Latest Articles Include:
- On the table
- Nat Genet 43(1):1 (2011)
Nature Genetics | Editorial On the table Journal name:Nature GeneticsVolume: 43,Page:1Year published:(2011)DOI:doi:10.1038/ng0111-1Published online28 December 2010 Data tables are a central element of most scientific papers. Simplified tables with separation of data storage from presentation format are ways to increase the impact and use of research data. View full text Additional data - Replication of association of 3p21.1 with susceptibility to bipolar disorder but not major depression
- Nat Genet 43(1):3-5 (2011)
Nature Genetics | Correspondence Replication of association of 3p21.1 with susceptibility to bipolar disorder but not major depression * Gerome Breen1, 2 Contact Gerome Breen Search for this author in: * NPG journals * PubMed * Google Scholar * Cathryn M Lewis1, 3 Search for this author in: * NPG journals * PubMed * Google Scholar * Evangelos Vassos1 Search for this author in: * NPG journals * PubMed * Google Scholar * Michele L Pergadia4 Search for this author in: * NPG journals * PubMed * Google Scholar * Douglas H R Blackwood5 Search for this author in: * NPG journals * PubMed * Google Scholar * Dorret I Boomsma6 Search for this author in: * NPG journals * PubMed * Google Scholar * Brenda Penninx7 Search for this author in: * NPG journals * PubMed * Google Scholar * Patrick F Sullivan8 Search for this author in: * NPG journals * PubMed * Google Scholar * Inti Pedroso1, 2 Search for this author in: * NPG journals * PubMed * Google Scholar * David Collier1 Search for this author in: * NPG journals * PubMed * Google Scholar * Peter McGuffin1, 2 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorJournal name:Nature GeneticsVolume: 43,Pages:3–5Year published:(2011)DOI:doi:10.1038/ng0111-3Published online28 December 2010 Read the full article * Instant access to this article: US$18Buy now * Subscribe to Nature Genetics for full access: SubscribeLogin for existing subscribers Additional access options: * Use a document delivery service * Login via Athens * Purchase a site license * Institutional access * British Library Document Supply Centre * Infotrieve * Thompson ISI Document Delivery * You can also request this document from your local library through inter-library loan services. To the Editor: McMahon and colleagues1 recently reported a genome-wide significant association of rs2251219 on chromosome 3p21.1 with mood disorders in a combined sample of individuals with bipolar affective disorder (BP, also known as 'manic depression') and individuals with major depressive disorder (MDD). They meta-analyzed published data from four genome-wide association studies (GWAS) of BP2, 3, 4, 5 and three published GWAS of MDD6, 7, plus an unpublished German BP sample. Their analysis supports the suggestive association with bipolar disorder in this region previously reported by Scott et al.3 in a GWAS meta-analysis of three of the same BP samples (National Institute of Mental Health-BP4, Wellcome Trust Case Control Consortium2 and the GlaxoSmithKline-BP samples3), but we report here alternative analyses and new data inconsistent with an association in this region with MDD. Thus, rs2251219 appears to be a susceptibility locus for BP alone, and the data do not support a general ass! ociation of this SNP with mood disorders. View full text Author information Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Affiliations * Medical Research Council Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, London, UK. * Gerome Breen, * Cathryn M Lewis, * Evangelos Vassos, * Inti Pedroso, * David Collier & * Peter McGuffin * National Institute for Health Research Biomedical Research Centre, South London and Maudsley National Health Service Trust and Institute of Psychiatry, King's College London, London, UK. * Gerome Breen, * Inti Pedroso & * Peter McGuffin * Medical and Molecular Genetics, King's College London, London, UK. * Cathryn M Lewis * Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, USA. * Michele L Pergadia * Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Edinburg, UK. * Douglas H R Blackwood * Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands. * Dorret I Boomsma * Department of Psychiatry, Vrije University Amsterdam, Amsterdam, The Netherlands. * Brenda Penninx * Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA. * Patrick F Sullivan Contributions G.B., C.M.L., I.P. and E.V. performed the data analysis. G.B., D.C. and P.M. wrote the manuscript. M.L.P., D.H.R.B., B.P., D.I.B. and P.F.S. provided additional replication data and comments. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Gerome Breen Read the full article * Instant access to this article: US$18Buy now * Subscribe to Nature Genetics for full access: SubscribeLogin for existing subscribers Additional access options: * Use a document delivery service * Login via Athens * Purchase a site license * Institutional access * British Library Document Supply Centre * Infotrieve * Thompson ISI Document Delivery * You can also request this document from your local library through inter-library loan services. Additional data - Reply to "Replication of association of 3p21.1 with susceptibility to bipolar disorder but not major depression"
- Nat Genet 43(1):5 (2011)
Nature Genetics | Correspondence Reply to "Replication of association of 3p21.1 with susceptibility to bipolar disorder but not major depression" * Francis J McMahon1 Contact Francis J McMahon Search for this author in: * NPG journals * PubMed * Google Scholar * Nirmala Akula1 Search for this author in: * NPG journals * PubMed * Google Scholar * Sven Cichon2, 3 Search for this author in: * NPG journals * PubMed * Google Scholar * Sevilla D Detera-Wadleigh1 Search for this author in: * NPG journals * PubMed * Google Scholar * Howard Edenberg4 Search for this author in: * NPG journals * PubMed * Google Scholar * Florian Holsboer5 Search for this author in: * NPG journals * PubMed * Google Scholar * Markus M Nöthen2, 3 Search for this author in: * NPG journals * PubMed * Google Scholar * John I Nurnberger4 Search for this author in: * NPG journals * PubMed * Google Scholar * James Potash6 Search for this author in: * NPG journals * PubMed * Google Scholar * Martin Preisig7 Search for this author in: * NPG journals * PubMed * Google Scholar * Marcella Rietschel8 Search for this author in: * NPG journals * PubMed * Google Scholar * Thomas G Schulze1, 8, 9 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Corresponding authorJournal name:Nature GeneticsVolume: 43,Page:5Year published:(2011)DOI:doi:10.1038/ng0111-5Published online28 December 2010 Read the full article * Instant access to this article: US$18Buy now * Subscribe to Nature Genetics for full access: SubscribeLogin for existing subscribers Additional access options: * Use a document delivery service * Login via Athens * Purchase a site license * Institutional access * British Library Document Supply Centre * Infotrieve * Thompson ISI Document Delivery * You can also request this document from your local library through inter-library loan services. McMahon et al. reply: Breen et al. report that their re-analysis of our published data1 supports association of rs2251219 with bipolar disorder (BP) at the P < 10−8 level. However, in the independent samples they examined, this SNP did not show much evidence of association with major depressive disorder (MDD). View full text Author information Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Affiliations * Genetic Basis of Mood and Anxiety Disorders Section, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, USA. * Francis J McMahon, * Nirmala Akula, * Sevilla D Detera-Wadleigh & * Thomas G Schulze * Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany. * Sven Cichon & * Markus M Nöthen * Institute of Human Genetics, University of Bonn, Bonn, Germany. * Sven Cichon & * Markus M Nöthen * Indiana University-Purdue University, Indianapolis, Indiana, USA. * Howard Edenberg & * John I Nurnberger * Max-Planck Institute of Psychiatry, Munich, Germany. * Florian Holsboer * Department of Psychiatry, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. * James Potash * University Hospital Center and University of Lausanne, Department of Psychiatry, Lausanne, Switzerland. * Martin Preisig * Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Mannheim, Germany. * Marcella Rietschel & * Thomas G Schulze * Department of Psychiatry and Psychotherapy, University of Goettingen, Goettingen, Germany. * Thomas G Schulze Corresponding author Correspondence to: * Francis J McMahon Read the full article * Instant access to this article: US$18Buy now * Subscribe to Nature Genetics for full access: SubscribeLogin for existing subscribers Additional access options: * Use a document delivery service * Login via Athens * Purchase a site license * Institutional access * British Library Document Supply Centre * Infotrieve * Thompson ISI Document Delivery * You can also request this document from your local library through inter-library loan services. Additional data - Barton Childs 1916–2010
- Nat Genet 43(1):7 (2011)
Nature Genetics | Obituary Barton Childs 1916–2010 * Barbara R Migeon1 Contact Barbara R Migeon Search for this author in: * NPG journals * PubMed * Google ScholarJournal name:Nature GeneticsVolume: 43,Page:7Year published:(2011)DOI:doi:10.1038/ng0111-7Published online28 December 2010 Read the full article * Instant access to this article: US$32Buy now * Subscribe to Nature Genetics for full access: SubscribeLogin for existing subscribers Additional access options: * Use a document delivery service * Login via Athens * Purchase a site license * Institutional access * British Library Document Supply Centre * Infotrieve * Thompson ISI Document Delivery * You can also request this document from your local library through inter-library loan services. Barton Childs, who defined the field of genetic medicine and provided the best rationale for its existence, died on February 23, 2010, just short of his 94th birthday. Until then, he continued to promote the application of genetics to the practice of medicine to all who might listen. A graduate of Williams College, Barton received his medical degree from Johns Hopkins School of Medicine, which also provided his training in pediatrics. The recipient of many honors, he was highly respected as a visionary geneticist. View full text Read the full article * Instant access to this article: US$32Buy now * Subscribe to Nature Genetics for full access: SubscribeLogin for existing subscribers Additional access options: * Use a document delivery service * Login via Athens * Purchase a site license * Institutional access * British Library Document Supply Centre * Infotrieve * Thompson ISI Document Delivery * You can also request this document from your local library through inter-library loan services. Additional data Affiliations * Barbara R. Migeon is at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, Maryland, USA. Corresponding author Correspondence to: * Barbara R Migeon - Sox9 marks adult organ progenitors
