * Google Scholar * Nigel W Rayner Search for this author in: * NPG journals * PubMed * Google Scholar * Kenneth Rice Search for this author in: * NPG journals * PubMed * Google Scholar * Samuli Ripatti Search for this author in: * NPG journals * PubMed * Google Scholar * Fernando Rivadeneira Search for this author in: * NPG journals * PubMed * Google Scholar * Michael Roden Search for this author in: * NPG journals * PubMed * Google Scholar * Olov Rolandsson Search for this author in: * NPG journals * PubMed * Google Scholar * Annelli Sandbaek Search for this author in: * NPG journals * PubMed * Google Scholar * Manjinder Sandhu Search for this author in: * NPG journals * PubMed * Google Scholar * Serena Sanna Search for this author in: * NPG journals * PubMed * Google Scholar * Avan Aihie Sayer Search for this author in: * NPG journals * PubMed * Google Scholar * Paul Scheet Search for this author in: * NPG journals * PubMed * Google Scholar * Laura J Scott Search for this author in: * NPG journals * PubMed * Google Scholar * Udo Seedorf Search for this author in: * NPG journals * PubMed * Google Scholar * Stephen J Sharp Search for this author in: * NPG journals * PubMed * Google Scholar * Beverley Shields Search for this author in: * NPG journals * PubMed * Google Scholar * Gunnar SigurÐsson Search for this author in: * NPG journals * PubMed * Google Scholar * Eric J G Sijbrands Search for this author in: * NPG journals * PubMed * Google Scholar * Angela Silveira Search for this author in: * NPG journals * PubMed * Google Scholar * Laila Simpson Search for this author in: * NPG journals * PubMed * Google Scholar * Andrew Singleton Search for this author in: * NPG journals * PubMed * Google Scholar * Nicholas L Smith Search for this author in: * NPG journals * PubMed * Google Scholar * Ulla Sovio Search for this author in: * NPG journals * PubMed * Google Scholar * Amy Swift Search for this author in: * NPG journals * PubMed * Google Scholar * Holly Syddall Search for this author in: * NPG journals * PubMed * Google Scholar * Ann-Christine Syvänen Search for this author in: * NPG journals * PubMed * Google Scholar * Toshiko Tanaka Search for this author in: * NPG journals * PubMed * Google Scholar * Barbara Thorand Search for this author in: * NPG journals * PubMed * Google Scholar * Jean Tichet Search for this author in: * NPG journals * PubMed * Google Scholar * Anke Tönjes Search for this author in: * NPG journals * PubMed * Google Scholar * Tiinamaija Tuomi Search for this author in: * NPG journals * PubMed * Google Scholar * André G Uitterlinden Search for this author in: * NPG journals * PubMed * Google Scholar * Ko Willems van Dijk Search for this author in: * NPG journals * PubMed * Google Scholar * Mandy van Hoek Search for this author in: * NPG journals * PubMed * Google Scholar * Dhiraj Varma Search for this author in: * NPG journals * PubMed * Google Scholar * Sophie Visvikis-Siest Search for this author in: * NPG journals * PubMed * Google Scholar * Veronique Vitart Search for this author in: * NPG journals * PubMed * Google Scholar * Nicole Vogelzangs Search for this author in: * NPG journals * PubMed * Google Scholar * Gérard Waeber Search for this author in: * NPG journals * PubMed * Google Scholar * Peter J Wagner Search for this author in: * NPG journals * PubMed * Google Scholar * Andrew Walley Search for this author in: * NPG journals * PubMed * Google Scholar * G Bragi Walters Search for this author in: * NPG journals * PubMed * Google Scholar * Kim L Ward Search for this author in: * NPG journals * PubMed * Google Scholar * Hugh Watkins Search for this author in: * NPG journals * PubMed * Google Scholar * Michael N Weedon Search for this author in: * NPG journals * PubMed * Google Scholar * Sarah H Wild Search for this author in: * NPG journals * PubMed * Google Scholar * Gonneke Willemsen Search for this author in: * NPG journals * PubMed * Google Scholar * Jaqueline C M Witteman Search for this author in: * NPG journals * PubMed * Google Scholar * John W G Yarnell Search for this author in: * NPG journals * PubMed * Google Scholar * Eleftheria Zeggini Search for this author in: * NPG journals * PubMed * Google Scholar * Diana Zelenika Search for