- Nat Genet 43(1):9-10 (2011)
Nature Genetics | News and Views Sox9 marks adult organ progenitors * Meritxell Huch1 Search for this author in: * NPG journals * PubMed * Google Scholar * Hans Clevers1 Contact Hans Clevers Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Corresponding authorJournal name:Nature GeneticsVolume: 43,Pages:9–10Year published:(2011)DOI:doi:10.1038/ng0111-9Published online28 December 2010 Read the full article * Instant access to this article: US$18Buy now * Subscribe to Nature Genetics for full access: SubscribeLogin for existing subscribers Additional access options: * Use a document delivery service * Login via Athens * Purchase a site license * Institutional access * British Library Document Supply Centre * Infotrieve * Thompson ISI Document Delivery * You can also request this document from your local library through inter-library loan services. Adult stem cells play pivotal roles in self-renewing tissues but also in the post-injury repair of adult organs that normally show little proliferative activity. A new study shows that Sox9 marks a putative adult stem cell population that contributes to the self-renewal and repair of the liver, exocrine pancreas and intestine, three organs of endodermal origin. View full text Author information Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Affiliations * Meritxell Huch and Hans Clevers are at the Hubrecht Institute and the University Medical Centre, Utrecht, The Netherlands. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Hans Clevers Read the full article * Instant access to this article: US$18Buy now * Subscribe to Nature Genetics for full access: SubscribeLogin for existing subscribers Additional access options: * Use a document delivery service * Login via Athens * Purchase a site license * Institutional access * British Library Document Supply Centre * Infotrieve * Thompson ISI Document Delivery * You can also request this document from your local library through inter-library loan services. Additional data - Coiled-coils and motile cilia
- Nat Genet 43(1):10-11 (2011)
Nature Genetics | News and Views Coiled-coils and motile cilia * Peter Satir1 Contact Peter Satir Search for this author in: * NPG journals * PubMed * Google ScholarJournal name:Nature GeneticsVolume: 43,Pages:10–11Year published:(2011)DOI:doi:10.1038/ng0111-10Published online28 December 2010 Read the full article * Instant access to this article: US$18Buy now * Subscribe to Nature Genetics for full access: SubscribeLogin for existing subscribers Additional access options: * Use a document delivery service * Login via Athens * Purchase a site license * Institutional access * British Library Document Supply Centre * Infotrieve * Thompson ISI Document Delivery * You can also request this document from your local library through inter-library loan services. Genetic mapping studies in dogs, mice, zebrafish and humans have identified two new genes required for the assembly of motile cilia. The resulting gene products, CCDC39 and CCDC40, may represent previously unidentified components of the dynein regulatory complex. View full text Author information Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Affiliations * Peter Satir is in the Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, New York, New York, USA. Competing financial interests The author declares no competing financial interests. Corresponding author Correspondence to: * Peter Satir Read the full article * Instant access to this article: US$18Buy now * Subscribe to Nature Genetics for full access: SubscribeLogin for existing subscribers Additional access options: * Use a document delivery service * Login via Athens * Purchase a site license * Institutional access * British Library Document Supply Centre * Infotrieve * Thompson ISI Document Delivery * You can also request this document from your local library through inter-library loan services. Additional data - Determination of transcription factor binding
- Nat Genet 43(1):11-12 (2011)
Nature Genetics | News and Views Determination of transcription factor binding * Edwin Cheung1 Search for this author in: * NPG journals * PubMed * Google Scholar * Yijun Ruan1 Contact Yijun Ruan Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Corresponding authorJournal name:Nature GeneticsVolume: 43,Pages:11–12Year published:(2011)DOI:doi:10.1038/ng0111-11Published online28 December 2010 Read the full article * Instant access to this article: US$18Buy now * Subscribe to Nature Genetics for full access: SubscribeLogin for existing subscribers Additional access options: * Use a document delivery service * Login via Athens * Purchase a site license * Institutional access * British Library Document Supply Centre * Infotrieve * Thompson ISI Document Delivery * You can also request this document from your local library through inter-library loan services. To understand transcriptional regulation, it is necessary to understand the factors that determine where a particular transcription factor binds in the genome. A new study demonstrates that a single protein, FoxA1, can dictate the global DNA binding profile and the transcriptional function of estrogen receptor a in breast cancer cells and in other cell types. View full text Author information Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Affiliations * Edwin Cheung and Yijun Ruan are at the Genome Institute of Singapore, Singapore. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Yijun Ruan Read the full article * Instant access to this article: US$18Buy now * Subscribe to Nature Genetics for full access: SubscribeLogin for existing subscribers Additional access options: * Use a document delivery service * Login via Athens * Purchase a site license * Institutional access * British Library Document Supply Centre * Infotrieve * Thompson ISI Document Delivery * You can also request this document from your local library through inter-library loan services. Additional data - Research highlights
- Nat Genet 43(1):15 (2011)
Nature Genetics | Research Highlights Research highlights Journal name:Nature GeneticsVolume: 43,Page:15Year published:(2011)DOI:doi:10.1038/ng0111-15Published online28 December 2010 Read the full article * Instant access to this article: US$32Buy now * Subscribe to Nature Genetics for full access: SubscribeLogin for existing subscribers Additional access options: * Use a document delivery service * Login via Athens * Purchase a site license * Institutional access * British Library Document Supply Centre * Infotrieve * Thompson ISI Document Delivery * You can also request this document from your local library through inter-library loan services. Plastic tunicate genome The larvacean tunicate Oikopleura dioica lives in the open sea and displays chordate morphology. Daniel Chourrout, Patrick Wincker and colleagues now report sequencing of its 70 Mb genome (Science330, 1381–1385, 2010). Compared to other metazoans, Oikopleura shows fast rates of protein evolution, which may be related to the absence of DNA repair proteins in its genome and the mutagenic environment of the ocean surface. Approximately 18,000 genes are predicted in the compact Oikopleura genome. Introns and intergenic regions are small, and transposable elements are relatively infrequent. Interestingly, a subset of genes enriched for developmental transcription factors display longer introns and intergenic regions, suggesting that compaction is harmful in this genomic context. Analysis of 5,589 introns showed that 76% had positions unique to Oikopleura compared to other species. The authors provide some evidence that reverse splicing, the mechanism by which introns that have ! been spliced out are ectopically reinserted into transcripts, may have contributed to this large percentage of recently gained introns. Low levels of chromosomal synteny were seen between Oikopleura and other invertebrates, and local gene order in Oikopleura is indistinguishable from random gene order. The authors suggest that conservation of genome architecture is not required for the conservation of ancestral morphologies. PC Sirt6, growth and obesity In yeast, SIR2 is required for lifespan extension caused by caloric restriction. The sirtuin family of proteins has also been associated with metabolic regulation and stress tolerance, although it is not clear whether sirtuins act as longevity factors in mammals. Frederick Alt and colleagues now report that mice that specifically lack Sirt6 in the brain (BS6ko) display postnatal growth retardation and obesity (Proc. Natl. Acad. Sci. USA, published online, doi:10.1073/pnas.1016306107, 22 November 2010). BS6ko mice were significantly smaller than wildtype littermates at 4 weeks of age, although by 6–7 weeks of age, they were not distinguishable from wildtype mice. Pituitaries from BS6ko mice appeared to have a growth hormone (GH) deficiency despite normal levels of growth hormone–releasing hormone (GHRH) and somatotropin release–inhibiting hormone (SRIH) transcript levels. BS6ko mice displayed increased adiposity by 6–8 months of age, likely through lower levels of GH ! and hypothalamic neuropeptides. Sirt6 is known to deacetylate the two chromatin marks H3K9 and H3K56. BS6ko mice display H3K9 hyperacetylation in the hippocampus and hypothalamus and H3K57 hyperacetylation in the hypothalamus, cortex, hippocampus and cerebellum. This study shows a role for Sirt6 in somatic growth and adult-onset obesity in mouse. PC View full text Read the full article * Instant access to this article: US$32Buy now * Subscribe to Nature Genetics for full access: SubscribeLogin for existing subscribers Additional access options: * Use a document delivery service * Login via Athens * Purchase a site license * Institutional access * British Library Document Supply Centre * Infotrieve * Thompson ISI Document Delivery * You can also request this document from your local library through inter-library loan services. Additional data - Genome-wide association analysis in primary sclerosing cholangitis identifies two non-HLA susceptibility loci
- Nat Genet 43(1):17-19 (2011)
Nature Genetics | Brief Communication Genome-wide association analysis in primary sclerosing cholangitis identifies two non-HLA susceptibility loci * Espen Melum1, 2, 27 Search for this author in: * NPG journals * PubMed * Google Scholar * Andre Franke3, 27 Search for this author in: * NPG journals * PubMed * Google Scholar * Christoph Schramm4 Search for this author in: * NPG journals * PubMed * Google Scholar * Tobias J Weismüller5, 6 Search for this author in: * NPG journals * PubMed * Google Scholar * Daniel Nils Gotthardt7 Search for this author in: * NPG journals * PubMed * Google Scholar * Felix A Offner8 Search for this author in: * NPG journals * PubMed * Google Scholar * Brian D Juran9 Search for this author in: * NPG journals * PubMed * Google Scholar * Jon K Laerdahl10 Search for this author in: * NPG journals * PubMed * Google Scholar * Verena Labi11 Search for this author in: * NPG journals * PubMed * Google Scholar * Einar Björnsson12 Search for this author in: * NPG journals * PubMed * Google Scholar * Rinse K Weersma13 Search for this author in: * NPG journals * PubMed * Google Scholar * Liesbet Henckaerts14 Search for this author in: * NPG journals * PubMed * Google Scholar * Andreas Teufel15 Search for this author in: * NPG journals * PubMed * Google Scholar * Christian Rust16 Search for this author in: * NPG journals * PubMed * Google Scholar * Eva Ellinghaus3 Search for this author in: * NPG journals * PubMed * Google Scholar * Tobias Balschun3 Search for this author in: * NPG journals * PubMed * Google Scholar * Kirsten Muri Boberg1 Search for this author in: * NPG journals * PubMed * Google Scholar * David Ellinghaus3 Search for this author in: * NPG journals * PubMed * Google Scholar * Annika Bergquist17 Search for this author in: * NPG journals * PubMed * Google Scholar * Peter Sauer7 Search for this author in: * NPG journals * PubMed * Google Scholar * Euijung Ryu18 Search for this author in: * NPG journals * PubMed * Google Scholar * Johannes Roksund Hov1, 2 Search for this author in: * NPG journals * PubMed * Google Scholar * Jochen Wedemeyer5, 6 Search for this author in: * NPG journals * PubMed * Google Scholar * Björn Lindkvist12 Search for this author in: * NPG journals * PubMed * Google Scholar * Michael Wittig3 Search for this author in: * NPG journals * PubMed * Google Scholar * Robert J Porte19 Search for this author in: * NPG journals * PubMed * Google Scholar * Kristian Holm1 Search for this author in: * NPG journals * PubMed * Google Scholar * Christian Gieger20 Search for this author in: * NPG journals * PubMed * Google Scholar * H-Erich Wichmann20, 21, 22 Search for this author in: * NPG journals * PubMed * Google Scholar * Pieter Stokkers23 Search for this author in: * NPG journals * PubMed * Google Scholar * Cyriel Y Ponsioen23 Search for this author in: * NPG journals * PubMed * Google Scholar * Heiko Runz24 Search for this author in: * NPG journals * PubMed * Google Scholar * Adolf Stiehl7 Search for this author in: * NPG journals * PubMed * Google Scholar * Cisca Wijmenga25 Search for this author in: * NPG journals * PubMed * Google Scholar * Martina Sterneck4 Search for this author in: * NPG journals * PubMed * Google Scholar * Severine Vermeire14 Search for this author in: * NPG journals * PubMed * Google Scholar * Ulrich Beuers23 Search for this author in: * NPG journals * PubMed * Google Scholar * Andreas Villunger11 Search for this author in: * NPG journals * PubMed * Google Scholar * Erik Schrumpf1 Search for this author in: * NPG journals * PubMed * Google Scholar * Konstantinos N Lazaridis9 Search for this author in: * NPG journals * PubMed * Google Scholar * Michael P Manns5, 6 Search for this author in: * NPG journals * PubMed * Google Scholar * Stefan Schreiber3, 26, 28 Search for this author in: * NPG journals * PubMed * Google Scholar * Tom H Karlsen1, 28 Contact Tom H Karlsen Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorJournal name:Nature GeneticsVolume: 43,Pages:17–19Year published:(2011)DOI:doi:10.1038/ng.728Received20 June 2010Accepted16 November 2010Published online12 December 2010 Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Primary sclerosing cholangitis (PSC) is a chronic bile duct disease affecting 2.4–7.5% of individuals with inflammatory bowel disease. We performed a genome-wide association analysis of 2,466,182 SNPs in 715 individuals with PSC and 2,962 controls, followed by replication in 1,025 PSC cases and 2,174 controls. We detected non-HLA associations at rs3197999 in MST1 and rs6720394 near BCL2L11 (combined P = 1.1 × 10−16 and P = 4.1 × 10−8, respectively). View full text Author information * Author information * Supplementary information Primary authors * These authors contributed equally to this work. * Espen Melum & * Andre Franke Affiliations * Norwegian PSC Research Center, Clinic for Specialized Medicine and Surgery, Oslo University Hospital, Rikshospitalet, Oslo, Norway. * Espen Melum, * Kirsten Muri Boberg, * Johannes Roksund Hov, * Kristian Holm, * Erik Schrumpf & * Tom H Karlsen * Research Institute for Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway. * Espen Melum & * Johannes Roksund Hov * Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany. * Andre Franke, * Eva Ellinghaus, * Tobias Balschun, * David Ellinghaus, * Michael Wittig & * Stefan Schreiber * 1st Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. * Christoph Schramm & * Martina Sterneck * Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany. * Tobias J Weismüller, * Jochen Wedemeyer & * Michael P Manns * Integrated Research and Treatment Center-Transplantation (IFB-Tx), Hannover Medical School, Hannover, Germany. * Tobias J Weismüller, * Jochen Wedemeyer & * Michael P Manns * Department of Medicine, University Hospital of Heidelberg, Heidelberg, Germany. * Daniel Nils Gotthardt, * Peter Sauer & * Adolf Stiehl * Academic Teaching Hospital Feldkirch, Feldkirch, Austria. * Felix A Offner * Center for Basic Research in Digestive Diseases, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA. * Brian D Juran & * Konstantinos N Lazaridis * Centre for Molecular Biology and Neuroscience (CMBN) and Institute of Medical Microbiology, Oslo University Hospital, Rikshospitalet, Oslo, Norway. * Jon K Laerdahl * Division of Developmental Immunology, Biocenter, Innsbruck Medical University, Innsbruck, Austria. * Verena Labi & * Andreas Villunger * Section of Gastroenterology and Hepatology, Department of Internal Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden. * Einar Björnsson & * Björn Lindkvist * Department of Gastroenterology and Hepatology, University Medical Center Groningen and University of Groningen, Groningen, The Netherlands. * Rinse K Weersma * Department of Gastroenterology, University Hospital Gasthuisberg, Leuven, Belgium. * Liesbet Henckaerts & * Severine Vermeire * 1st Department of Medicine, University of Mainz, Mainz, Germany. * Andreas Teufel * Department of Medicine 2, Grosshadern, University of Munich, Munich, Germany. * Christian Rust * Department of Gastroenterology and Hepatology, Karolinska University Hospital Huddinge, Stockholm, Sweden. * Annika Bergquist * Division of Biomedical Statistics and Informatics, Mayo Clinic College of Medicine, Rochester, Minnesota, USA. * Euijung Ryu * Hepatobiliary Surgery and Liver Transplantation, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. * Robert J Porte * Institute of Epidemiology, Helmholtz Centre Munich, German Research Center for Environmental Health, Neuherberg, Germany. * Christian Gieger & * H-Erich Wichmann * Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-University, Munich, Germany. * H-Erich Wichmann * Klinikum Grosshadern, Munich, Germany. * H-Erich Wichmann * Department of Gastroenterology and Hepatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. * Pieter Stokkers, * Cyriel Y Ponsioen & * Ulrich Beuers * Department of Human Genetics, University Hospital of Heidelberg, Heidelberg, Germany. * Heiko Runz * Department of Genetics, University Medical Center Groningen and University of Groningen, Groningen, The Netherlands. * Cisca Wijmenga * Department for General Internal Medicine, Christian-Albrechts-University, Kiel, Germany. * Stefan Schreiber * These authors jointly directed this work. * Stefan Schreiber & * Tom H Karlsen Contributions E.M. performed data analysis. A.F. and T.H.K. supervised data analysis and coordinated project contributions. E.E., T.B., D.E., J.R.H. and E.R. helped with data analysis. F.A.O., V.L. and A.V. performed the Bcl2l11−/− animal work and liver histology assessments. J.K.L. performed in silico analysis of chromosome 2q13 transcripts. M.W. and K.H. were responsible for in-house conversion and database management of genome-wide association study data. C.S., T.J.W., D.N.G., B.D.J., E.B., R.K.W., L.H., A.T., C.R., K.M.B., C.G., H.-E.W., A.B., P. Sauer, J.W., B.L., R.J.P., P. Stokkers, C.Y.P., H.R., A.S., C.W., M.S., S.V., U.B., E.S., K.N.L., M.P.M. and S.S. provided the case populations and healthy controls. S.S., A.F., T.H.K. and E.M. designed the experiment. E.M. and T.H.K. drafted the manuscript. All authors revised the manuscript and approved of the final version. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Tom H Karlsen Supplementary information * Author information * Supplementary information PDF files * Supplementary Text and Figures (4M) Supplementary Tables 1 and 2, Supplementary Figures 1–5 and Supplementary Methods Additional data - Mutations in genes encoding subunits of RNA polymerases I and III cause Treacher Collins syndrome
- Nat Genet 43(1):20-22 (2011)