this author in: * NPG journals * PubMed * Google Scholar * Björn Zethelius Search for this author in: * NPG journals * PubMed * Google Scholar * Guangju Zhai Search for this author in: * NPG journals * PubMed * Google Scholar * Jing Hua Zhao Search for this author in: * NPG journals * PubMed * Google Scholar * M Carola Zillikens Search for this author in: * NPG journals * PubMed * Google Scholar * DIAGRAM Consortium Search for this author in: * NPG journals * PubMed * Google Scholar * GIANT Consortium Search for this author in: * NPG journals * PubMed * Google Scholar * Global BPgen Consortium Search for this author in: * NPG journals * PubMed * Google Scholar * Ingrid B Borecki Search for this author in: * NPG journals * PubMed * Google Scholar * Ruth J F Loos Search for this author in: * NPG journals * PubMed * Google Scholar * Pierre Meneton Search for this author in: * NPG journals * PubMed * Google Scholar * Patrik K E Magnusson Search for this author in: * NPG journals * PubMed * Google Scholar * David M Nathan Search for this author in: * NPG journals * PubMed * Google Scholar * Gordon H Williams Search for this author in: * NPG journals * PubMed * Google Scholar * Andrew T Hattersley Search for this author in: * NPG journals * PubMed * Google Scholar * Kaisa Silander Search for this author in: * NPG journals * PubMed * Google Scholar * Veikko Salomaa Search for this author in: * NPG journals * PubMed * Google Scholar * George Davey Smith Search for this author in: * NPG journals * PubMed * Google Scholar * Stefan R Bornstein Search for this author in: * NPG journals * PubMed * Google Scholar * Peter Schwarz Search for this author in: * NPG journals * PubMed * Google Scholar * Joachim Spranger Search for this author in: * NPG journals * PubMed * Google Scholar * Fredrik Karpe Search for this author in: * NPG journals * PubMed * Google Scholar * Alan R Shuldiner Search for this author in: * NPG journals * PubMed * Google Scholar * Cyrus Cooper Search for this author in: * NPG journals * PubMed * Google Scholar * George V Dedoussis Search for this author in: * NPG journals * PubMed * Google Scholar * Manuel Serrano-Ríos Search for this author in: * NPG journals * PubMed * Google Scholar * Andrew D Morris Search for this author in: * NPG journals * PubMed * Google Scholar * Lars Lind Search for this author in: * NPG journals * PubMed * Google Scholar * Lyle J Palmer Search for this author in: * NPG journals * PubMed * Google Scholar * Frank B Hu Search for this author in: * NPG journals * PubMed * Google Scholar * Paul W Franks Search for this author in: * NPG journals * PubMed * Google Scholar * Shah Ebrahim Search for this author in: * NPG journals * PubMed * Google Scholar * Michael Marmot Search for this author in: * NPG journals * PubMed * Google Scholar * W H Linda Kao Search for this author in: * NPG journals * PubMed * Google Scholar * James S Pankow Search for this author in: * NPG journals * PubMed * Google Scholar * Michael J Sampson Search for this author in: * NPG journals * PubMed * Google Scholar * Johanna Kuusisto Search for this author in: * NPG journals * PubMed * Google Scholar * Markku Laakso Search for this author in: * NPG journals * PubMed * Google Scholar * Torben Hansen Search for this author in: * NPG journals * PubMed * Google Scholar * Oluf Pedersen Search for this author in: * NPG journals * PubMed * Google Scholar * Peter Paul Pramstaller Search for this author in: * NPG journals * PubMed * Google Scholar * H Erich Wichmann Search for this author in: * NPG journals * PubMed * Google Scholar * Thomas Illig Search for this author in: * NPG journals * PubMed * Google Scholar * Igor Rudan Search for this author in: * NPG journals * PubMed * Google Scholar * Alan F Wright Search for this author in: * NPG journals * PubMed * Google Scholar * Michael Stumvoll Search for this author in: * NPG journals * PubMed * Google Scholar * Harry Campbell Search for this author in: * NPG journals * PubMed * Google Scholar * James F Wilson Search for this author in: * NPG journals * PubMed * Google Scholar * Anders Hamsten Search for this author in: * NPG journals * PubMed * Google Scholar * Richard N Bergman Search for this author in: * NPG journals * PubMed * Google Scholar * Thomas A Buchanan Search for this author in: * NPG journals * PubMed * Google Scholar * Francis S Collins Search for this author in: * NPG journals * PubMed * Google Scholar * Karen L Mohlke Search for this author in: * NPG journals * PubMed * Google Scholar * Jaakko Tuomilehto Search for this author in: * NPG journals * PubMed * Google Scholar * Timo T Valle Search for this author in: * NPG journals * PubMed * Google Scholar * David Altshuler Search for this author in: * NPG journals * PubMed * Google Scholar * Jerome I Rotter Search for this author in: * NPG journals * PubMed * Google Scholar * David S Siscovick Search for this author in: * NPG journals * PubMed * Google Scholar * Brenda W J H Penninx Search for this author in: * NPG journals * PubMed * Google Scholar * Dorret I Boomsma Search for this author in: * NPG journals * PubMed * Google Scholar * Panos Deloukas Search for this author in: * NPG journals * PubMed * Google Scholar * Timothy D Spector Search for this author in: * NPG journals * PubMed * Google Scholar * Timothy M Frayling Search for this author in: * NPG journals * PubMed * Google Scholar * Luigi Ferrucci Search for this author in: * NPG journals * PubMed * Google Scholar * Augustine Kong Search for this author in: * NPG journals * PubMed * Google Scholar * Unnur Thorsteinsdottir Search for this author in: * NPG journals * PubMed * Google Scholar * Kari Stefansson Search for this author in: * NPG journals * PubMed * Google Scholar * Cornelia M van Duijn Search for this author in: * NPG journals * PubMed * Google Scholar * Yurii S Aulchenko Search for this author in: * NPG journals * PubMed * Google Scholar * Antonio Cao Search for this author in: * NPG journals * PubMed * Google Scholar * Angelo Scuteri Search for this author in: * NPG journals * PubMed * Google Scholar * David Schlessinger Search for this author in: * NPG journals * PubMed * Google Scholar * Manuela Uda Search for this author in: * NPG journals * PubMed * Google Scholar * Aimo Ruokonen Search for this author in: * NPG journals * PubMed * Google Scholar * Marjo-Riitta Jarvelin Search for this author in: * NPG journals * PubMed * Google Scholar * Dawn M Waterworth Search for this author in: * NPG journals * PubMed * Google Scholar * Peter Vollenweider Search for this author in: * NPG journals * PubMed * Google Scholar * Leena Peltonen Search for this author in: * NPG journals * PubMed * Google Scholar * Vincent Mooser Search for this author in: * NPG journals * PubMed * Google Scholar * Goncalo R Abecasis Search for this author in: * NPG journals * PubMed * Google Scholar * Nicholas J Wareham Search for this author in: * NPG journals * PubMed * Google Scholar * Robert Sladek Search for this author in: * NPG journals * PubMed * Google Scholar * Philippe Froguel Search for this author in: * NPG journals * PubMed * Google Scholar * Richard M Watanabe Search for this author in: * NPG journals * PubMed * Google Scholar * James B Meigs Search for this author in: * NPG journals * PubMed * Google Scholar * Leif Groop Search for this author in: * NPG journals * PubMed * Google Scholar * Michael Boehnke Search for this author in: * NPG journals * PubMed * Google Scholar * Mark I McCarthy Search for this author in: * NPG journals * PubMed * Google Scholar * Jose C Florez Search for this author in: * NPG journals * PubMed * Google Scholar * Inês Barroso Search for this author in: * NPG journals * PubMed * Google ScholarJournal name:Nature GeneticsVolume:42,Page:464Year published:(2010)DOI:doi:10.1038/ng0510-464a Article tools * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Nat. Genet.42, 105–116 (2010); published online 17 January 2010; corrected after print 26 March 2010 In the version of this article initially published, there were several errors in the author affiliations. These errors have been corrected in the HTML and PDF versions of the article. Additional data
• Corrigendum: A TARBP2 mutation in human cancer impairs microRNA processing and DICER1 function
  - Nature Genetics 42(5):464 (2010)
  Nature Genetics | Corrigendum Corrigendum: A TARBP2 mutation in human cancer impairs microRNA processing and DICER1 function * Sonia A Melo Search for this author in: * NPG journals * PubMed * Google Scholar * Santiago Ropero Search for this author in: * NPG journals * PubMed * Google Scholar * Catia Moutinho Search for this author in: * NPG journals * PubMed * Google Scholar * Lauri A Aaltonen Search for this author in: * NPG journals * PubMed * Google Scholar * Hiroyuki Yamamoto Search for this author in: * NPG journals * PubMed * Google Scholar * George A Calin Search for this author in: * NPG journals * PubMed * Google Scholar * Simona Rossi Search for this author in: * NPG journals * PubMed * Google Scholar * Agustin F Fernandez Search for this author in: * NPG journals * PubMed * Google Scholar * Fatima Carneiro Search for this author in: * NPG journals * PubMed * Google Scholar * Carla Oliveira Search for this author in: * NPG journals * PubMed * Google Scholar * Bibiana Ferreira Search for this author in: * NPG journals * PubMed * Google Scholar * Chang-Gong Liu Search for this author in: * NPG journals * PubMed * Google Scholar * Alberto Villanueva Search for this author in: * NPG journals * PubMed * Google Scholar * Gabriel Capella Search for this author in: * NPG journals * PubMed * Google Scholar * Simo Schwartz Jr Search for this author in: * NPG journals * PubMed * Google Scholar * Ramin Shiekhattar Search for this author in: * NPG journals * PubMed * Google Scholar * Manel Esteller Search for this author in: * NPG journals * PubMed * Google ScholarJournal name:Nature GeneticsVolume:42,Page:464Year published:(2010)DOI:doi:10.1038/ng0510-464b Article tools * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Nat. Genet.41, 365–370 (2009); published online 15 February 2009; corrected after print 9 April 2010 In the version of this article initially published, the colony formation assay image labeled "Co115.DICER1" was the incorrect image. The error has been corrected and a corrected version of Figure 4 panel e is provided in the HTML and PDF versions of the article. Additional data
• Corrigendum: Multiple common variants for celiac disease influencing immune gene expression
  - Nature Genetics 42(5):465 (2010)
  Nature Genetics | Corrigendum Corrigendum: Multiple common variants for celiac disease influencing immune gene expression * Patrick C A Dubois Search for this author in: * NPG journals * PubMed * Google Scholar * Gosia Trynka Search for this author in: * NPG journals * PubMed * Google Scholar * Lude Franke Search for this author in: * NPG journals * PubMed * Google Scholar * Karen A Hunt Search for this author in: * NPG journals * PubMed * Google Scholar * Jihane Romanos Search for this author in: * NPG journals * PubMed * Google Scholar * Alessandra Curtotti Search for this author in: * NPG journals * PubMed * Google Scholar * Alexandra Zhernakova Search for this author in: * NPG journals * PubMed * Google Scholar * Graham A R Heap Search for this author in: * NPG journals * PubMed * Google Scholar * Róza Ádány Search for this author in: * NPG journals * PubMed * Google Scholar * Arpo Aromaa Search for this author in: * NPG journals * PubMed * Google Scholar * Maria Teresa Bardella Search for this author in: * NPG journals * PubMed * Google Scholar * Leonard H van den Berg Search for this author in: * NPG journals * PubMed * Google Scholar * Nicholas A Bockett Search for this author in: * NPG journals * PubMed * Google Scholar * Emilio G de la Concha Search for this author in: * NPG journals * PubMed * Google Scholar * Bárbara Dema Search for this author in: * NPG journals * PubMed * Google Scholar * Rudolf S N Fehrmann Search for this author in: * NPG journals * PubMed * Google Scholar * Miguel Fernández-Arquero Search for this author in: * NPG journals * PubMed * Google Scholar * Szilvia Fiatal Search for this author in: * NPG journals * PubMed * Google Scholar * Elvira Grandone Search for this author in: * NPG journals * PubMed * Google Scholar * Peter M Green Search for this author in: * NPG journals * PubMed * Google Scholar * Harry J M Groen Search for this author in: * NPG journals * PubMed * Google Scholar * Rhian Gwilliam Search for this author in: * NPG journals * PubMed * Google Scholar * Roderick H J Houwen Search for this author in: * NPG journals * PubMed * Google Scholar * Sarah E Hunt Search for this