Nature Genetics | Brief Communication Mutations in genes encoding subunits of RNA polymerases I and III cause Treacher Collins syndrome * Johannes G Dauwerse1 Contact Johannes G Dauwerse Search for this author in: * NPG journals * PubMed * Google Scholar * Jill Dixon2 Search for this author in: * NPG journals * PubMed * Google Scholar * Saskia Seland3 Search for this author in: * NPG journals * PubMed * Google Scholar * Claudia A L Ruivenkamp1 Search for this author in: * NPG journals * PubMed * Google Scholar * Arie van Haeringen1 Search for this author in: * NPG journals * PubMed * Google Scholar * Lies H Hoefsloot4 Search for this author in: * NPG journals * PubMed * Google Scholar * Dorien J M Peters1 Search for this author in: * NPG journals * PubMed * Google Scholar * Agnes Clement-de Boers5 Search for this author in: * NPG journals * PubMed * Google Scholar * Cornelia Daumer-Haas6 Search for this author in: * NPG journals * PubMed * Google Scholar * Robert Maiwald7 Search for this author in: * NPG journals * PubMed * Google Scholar * Christiane Zweier8 Search for this author in: * NPG journals * PubMed * Google Scholar * Bronwyn Kerr2 Search for this author in: * NPG journals * PubMed * Google Scholar * Ana M Cobo9 Search for this author in: * NPG journals * PubMed * Google Scholar * Joaquín F Toral10 Search for this author in: * NPG journals * PubMed * Google Scholar * A Jeannette M Hoogeboom11 Search for this author in: * NPG journals * PubMed * Google Scholar * Dietmar R Lohmann3 Search for this author in: * NPG journals * PubMed * Google Scholar * Ute Hehr12 Search for this author in: * NPG journals * PubMed * Google Scholar * Michael J Dixon2, 13 Search for this author in: * NPG journals * PubMed * Google Scholar * Martijn H Breuning1 Search for this author in: * NPG journals * PubMed * Google Scholar * Dagmar Wieczorek3 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorJournal name:Nature GeneticsVolume: 43,Pages:20–22Year published:(2011)DOI:doi:10.1038/ng.724Received14 July 2010Accepted29 October 2010Published online05 December 2010 Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg We identified a deletion of a gene encoding a subunit of RNA polymerases I and III, POLR1D, in an individual with Treacher Collins syndrome (TCS). Subsequently, we detected 20 additional heterozygous mutations of POLR1D in 252 individuals with TCS. Furthermore, we discovered mutations in both alleles of POLR1C in three individuals with TCS. These findings identify two additional genes involved in TCS, confirm the genetic heterogeneity of TCS and support the hypothesis that TCS is a ribosomopathy. View full text Author information * Author information * Supplementary information Affiliations * Center for Human and Clinical Genetics, Leiden University Medical Center (LUMC), Leiden, The Netherlands. * Johannes G Dauwerse, * Claudia A L Ruivenkamp, * Arie van Haeringen, * Dorien J M Peters & * Martijn H Breuning * Faculty of Medical and Human Sciences, Manchester Academic Health Sciences Centre, University of Manchester, Manchester, UK. * Jill Dixon, * Bronwyn Kerr & * Michael J Dixon * Institut für Humangenetik, Universitaetsklinikum Essen, Essen, Germany. * Saskia Seland, * Dietmar R Lohmann & * Dagmar Wieczorek * Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. * Lies H Hoefsloot * Department of Pediatrics, Medical Center Haaglanden, The Hague, The Netherlands. * Agnes Clement-de Boers * Praenatal-Medizin München, München, Germany. * Cornelia Daumer-Haas * Medizinisches Versorgungszentrum für Laboratoriumsmedizin, Mikrobiologie und Humangenetik, Mönchengladbach, Germany. * Robert Maiwald * Institute of Human Genetics, Friedrich-Alexander-University of Erlangen-Nuremberg, Erlangen, Germany. * Christiane Zweier * Centre de Référence Neuromusculaire, Hôpital Marin Assistance Publique-Hôpitaux de Paris (AP-HP), Hendaye, France. * Ana M Cobo * Hospital Universitario Central de Asturias, Oviedo, Spain. * Joaquín F Toral * Department of Clinical Genetics, Erasmus Medical Center Rotterdam, The Netherlands. * A Jeannette M Hoogeboom * Zentrum für Humangenetik am Universitaetsklinikum Regensburg, Regensburg, Germany. * Ute Hehr * Faculty of Life Sciences, University of Manchester, Manchester, UK. * Michael J Dixon Contributions : J.G.D., S.S., D.R.L. Patient ascertainment including clinical data and/or TCOF1 mutation analysis: J.D., A.v.H., L.H.H., D.J.M.P., A.C.-d.B., C.D.-H., R.M., C.Z., B.K., A.M.C., J.F.T., A.J.M.H., U.H., M.J.D., D.W. : C.A.L.R. : J.G.D., M.J.D., D.R.L., M.H.B., D.W. : J.G.D., A.v.H., D.W. All authors contributed to the final version of the paper. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Johannes G Dauwerse Supplementary information * Author information * Supplementary information PDF files * Supplementary Text and Figures (4M) Supplementary Methods, Supplementary Tables 1 and 2 and Supplementary Figures 1–4 Additional data - CEP152 is a genome maintenance protein disrupted in Seckel syndrome
- Nat Genet 43(1):23-26 (2011)
Nature Genetics | Brief Communication CEP152 is a genome maintenance protein disrupted in Seckel syndrome * Ersan Kalay1, 23 Contact Ersan Kalay Search for this author in: * NPG journals * PubMed * Google Scholar * Gökhan Yigit2, 3, 4, 23 Search for this author in: * NPG journals * PubMed * Google Scholar * Yakup Aslan5 Search for this author in: * NPG journals * PubMed * Google Scholar * Karen E Brown6 Search for this author in: * NPG journals * PubMed * Google Scholar * Esther Pohl2, 3 Search for this author in: * NPG journals * PubMed * Google Scholar * Louise S Bicknell7 Search for this author in: * NPG journals * PubMed * Google Scholar * Hülya Kayserili8 Search for this author in: * NPG journals * PubMed * Google Scholar * Yun Li2, 3 Search for this author in: * NPG journals * PubMed * Google Scholar * Beyhan Tüysüz9 Search for this author in: * NPG journals * PubMed * Google Scholar * Gudrun Nürnberg3, 4, 10 Search for this author in: * NPG journals * PubMed * Google Scholar * Wieland Kiess11 Search for this author in: * NPG journals * PubMed * Google Scholar * Manfred Koegl12 Search for this author in: * NPG journals * PubMed * Google Scholar * Ingelore Baessmann3, 10 Search for this author in: * NPG journals * PubMed * Google Scholar * Kurtulus Buruk13 Search for this author in: * NPG journals * PubMed * Google Scholar * Bayram Toraman1 Search for this author in: * NPG journals * PubMed * Google Scholar * Saadettin Kayipmaz14 Search for this author in: * NPG journals * PubMed * Google Scholar * Sibel Kul15 Search for this author in: * NPG journals * PubMed * Google Scholar * Mevlit Ikbal16 Search for this author in: * NPG journals * PubMed * Google Scholar * Daniel J Turner17 Search for this author in: * NPG journals * PubMed * Google Scholar * Martin S Taylor7 Search for this author in: * NPG journals * PubMed * Google Scholar * Jan Aerts17 Search for this author in: * NPG journals * PubMed * Google Scholar * Carol Scott17 Search for this author in: * NPG journals * PubMed * Google Scholar * Karen Milstein18 Search for this author in: * NPG journals * PubMed * Google Scholar * Helene Dollfus19 Search for this author in: * NPG journals * PubMed * Google Scholar * Dagmar Wieczorek20 Search for this author in: * NPG journals * PubMed * Google Scholar * Han G Brunner21 Search for this author in: * NPG journals * PubMed * Google Scholar * Matthew Hurles17 Search for this author in: * NPG journals * PubMed * Google Scholar * Andrew P Jackson7 Search for this author in: * NPG journals * PubMed * Google Scholar * Anita Rauch22 Search for this author in: * NPG journals * PubMed * Google Scholar * Peter Nürnberg3, 4, 10 Search for this author in: * NPG journals * PubMed * Google Scholar * Ahmet Karagüzel1 Search for this author in: * NPG journals * PubMed * Google Scholar * Bernd Wollnik2, 3, 4 Contact Bernd Wollnik Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorsJournal name:Nature GeneticsVolume: 43,Pages:23–26Year published:(2011)DOI:doi:10.1038/ng.725Received09 August 2010Accepted12 November 2010Published online05 December 2010 Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Functional impairment of DNA damage response pathways leads to increased genomic instability. Here we describe the centrosomal protein CEP152 as a new regulator of genomic integrity and cellular response to DNA damage. Using homozygosity mapping and exome sequencing, we identified CEP152 mutations in Seckel syndrome and showed that impaired CEP152 function leads to accumulation of genomic defects resulting from replicative stress through enhanced activation of ATM signaling and increased H2AX phosphorylation. View full text Subject terms: * Developmental biology Figures at a glance * Figure 1: Clinical and molecular characterization of CEP152 Seckel subjects. () Clinical characteristics of subjects 442, 443 and 586 presenting with microcephaly, sloping forehead, high nasal bridge, beaked nose and retrognathia. Informed consents to publish the photographs were obtained from the subjects' parents. Cranial magnetic resonance imaging of subjects 586 and 935 showing simplified gyri. () Genome-wide graphical view of LOD scores using SNP array homozygosity mapping in four affected subjects, 442, 443, 586 and 633, indicated significant linkage to chromosome 15q21.1–q21.2. () Above, homozygosity (blue line) was measured as the percent of homozygous sites within a sliding window of 100 variant sites, relative to the reference genome, obtained from the exome sequencing data. CEP152 is located on chromosome 15, which harbors one of the longest stretches of homozygosity in this genome. Below, the chromosomal locations of all single nucleotide variants called on chromosome 15 are plotted against the genotype quality for that variant. Homozyg! ous variants are plotted in red, and heterozygous variants are plotted in black. Homozygosity (blue line) is measured as the fraction of homozygous sites within a sliding window of 50 variant sites (relative to the reference genome) called from the exome sequencing data. () Above, the genomic structure of human CEP152. The position of each mutation is shown on the coding DNA level. Below, the protein structure of CEP152 with predicted coiled-coil domains (blue boxes) and Thr/Ser-phosphorylation sites (red). The position and the predicted effects of the mutations on CEP152 are marked by arrows. * Figure 2: Characterization of CEP152 Seckel cells. () Mitotic morphology of CEP152 Seckel fibroblasts. Immunofluorescence staining of CEP152 Seckel fibroblasts carrying the c.261+1G>C mutation with antibodies against α-tubulin (green), pericentrin (red) and DAPI staining of DNA (blue). Above, from left to right, control fibroblasts showing normal mitotic morphology of interphase, metaphase, anaphase and telophase. Middle, Seckel interphase cells containing three equally sized nuclei and two centrosomes without astral microtubules (inset, tenfold magnification), two unseparated centrosomes per nucleus without asters (inset, threefold magnification), fragmented centrosomes without asters and micronuclei (inset, twofold magnification), and partially depolymerized microtubules together with micronuclei in addition to a main nucleus. Below, abnormal Seckel metaphases showing incorrectly aligned chromosomes on the metaphase plate, a monopolar spindle with a large centrosome and reduced spindle, a tripolar spindle with differently! sized and structurally compromised centrosomes, and an abnormal Seckel telophase showing defects in cytokinesis (inset, twofold magnification). Scale bars, 5 μm. () Aneuploid metaphase karyotype of a CEP152 Seckel lymphocyte. () Centrosomal localization of wildtype CEP152 in HEK293T cells expressing either GFP-tagged wildtype CEP152 (above) or GFP as a control (below). Additional staining was with pericentrin (red) and DAPI (blue). () DNA-damage response in wildtype and Seckel fibroblasts. H2AX phosphorylation of wildtype and CEP152 Seckel primary fibroblasts after treatment with hydroxyurea (HU) (left). Protein blot