author in: * NPG journals * PubMed * Google Scholar * Katri Kaukinen Search for this author in: * NPG journals * PubMed * Google Scholar * Dermot Kelleher Search for this author in: * NPG journals * PubMed * Google Scholar * Ilma Korponay-Szabo Search for this author in: * NPG journals * PubMed * Google Scholar * Kalle Kurppa Search for this author in: * NPG journals * PubMed * Google Scholar * Padraic MacMathuna Search for this author in: * NPG journals * PubMed * Google Scholar * Markku Mäki Search for this author in: * NPG journals * PubMed * Google Scholar * Maria Cristina Mazzilli Search for this author in: * NPG journals * PubMed * Google Scholar * Owen T McCann Search for this author in: * NPG journals * PubMed * Google Scholar * M Luisa Mearin Search for this author in: * NPG journals * PubMed * Google Scholar * Charles A Mein Search for this author in: * NPG journals * PubMed * Google Scholar * Muddassar M Mirza Search for this author in: * NPG journals * PubMed * Google Scholar * Vanisha Mistry Search for this author in: * NPG journals * PubMed * Google Scholar * Barbara Mora Search for this author in: * NPG journals * PubMed * Google Scholar * Katherine I Morley Search for this author in: * NPG journals * PubMed * Google Scholar * Chris J Mulder Search for this author in: * NPG journals * PubMed * Google Scholar * Joseph A Murray Search for this author in: * NPG journals * PubMed * Google Scholar * Concepción Núñez Search for this author in: * NPG journals * PubMed * Google Scholar * Elvira Oosterom Search for this author in: * NPG journals * PubMed * Google Scholar * Roel A Ophoff Search for this author in: * NPG journals * PubMed * Google Scholar * Isabel Polanco Search for this author in: * NPG journals * PubMed * Google Scholar * Leena Peltonen Search for this author in: * NPG journals * PubMed * Google Scholar * Mathieu Platteel Search for this author in: * NPG journals * PubMed * Google Scholar * Anna Rybak Search for this author in: * NPG journals * PubMed * Google Scholar * Veikko Salomaa Search for this author in: * NPG journals * PubMed * Google Scholar * Joachim J Schweizer Search for this author in: * NPG journals * PubMed * Google Scholar * Maria Pia Sperandeo Search for this author in: * NPG journals * PubMed * Google Scholar * Greetje J Tack Search for this author in: * NPG journals * PubMed * Google Scholar * Graham Turner Search for this author in: * NPG journals * PubMed * Google Scholar * Jan H Veldink Search for this author in: * NPG journals * PubMed * Google Scholar * Wieke H M Verbeek Search for this author in: * NPG journals * PubMed * Google Scholar * Rinse K Weersma Search for this author in: * NPG journals * PubMed * Google Scholar * Victorien M Wolters Search for this author in: * NPG journals * PubMed * Google Scholar * Elena Urcelay Search for this author in: * NPG journals * PubMed * Google Scholar * Bozena Cukrowska Search for this author in: * NPG journals * PubMed * Google Scholar * Luigi Greco Search for this author in: * NPG journals * PubMed * Google Scholar * Susan L Neuhausen Search for this author in: * NPG journals * PubMed * Google Scholar * Ross McManus Search for this author in: * NPG journals * PubMed * Google Scholar * Donatella Barisani Search for this author in: * NPG journals * PubMed * Google Scholar * Panos Deloukas Search for this author in: * NPG journals * PubMed * Google Scholar * Jeffrey C Barrett Search for this author in: * NPG journals * PubMed * Google Scholar * Paivi Saavalainen Search for this author in: * NPG journals * PubMed * Google Scholar * Cisca Wijmenga Search for this author in: * NPG journals * PubMed * Google Scholar * David A van Heel Search for this author in: * NPG journals * PubMed * Google ScholarJournal name:Nature GeneticsVolume:42,Page:465Year published:(2010)DOI:doi:10.1038/ng0510-465 Article tools * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Nat. Genet.; doi:10.1038/ng.543; corrected online 12 March 2010 In the version of this article initially published online, the P value ranges in the second paragraph of the Results section under (iii) and (iv) were noted incorrectly. These errors have been corrected for the print, PDF and HTML versions of this article. Additional data