analysis of HU-induced phosphorylation of CHK1 (Ser345) and H2AX (Ser139) (right). Equal protein loading was confirmed by re-probing of the membranes with antibodies against CHK1 or H2AX and actin antibodies. Accession codes * Accession codes * Author information * Supplementary information Referenced accessions Entrez Nucleotide * NM_014985.2 Author information * Accession codes * Author information * Supplementary information Primary authors * These authors contributed equally to this work. * Ersan Kalay & * Gökhan Yigit Affiliations * Department of Medical Biology, Faculty of Medicine, Karadeniz Technical University, Trabzon, Turkey. * Ersan Kalay, * Bayram Toraman & * Ahmet Karagüzel * Institute of Human Genetics, University of Cologne, Cologne, Germany. * Gökhan Yigit, * Esther Pohl, * Yun Li & * Bernd Wollnik * Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany. * Gökhan Yigit, * Esther Pohl, * Yun Li, * Gudrun Nürnberg, * Ingelore Baessmann, * Peter Nürnberg & * Bernd Wollnik * Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany. * Gökhan Yigit, * Gudrun Nürnberg, * Peter Nürnberg & * Bernd Wollnik * Department of Pediatrics, Faculty of Medicine, Karadeniz Technical University, Trabzon, Turkey. * Yakup Aslan * Chromosome Biology Group, Medical Research Council Clinical Sciences Centre, Imperial College School of Medicine, Hammersmith Hospital, London, UK. * Karen E Brown * Medical Research Council (MRC) Human Genetics Unit, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, UK. * Louise S Bicknell, * Martin S Taylor & * Andrew P Jackson * Department of Medical Genetics, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey. * Hülya Kayserili * Department of Pediatric Genetics, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey. * Beyhan Tüysüz * Cologne Center for Genomics, University of Cologne, Cologne, Germany. * Gudrun Nürnberg, * Ingelore Baessmann & * Peter Nürnberg * Department of Women and Child Health, Hospital for Children and Adolescents, University of Leipzig, Leipzig, Germany. * Wieland Kiess * Preclinical Target Development and Genomics and Proteomics Core Facilities, German Cancer Research Center, Heidelberg, Germany. * Manfred Koegl * Department of Clinical Microbiology, Faculty of Medicine, Karadeniz Technical University, Trabzon, Turkey. * Kurtulus Buruk * Department of Oral Diagnosis and Radiology, Faculty of Dentistry, Karadeniz Technical University, Trabzon, Turkey. * Saadettin Kayipmaz * Department of Radiology, Faculty of Medicine, Karadeniz Technical University, Trabzon, Turkey. * Sibel Kul * Department of Medical Genetics, Faculty of Medicine, Karadeniz Technical University, Trabzon, Turkey. * Mevlit Ikbal * Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK. * Daniel J Turner, * Jan Aerts, * Carol Scott & * Matthew Hurles * Division of Human Genetics, National Health Laboratory Service and The University of Witwatersrand, Johannesburg, South Africa. * Karen Milstein * Centre de Référence pour les Affections Rares Génétique Ophtalmologique, Service de Génétique Médicale, Hôpitaux Universitaires de Strasbourg, Strasbourg, France. * Helene Dollfus * Institut für Humangenetik, Universitätsklinikum Essen, Essen, Germany. * Dagmar Wieczorek * Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. * Han G Brunner * Institute of Medical Genetics, Zürich University, Zürich, Switzerland. * Anita Rauch Contributions The project was conceived and the experiments were planned by E.K. and B.W. We would like to note that Y.A. and K.E.B. had a comparable contribution to this study. The review of phenotypes and the sample collection were performed by B.W., E.K., Y.A., A.P.J., H.K., B. Tüysüz, W.K., B. Toraman., S. Kayipmaz, S. Kul, M.I., K.M., H.D., D.W., H.G.B. and A.R. Experiments were performed by E.K., G.Y., K.E.B., E.P., L.S.B., Y.L., M.K., I.B., K.B., D.J.T. and C.S. Data analysis was performed by B.W., E.K., G.N., P.N., A.K., J.A., M.S.T., M.H. and A.P.J. The manuscript was written by B.W., G.Y., E.K. and K.E.B. All aspects of the study were supervised by B.W. Competing financial interests The authors declare no competing financial interests. Corresponding authors Correspondence to: * Bernd Wollnik or * Ersan Kalay Supplementary information * Accession codes * Author information * Supplementary information PDF files * Supplementary Text and Figures (4M) Supplementary Figures 1–8, Supplementary Tables 1–4 and Supplementary Methods Additional data - FOXA1 is a key determinant of estrogen receptor function and endocrine response
- Nat Genet 43(1):27-33 (2011)
Nature Genetics | Article FOXA1 is a key determinant of estrogen receptor function and endocrine response * Antoni Hurtado1, 2 Search for this author in: * NPG journals * PubMed * Google Scholar * Kelly A Holmes1, 2 Search for this author in: * NPG journals * PubMed * Google Scholar * Caryn S Ross-Innes1 Search for this author in: * NPG journals * PubMed * Google Scholar * Dominic Schmidt1 Search for this author in: * NPG journals * PubMed * Google Scholar * Jason S Carroll1 Contact Jason S Carroll Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorJournal name:Nature GeneticsVolume: 43,Pages:27–33Year published:(2011)DOI:doi:10.1038/ng.730Received24 August 2010Accepted01 November 2010Published online12 December 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 Estrogen receptor-α (ER) is the key feature of most breast cancers and binding of ER to the genome correlates with expression of the Forkhead protein FOXA1 (also called HNF3α). Here we show that FOXA1 is a key determinant that can influence differential interactions between ER and chromatin. Almost all ER-chromatin interactions and gene expression changes depended on the presence of FOXA1 and FOXA1 influenced genome-wide chromatin accessibility. Furthermore, we found that CTCF was an upstream negative regulator of FOXA1-chromatin interactions. In estrogen-responsive breast cancer cells, the dependency on FOXA1 for tamoxifen-ER activity was absolute; in tamoxifen-resistant cells, ER binding was independent of ligand but depended on FOXA1. Expression of FOXA1 in non-breast cancer cells can alter ER binding and function. As such, FOXA1 is a major determinant of estrogen-ER activity and endocrine response in breast cancer cells. View full text Figures at a glance * Figure 1: Differential binding of FOXA1 and ER overlaps in a cell context–dependent manner. () Overlap in FOXA1 binding events among MCF-7, ZR75-1 and T-47D cells. () Overlap between binding of ER and FOXA1 in the three ER-positive breast cancer cell lines. () Relative overlap of ER and FOXA1 binding events within and between the three cell lines. The percentages represent the fraction of ER binding events in that cell line. An overlap was considered if the peaks shared at least one base pair. () Examples of regions showing cell line–specific binding of ER and FOXA1. An example of a region bound by ER and FOXA1 in all three cell lines is also shown. () Average signal intensity of ER binding sites that are or are not shared with FOXA1 binding regions. The signal intensity of ER binding events that are not shared with FOXA1 is similar to that of those that overlap with FOXA1. Also included is the average signal intensity for FOXA1 binding at these two ER binding categories. * Figure 2: Binding of ER to chromatin and transcriptional activity requires FOXA1. () Protein blot of cells transfected with siControl or siFOXA1. () An example of ER binding in cells transfected with siControl or siFOXA1. () Heatmap showing the signal intensity of ER binding in cells transfected with siControl or siFOXA1 in a window of ±5 kb. Signal intensity for FOXA1 at the equivalent genomic region is also shown. The heatmap represents binding events ranked from the strongest to weakest ER binding (in the siControl condition), and the adjacent columns represent the signal from the corresponding genomic region but under the different experimental conditions. () Smoothened scatterplot comparing ER binding intensity in cells transfected with siControl and those transfected with siFOXA1. As a control, a scatterplot representing two different siControl experiments is shown. () Cells were transfected with siControl or siFOXA1, treated with vehicle (V) or estrogen (E) and were fractionated to enrich for the chromatin fraction, which was protein blotted. Hist! one H3 was used as a loading control. The uncropped protein blot is in Supplementary Figure 2. () Oligonucleotide pull-down using total protein from cells transfected with siControl or siFOXA1. A double-stranded, biotin-labeled oligonucleotide containing a perfect ERE sequence or a mutant sequence was used and protein enriched by the oligonucleotide was protein blotted. () Gene expression microarray analysis following transfection of siControl or siFOXA1 and treatment with vehicle or estrogen for 6 h. * Figure 3: Tamoxifen induces similar ER binding events to estrogen in a FOXA1-dependent manner. () Heatmap representing the signal intensity of ER binding in hormone-deprived MCF-7 cells treated with vehicle, estrogen or tamoxifen for 45 min. The window represents ±5 kb. The heatmap represents binding events ranked from the strongest to weakest ER binding (in the estrogen condition). () Example of ER binding under the different ligand conditions. () Venn diagram representing the overlap in ER binding events between estrogen- and tamoxifen-treated cells. Comparisons with published data are provided in Supplementary Figure 5. () Hormone-deprived MCF-7 cells were transfected with siControl or siFOXA1 and treated with tamoxifen. ER ChIP was performed followed by real-time PCR of known ER binding regions. The data are the fold enrichment over input. The data are the mean of independent replicates ± s.d. () ER ChIP-seq binding data from hormone-deprived, tamoxifen-resistant MCF-7 cells (Tam-R) treated with vehicle or tamoxifen. () Tam-R cells were hormone deprived, transfe! cted with siControl or siFOXA1 and treated with tamoxifen. Total cell growth was assessed. The data are the mean of independent replicates ± s.d. * Figure 4: FOXA1 expression in U20S-ER osteosarcoma cancer cells renders ER functional. () FOXA1 or control plasmids were transfected into U20S-ER cells and protein blotting was used to confirm expression. () In control or FOXA1-expressing U20S-ER cells, ER ChIP was performed followed by real-time PCR of known ER binding events derived from breast cancer cells. **P < 0.01. The data are the mean of independent replicates ± s.d. () U20S-ER cells were transfected with control or FOXA1-expressing vector and total chromatin fraction was collected and protein blotted for ER. Histone H3 was used as a control. () Oligonucleotide pull-down using total protein from control or FOXA1-transfected U20S-ER cells. A double-stranded, biotin-labeled oligonucleotide containing a perfect ERE or a mutant sequence was used and protein enriched by the oligonucleotide was protein blotted. () Control or FOXA1-expressing U20S ER cells were treated with estrogen or tamoxifen and mRNA levels of known breast cancer–associated target genes were assessed. The data are the mean of independ! ent replicates ± s.d. *P < 0.05. Specifically for TFF1, the fold change is ×10 of the y-axis values. () Cell proliferation was performed and cell confluence assessed in U20S-ER cells transfected with control or FOXA1 and treated with tamoxifen. The data are the mean of independent replicates ± s.d. * Figure 5: FOXA1 is required for maintaining chromatin structure. () Genome-wide FAIRE (formaldehyde-assisted isolation of regulatory elements) was performed in MCF-7 cells transfected with siControl or siFOXA1 and treated with vehicle or estrogen for 1 h. Chart shows overlap in FAIRE regions between vehicle-treated and estrogen-treated control cells. () Examples of FAIRE regions that depend on FOXA1 and adjacent regions that do not. () Overlap between FAIRE (vehicle-and estrogen-treated cells combined) and ER binding. The different categories (ER and FAIRE-positive regions versus ER but not FAIRE positive) were assessed for the fraction that represent either ER but not FOXA1 binding or shared ER and FOXA1 binding regions. Also included are the changes in FAIRE and ER binding signal within the two categories. () Fraction of promoter proximal regions of genes induced or repressed by 6 h estrogen treatment that possess FAIRE signal. The relative difference in FAIRE signal in cells transfected with siControl or siFOXA1 is shown. * Figure 6: Binding events that are shared between ER and FOXA1 are exclusively independent of CTCF, and CTCF can repress the binding and activity of FOXA1. () Overlap between FOXA1, ER and CTCF binding events in MCF-7 cells. () Heatmap representing binding signal from regions where ER, FOXA1 and CTCF overlap. The categories are: I, ER and FOXA1 shared (but not CTCF) binding events; II, regions bound by ER, FOXA1 and CTCF; III, FOXA1 and CTCF shared (but not ER) binding regions. The window represents ±5 kb. The FOXA1 binding events that overlap with CTCF tend to be the weakest FOXA1 binding events. () Protein blot of MCF-7 and ZR75-1 cells transfected with siControl or siCTCF. () Heatmap showing FOXA1 binding regions that are unique to MCF-7 or ZR75-1 cells. ZR75-1 and MCF-7 cells were transfected with siControl or siCTCF. FOXA1 and H3K4me1 ChIP was performed, followed by real-time PCR of three regions that bound FOXA1 exclusively in the other cell line. The data are the mean of independent replicates ± s.d. Author information * Abstract * Author information * Supplementary information Primary authors * These authors contributed equally to this work. * Antoni Hurtado & * Kelly A Holmes Affiliations * Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Cambridge, UK. * Antoni Hurtado, * Kelly A Holmes, * Caryn S Ross-Innes, * Dominic Schmidt & * Jason S Carroll Contributions All experiments were conceived by A.H., K.A.H. and J.S.C. Experiments were conducted by A.H., K.A.H. and C.S.R.-I. Computational analysis was conducted by A.H. and D.S. The manuscript was written by A.H., K.A.H. and J.S.C. with help from C.S.R.-I. and D.S. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Jason S Carroll Supplementary information * Abstract * Author information * Supplementary information PDF files * Supplementary Text and Figures (1M) Supplementary Figures 1–8 and Supplementary Table 1 Additional data - Continuous cell supply from a Sox9-expressing progenitor zone in adult liver, exocrine pancreas and intestine
- Nat Genet 43(1):34-41 (2011)
Nature Genetics | Article Continuous cell supply from a Sox9-expressing progenitor zone in adult liver, exocrine pancreas and intestine * Kenichiro Furuyama1 Search for this author in: * NPG journals * PubMed * Google Scholar * Yoshiya Kawaguchi1 Contact Yoshiya Kawaguchi Search for this author in: * NPG journals * PubMed * Google Scholar * Haruhiko Akiyama2 Contact Haruhiko Akiyama Search for this author in: * NPG journals * PubMed * Google Scholar * Masashi Horiguchi1 Search for this author in: * NPG journals * PubMed * Google Scholar * Sota Kodama1 Search for this author in: * NPG journals * PubMed * Google Scholar * Takeshi Kuhara1 Search for this author in: * NPG journals * PubMed * Google Scholar * Shinichi Hosokawa1 Search for this author in: * NPG journals * PubMed * Google Scholar * Ashraf Elbahrawy1 Search for this author in: * NPG journals * PubMed * Google Scholar * Tsunemitsu Soeda2 Search for this author in: * NPG journals * PubMed * Google Scholar * Masayuki Koizumi1 Search for this author in: * NPG journals * PubMed * Google Scholar * Toshihiko Masui1 Search for this author in: * NPG journals * PubMed * Google Scholar * Michiya Kawaguchi1 Search for this author in: * NPG journals * PubMed * Google Scholar * Kyoichi Takaori1 Search for this author in: * NPG journals * PubMed * Google Scholar * Ryuichiro Doi1 Search for this author in: * NPG journals * PubMed * Google Scholar * Eiichiro Nishi3 Search for this author in: * NPG journals * PubMed * Google Scholar * Ryosuke Kakinoki2 Search for this author in: * NPG journals * PubMed * Google Scholar * Jian Min Deng4 Search for this author in: * NPG journals * PubMed * Google Scholar * Richard R Behringer4 Search for this author in: * NPG journals * PubMed * Google Scholar * Takashi Nakamura2 Search for this author in: * NPG journals * PubMed * Google Scholar * Shinji Uemoto1 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorsJournal name:Nature GeneticsVolume: 43,Pages:34–41Year published:(2011)DOI:doi:10.1038/ng.722Received02 September 2010Accepted03 November 2010Published online28 November 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 The liver and exocrine pancreas share a common structure, with functioning units (hepatic plates and pancreatic acini) connected to the ductal tree. Here we show that Sox9 is expressed throughout the biliary and pancreatic ductal epithelia, which are connected to the intestinal stem-cell zone. Cre-based lineage tracing showed that adult intestinal cells, hepatocytes and pancreatic acinar cells are supplied physiologically from Sox9-expressing progenitors. Combination of lineage analysis and hepatic injury experiments showed involvement of Sox9-positive precursors in liver regeneration. Embryonic pancreatic Sox9-expressing cells differentiate into all types of mature cells, but their capacity for endocrine differentiation diminishes shortly after birth, when endocrine cells detach from the epithelial lining of the ducts and form the islets of Langerhans. We observed a developmental switch in the hepatic progenitor cell type from Sox9-negative to Sox9-positive progenitors as t! he biliary tree develops. These results suggest interdependence between the structure and homeostasis of endodermal organs, with Sox9 expression being linked to progenitor status. View full text Subject terms: * Stem cells * Developmental biology Figures at a glance * Figure 1: Sox9 is expressed in adult intestinal crypt, pancreatic duct and bile duct. (–) Expression of Sox9 in humans. Sox9 is detected in the adult duodenal crypt, pancreatic duct and bile duct of the liver (arrowheads in and correspond to centroacinar cells and bile duct cells, respectively). () Generation of Sox9IRES-eGFP knock-in mice (Online Methods). B, BamHI; TK, thymidine kinase. (–) Expression of Sox9 and indicated markers in the gastrointestinal organs of 8-week-old Sox9IRES-eGFP mice (–, –) and in Sox9IRES-LacZ mice (,,,). Intestinal Sox9 expression is restricted to the crypt (,,), including Lgr5-expressing crypt base columnar cells (arrowheads in –; and are adjacent serial sections and and are of the same section). In the pancreas, Sox9 is expressed in the pancreatic duct cells (–,), including centroacinar cells (arrowhead in ), but not in exocrine acinar cells () or in endocrine islet cells (). Almost all the CK+ duct cells co-express Sox9 (). In the liver, Sox9-eGFP is detected throughout the CK+ bile duct tree (–) but not in hepa! tocytes (). Arrow in indicates the canals of Hering. Sox9 is also expressed in the extrahepatic bile duct cells and duodenal papilla (arrowheads in and , respectively). Sox9 expression in the pancreatic and intrahepatic ductal tree is visualized in the X-gal–stained tissues of Sox9IRES-LacZ mice (,). () Schematic presentation of the Sox9-expressing zone. CK, cytokeratin; C, central vein; P, portal vein. Scale bars, 50 μm. * Figure 2: Physiological cell supply from the Sox9-expressing progenitors in the adult intestine, pancreas and liver. () Experimental strategy of tamoxifen-inducible Cre-mediated cell tracking using Sox9IRES-CreERT2; Rosa26R mice. (–) Lineage tracing of Sox9-expressing cells by single injection (–) or five injections (–) of tamoxifen (4 mg) using 8-week-old mice. (,,,,,,,) Quantitative analysis of the lineage tracing. (,,) Percentage of lineage-labeled cells of the Sox9+ or Sox9− populations on the day after injection, the earliest time point that Cre recombination could be detected by X-gal staining. Blue dots in , and indicate individual animals, with representative samples (red circles) shown in , and , respectively. Progenies of Sox9-expressing cells (blue, X-gal stained) differentiate and expand in the intestinal cells in the villi (–,), pancreatic acinar cells (–,,) and hepatocytes (–,,). On the day after a single tamoxifen injection, 28.4% of the lineage-labeled intestinal cells were detected beyond the Sox9-experssing domain (,), but very few were detected in the pancr! eas and liver (, and ,, respectively). Arrowheads in and indicate lineage-labeled duct cells. Arrows in and indicate lineage-labeled acinar cells and hepatocytes, respectively. (,) Representative figure of 10 days and 30 days after injection, respectively. In the long-term chase after the more efficient labeling by five tamoxifen injections, a majority of the acinar cells become X-gal positive (,); however, no islet cells were labeled at any of the stages analyzed (arrowheads in ). Lineage-labeled hepatocytes gradually spread from the periportal region toward the central vein (asterisks) (,). Note that intestinal cells throughout the crypt-villi (), pancreatic and hepatic duct cells (,), as well as the epithelial cells in the extrahepatic biliary tract (–), retained their X-gal+ status one year after labeling, suggesting the self-renewal capacity of the Sox9-expressing precursors. Asterisks in and indicate P < 0.05. Scale bars, 50 μm (,,,,,) and 100 μm (,,–). * Figure 3: Accelerated hepatocyte differentiation from the Sox9-expressing precursors during liver regeneration (a–p). Activated hepatocyte differentiation and subsequent cell duplication after acute liver damage by CCl4 treatment (–,,) and bile duct ligation (–,,). Sox9+ cells are labeled either before (–,–) or after (–) initiation of the injury. Note that lineage-positive hepatocytes increased regardless of the timing of the cell labeling. The extent of the increase in labeled cells is not obviously greater in post-marking experiments than in pre-marking experiments (compare with and with ). These injuries do not induce Sox9 expression in hepatocytes (red in and , albumin); Sox9 expression is confined to the cytokeratin-positive duct cells (red in and ). Phospho-histone H3 (pHH3) staining shows activated proliferation of the cytokeratin-positive, Sox9-positive duct cells (arrowheads in and ) in addition to the Sox9-negative hepatocytes (arrows in and ). Asterisks, pericentral necrosis (,,,). Scale bars, 100 μm. CK, cytokeratin; BDL, bile duct ligation; i.p., intraperitoneal inje! ction. * Figure 4: Sox9 expression in the embryonic intestine, pancreas, liver and bile duct. (–) Macroscopic view. (–) Sox9 was expressed broadly in the intestinal epithelia at E13.5 () and E16.5 () and was restricted to the crypt at E18.5 (). () Primitive pancreatic epithelia expresses Sox9 at E13.5. (,) Sox9 expression was confined to pancreatic duct cells at E16.5 () and E18.5 (). (–) Sox9 was not detected in the developing liver at E13.5 () but was expressed in bile duct cells adjacent to the portal vein at E16.5 () and E18.5 (). Note that Sox9 does not co-localize with differentiated cell markers, amylase-positive pancreatic acinar cells (,) or Hnf4α+ hepatocytes (,). (–) The extrahepatic biliary tract expresses Sox9 earlier than the intrahepatic bile duct (arrowheads in – and –). The junction between the Sox9-negative intrahepatic bile duct and the Sox9-positive extrahepatic bile duct at E14.5 is shown in . D, duodenum; Dp, dorsal pancreas; I, intestine; L, liver; P, pancreas; Pap, duodenal papilla; PV, portal vein; S, stomach; Vp, ventral pancrea! s. Scale bars, 50 μm. * Figure 5: Behavior of Sox9-expressing cells during organogenesis of the intestine, pancreas and liver. () Lineage tracing of embryonic Sox9-expressing cells in Sox9IRES-Cre; Rosa26R mice. All the intestinal and pancreatic cells are the progeny of Sox9-expressing precursors, but only a subset of liver cells are X-gal–positive at P1. Proximal region–dominant hepatocyte differentiation from Sox9-expressing progenitors should be noted. (–) Diminishing multipotency of pancreatic Sox9-expressing progenitors. Single-dose tamoxifen-inducible cell marking using Sox9IRES-CreERT2; Rosa26R mice at E16.5 and P1 results in both exocrine and endocrine differentiation (,, arrows indicate marked endocrine cells), but recombination at P7 and P14 shows exocrine-specific differentiation (,). Note that single-dose cell marking does not result in 100% labeling because of the insufficient tamoxifen content. The frequency with which Sox9-expressing cells adopt exocrine, endocrine or duct-cell fates was counted (–). Scale bars, 100 μm. * Figure 6: The proposed interdependent relationship among the structure, function and homeostasis of the intestine, liver and pancreas and Sox9 expression is linked to progenitor status. The left panel shows the change in progenitor cell types during organogenesis. At early embryonic stages, Sox9 is expressed throughout the intestinal epithelia. As development proceeds, Sox9 expression becomes restricted to the crypt cells (crypt base columnar (CBC), enteroendocrine and Paneth cells). Intestinal Sox9-expressing progenitors retain multipotency from the early developmental stages throughout the lifespan. Embryonic hepatic progenitors (hepatoblasts) do not express Sox9, and Sox9 expression begins to be detected in the intrahepatic bile duct cells during mid-to-late embryogenesis. We observed a progenitor cell-type switch from the Sox9-negative to the Sox9-positive progenitors as the intrahepatic ductal tree developed, suggesting the preparation of a 'functional switch' from the embryonic hematopoietic organ to the metabolic organ. In the pancreas, Sox9 is expressed in the undifferentiated epithelia and becomes restricted to the pancreatic ducts. Sox9-positive e! mbryonic pancreatic progenitors lose their capacity for endocrine differentiation shortly after birth, around the time of islet formation. The right panel shows adult organ structure, function and maintenance. Adult intestine and liver cells have a dual function (exocrine and endocrine). However, pancreatic exocrine and endocrine functions are mediated separately by independent functional units (pancreatic acinus and the islet of Langerhans, respectively). The functional units of the intestine, liver and exocrine pancreas are anatomically connected to the Sox9-expressing progenitor zone and receive a continuous supply of cells, but the islets of Langerhans lose their histological connection to the ductal tree and are unable to receive cells from the Sox9+ precursors. The duplication of intestinal cells at the transit-amplifying zone, hepatocytes, pancreatic acinar cells and β cells has been described previously1, 2, 3, 4. Author information * Abstract * Author information * Supplementary information Affiliations * Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan. * Kenichiro Furuyama, * Yoshiya Kawaguchi, * Masashi Horiguchi, * Sota Kodama, * Takeshi Kuhara, * Shinichi Hosokawa, * Ashraf Elbahrawy, * Masayuki Koizumi, * Toshihiko Masui, * Michiya Kawaguchi, * Kyoichi Takaori, * Ryuichiro Doi & * Shinji Uemoto * Department of Orthopedic Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan. * Haruhiko Akiyama, * Tsunemitsu Soeda, * Ryosuke Kakinoki & * Takashi Nakamura * Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan. * Eiichiro Nishi * Department of Genetics, University of Texas, M.D. Anderson Cancer Center, Houston, Texas, USA. * Jian Min Deng & * Richard R Behringer Contributions Y.K. and K.F. designed the study, analyzed the data and prepared the manuscript. K.F. performed the experiments. H.A. and R.R.B. generated mice. T.S. screened mouse lines. J.M.D. cultured embryonic stem cells. E.N., M.H., S.K., T.K., S.H., A.E., M. Koizumi, T.M., M. Kawaguchi, K.T., R.K. and R.D. gave technical support and discussion. T.N. and S.U. supervised the project. Competing financial interests The authors declare no competing financial interests. Corresponding authors Correspondence to: * Yoshiya Kawaguchi or * Haruhiko Akiyama Supplementary information * Abstract * Author information * Supplementary information PDF files * Supplementary Text and Figures (5M) Supplementary Figures 1–13 and Supplementary Tables 1–5 Additional data - Resequencing of positional candidates identifies low frequency IL23R coding variants protecting against inflammatory bowel disease
- Nat Genet 43(1):43-47 (2011)
Nature Genetics | Letter Resequencing of positional candidates identifies low frequency IL23R coding variants protecting against inflammatory bowel disease * Yukihide Momozawa1 Search for this author in: * NPG journals * PubMed * Google Scholar * Myriam Mni1 Search for this author in: * NPG journals * PubMed * Google Scholar * Kayo Nakamura1 Search for this author in: * NPG journals * PubMed * Google Scholar * Wouter Coppieters1 Search for this author in: * NPG journals * PubMed * Google Scholar * Sven Almer2 Search for this author in: * NPG journals * PubMed * Google Scholar * Leila Amininejad3 Search for this author in: * NPG journals * PubMed * Google Scholar * Isabelle Cleynen4 Search for this author in: * NPG journals * PubMed * Google Scholar * Jean-Frédéric Colombel5 Search for this author in: * NPG journals * PubMed * Google Scholar * Peter de Rijk6 Search for this author in: * NPG journals * PubMed * Google Scholar * Olivier Dewit7 Search for this author in: * NPG journals * PubMed * Google Scholar * Yigael Finkel8 Search for this author in: * NPG journals * PubMed * Google Scholar * Miquel A Gassull9 Search for this author in: * NPG journals * PubMed * Google Scholar * Dirk Goossens6 Search for this author in: * NPG journals * PubMed * Google Scholar * Debby Laukens10 Search for this author in: * NPG journals * PubMed * Google Scholar * Marc Lémann11 Search for this author in: * NPG journals * PubMed * Google Scholar * Cécile Libioulle1 Search for this author in: * NPG journals * PubMed * Google Scholar * Colm O'Morain12 Search for this author in: * NPG journals * PubMed * Google Scholar * Catherine Reenaers13 Search for this author in: * NPG journals * PubMed * Google Scholar * Paul Rutgeerts4 Search for this author in: * NPG journals * PubMed * Google Scholar * Curt Tysk14 Search for this author in: * NPG journals * PubMed * Google Scholar * Diana Zelenika15 Search for this author in: * NPG journals * PubMed * Google Scholar * Mark Lathrop15 Search for this author in: * NPG journals * PubMed * Google Scholar * Jurgen Del-Favero6 Search for this author in: * NPG journals * PubMed * Google Scholar * Jean-Pierre Hugot16 Search for this author in: * NPG journals * PubMed * Google Scholar * Martine de Vos10 Search for this author in: * NPG journals * PubMed * Google Scholar * Denis Franchimont3 Search for this author in: * NPG journals * PubMed * Google Scholar * Severine Vermeire4 Search for this author in: * NPG journals * PubMed * Google Scholar * Edouard Louis13 Search for this author in: * NPG journals * PubMed * Google Scholar * Michel Georges1 Contact Michel Georges Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorJournal name:Nature GeneticsVolume: 43,Pages:43–47Year published:(2011)DOI:doi:10.1038/ng.733Received03 August 2010Accepted18 November 2010Published online12 December 2010 Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Genome-wide association studies (GWAS) have identified dozens of risk loci for many complex disorders, including Crohn's disease1, 2. However, common disease-associated SNPs explain at most ~20% of the genetic variance for Crohn's disease. Several factors may account for this unexplained heritability3, 4, 5, including rare risk variants not adequately tagged thus far in GWAS6, 7, 8. That rare susceptibility variants indeed contribute to variation in multifactorial phenotypes has been demonstrated for colorectal cancer9, plasma high-density lipoprotein cholesterol levels10, blood pressure11, type 1 diabetes12, hypertriglyceridemia13 and, in the case of Crohn's disease, for NOD2 (refs. 14,15). Here we describe the use of high-throughput resequencing of DNA pools to search for rare coding variants influencing susceptibility to Crohn's disease in 63 GWAS-identified positional candidate genes. We identify low frequency coding variants conferring protection against inflammatory bo! wel disease in IL23R, but we conclude that rare coding variants in positional candidates do not make a large contribution to inherited predisposition to Crohn's disease. View full text Accession codes * Accession codes * Author information * Supplementary information Referenced accessions GenBank * NP_071445.1 * NP_653302.2 * NP_919410.1 Author information * Accession codes * Author information * Supplementary information Affiliations * Unit of Animal Genomics, Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA-R) and Faculty of Veterinary Medicine, University of Liège (B34), Liège, Belgium. * Yukihide Momozawa, * Myriam Mni, * Kayo Nakamura, * Wouter Coppieters, * Cécile Libioulle & * Michel Georges * Division of Gastroenterology and Hepatology, Institutionen för molekylär och klinisk medicin (IMK) Linköpings Universitet, Linköping, Sweden. * Sven Almer * Department of Gastroenterology, Erasme Hospital, Université Libre de Bruxelles (ULB), Brussels, Belgium. * Leila Amininejad & * Denis Franchimont * Department of Pathophysiology, Gastroenterology Section, Catholic University of Leuven, Leuven, Belgium. * Isabelle Cleynen, * Paul Rutgeerts & * Severine Vermeire * Registre des MICI du Nord-Quest de la France (EPIMAD), Hôpital Calmette, Lille, France. * Jean-Frédéric Colombel * Applied Molecular Genomics, Department of Molecular Genetics, Vlaams Instituut voor Biotechnologie (VIB), University of Antwerp, Antwerp, Belgium. * Peter de Rijk, * Dirk Goossens & * Jurgen Del-Favero * Department of Gastroenterology, Clinique Universitaire St Luc, Université Catholique de Louvain (UCL), Brussels, Belgium. * Olivier Dewit * Department of Gastroenterology, Karolinska Children's Hospital, Stockholm, Sweden. * Yigael Finkel * Gastroenterology Department, Hospital Universitari Germans Trias i Pujol, Badalona, Spain. * Miquel A Gassull * Department of Gastroenterology, University Hospital, Ghent University, Ghent, Belgium. * Debby Laukens & * Martine de Vos * Department of Gastroenterology, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Saint-Louis, Université Paris Diderot Paris-VII, Paris, France. * Marc Lémann * Adelaide and Meath Hospital, Dublin, Ireland. * Colm O'Morain * Unit of Hepato-gastroenterology, GIGA-R and Faculty of Medicine, University of Liège (B34), Liège, Belgium. * Catherine Reenaers & * Edouard Louis * Department of Gastroenterology, Örebro Medical Center Hospital, Örebro, Sweden. * Curt Tysk * Centre National de Génotypage, Evry, France. * Diana Zelenika & * Mark Lathrop * INSERM U843, Hopital Robert Debré, Paris, France. * Jean-Pierre Hugot Contributions Y.M., M.M., K.N., L.A., D.G. and D.Z. performed experiments. Y.M., W.C., P.d.R. and M.G. analyzed data. M. Lathrop and J.D.-F. supervised experiments. S.A., L.A., J.-F.C., O.D., Y.F., M.A.G., M. Lémann, C.O., C.R., P.R., C.T., J.-P.H., M.d.V., D.F., S.V. and E.L. examined cases and collected samples. I.C., D.L. and C.L. prepared and organized samples. Y.M. and M.G. wrote the manuscript. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Michel Georges Supplementary information * Accession codes * Author information * Supplementary information PDF files * Supplementary Text and Figures (1016K) Supplementary Note, Supplementary Tables 1–10 and Supplementary Figures 1–3 Additional data - Common variants in DGKK are strongly associated with risk of hypospadias
- Nat Genet 43(1):48-50 (2011)
Nature Genetics | Letter Common variants in DGKK are strongly associated with risk of hypospadias * Loes F M van der Zanden1, 2 Search for this author in: * NPG journals * PubMed * Google Scholar * Iris A L M van Rooij1 Search for this author in: * NPG journals * PubMed * Google Scholar * Wout F J Feitz3 Search for this author in: * NPG journals * PubMed * Google Scholar * Jo Knight4, 5 Search for this author in: * NPG journals * PubMed * Google Scholar * A Rogier T Donders1 Search for this author in: * NPG journals * PubMed * Google Scholar * Kirsten Y Renkema2 Search for this author in: * NPG journals * PubMed * Google Scholar * Ernie M H F Bongers2 Search for this author in: * NPG journals * PubMed * Google Scholar * Sita H H M Vermeulen1, 2 Search for this author in: * NPG journals * PubMed * Google Scholar * Lambertus A L M Kiemeney1, 3 Search for this author in: * NPG journals * PubMed * Google Scholar * Joris A Veltman2 Search for this author in: * NPG journals * PubMed * Google Scholar * Alejandro Arias-Vásquez2, 6 Search for this author in: * NPG journals * PubMed * Google Scholar * Xufeng Zhang7 Search for this author in: * NPG journals * PubMed * Google Scholar * Ellen Markljung7 Search for this author in: * NPG journals * PubMed * Google Scholar * Liang Qiao8 Search for this author in: * NPG journals * PubMed * Google Scholar * Laurence S Baskin8 Search for this author in: * NPG journals * PubMed * Google Scholar * Agneta Nordenskjöld7, 9 Search for this author in: * NPG journals * PubMed * Google Scholar * Nel Roeleveld1, 10 Search for this author in: * NPG journals * PubMed * Google Scholar * Barbara Franke2, 6, 10 Contact Barbara Franke Search for this author in: * NPG journals * PubMed * Google Scholar * Nine V A M Knoers2, 10 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorJournal name:Nature GeneticsVolume: 43,Pages:48–50Year published:(2011)DOI:doi:10.1038/ng.721Received13 July 2010Accepted02 November 2010Published online28 November 2010 Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Hypospadias is a common congenital malformation of the male external genitalia. We performed a genome-wide association study using pooled DNA from 436 individuals with hypospadias (cases) and 494 controls of European descent and selected the highest ranked SNPs for individual genotyping in the discovery sample, an additional Dutch sample of 133 cases and their parents, and a Swedish series of 266 cases and 402 controls. Individual genotyping of two SNPs (rs1934179 and rs7063116) in DGKK, encoding diacylglycerol kinase κ, produced compelling evidence for association with hypospadias in the discovery sample (allele-specific odds ratio (OR) = 2.5, P = 2.5 × 10−11 and OR = 2.3, P = 2.9 × 10−9, respectively) and in the Dutch (OR = 3.9, P = 2.4 × 10−5 and OR = 3.8, P = 3.4 × 10−5) and Swedish (OR = 2.5, P = 2.6 × 10−8 and OR = 2.2, P = 2.7 × 10−6) replication samples. Expression studies showed expression of DGKK in preputial tissue of cases and controls, which w! as lower in carriers of the risk allele of rs1934179 (P = 0.047). We propose DGKK as a major risk gene for hypospadias. View full text Author information * Author information * Supplementary information Primary authors * These authors contributed equally to this work. * Nel Roeleveld, * Barbara Franke & * Nine V A M Knoers Affiliations * Department of Epidemiology, Biostatistics and HTA, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. * Loes F M van der Zanden, * Iris A L M van Rooij, * A Rogier T Donders, * Sita H H M Vermeulen, * Lambertus A L M Kiemeney & * Nel Roeleveld * Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. * Loes F M van der Zanden, * Kirsten Y Renkema, * Ernie M H F Bongers, * Sita H H M Vermeulen, * Joris A Veltman, * Alejandro Arias-Vásquez, * Barbara Franke & * Nine V A M Knoers * Department of Urology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. * Wout F J Feitz & * Lambertus A L M Kiemeney * Division of Genetics and Molecular Medicine, King's College London School of Medicine, London, UK. * Jo Knight * National Institute for Health Research (NIHR), Biomedical Research Centre, Guy's and St. Thomas' National Health Service (NHS) Foundation Trust and King's College London, London, UK. * Jo Knight * Department of Psychiatry, Donders Institute for Brain, Cognition and Behavior, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. * Alejandro Arias-Vásquez & * Barbara Franke * Department of Women's and Children's Health and Center of Molecular Medicine, Karolinska Institutet, Stockholm, Sweden. * Xufeng Zhang, * Ellen Markljung & * Agneta Nordenskjöld * Department of Urology, University of California, San Francisco, California, USA. * Liang Qiao & * Laurence S Baskin * Department of Pediatric Surgery, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden. * Agneta Nordenskjöld Contributions L.F.M.v.d.Z. was the principal investigator who conducted the study. I.A.L.M.v.R., N.R., B.F. and N.V.A.M.K. designed the study and obtained financial support. L.F.M.v.d.Z., I.A.L.M.v.R., W.F.J.F., K.Y.R., E.M.H.F.B., S.H.H.M.V., L.A.L.M.K., N.R., B.F. and N.V.A.M.K. were involved in the collection of the discovery sample and the Dutch replication sample. J.A.V., A.A.-V. and B.F. collected the in-house controls. X.Z., E.M. and A.N. were responsible for the collection of the Swedish replication sample. L.Q. and L.S.B. collected the prepuce samples and performed the expression studies. L.F.M.v.d.Z. conducted all statistical analyses in collaboration with I.A.L.M.v.R., J.K. and A.R.T.D. L.F.M.v.d.Z. took primary responsibility for drafting the manuscript, with intellectual contributions, editing and approval from all other authors. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Barbara Franke Supplementary information * Author information * Supplementary information PDF files * Supplementary Text and Figures (1M) Supplementary Figures 1–3, Supplementary Tables 1–8 and Supplementary Note Additional data - Genome-wide association study identifies a locus at 7p15.2 associated with endometriosis
- Nat Genet 43(1):51-54 (2011)
Nature Genetics | Letter Genome-wide association study identifies a locus at 7p15.2 associated with endometriosis * Jodie N Painter1, 13 Contact Jodie N Painter Search for this author in: * NPG journals * PubMed * Google Scholar * Carl A Anderson2, 3, 13 Search for this author in: * NPG journals * PubMed * Google Scholar * Dale R Nyholt4, 13 Search for this author in: * NPG journals * PubMed * Google Scholar * Stuart Macgregor5 Search for this author in: * NPG journals * PubMed * Google Scholar * Jianghai Lin6 Search for this author in: * NPG journals * PubMed * Google Scholar * Sang Hong Lee5 Search for this author in: * NPG journals * PubMed * Google Scholar * Ann Lambert6 Search for this author in: * NPG journals * PubMed * Google Scholar * Zhen Z Zhao1 Search for this author in: * NPG journals * PubMed * Google Scholar * Fenella Roseman6 Search for this author in: * NPG journals * PubMed * Google Scholar * Qun Guo7 Search for this author in: * NPG journals * PubMed * Google Scholar * Scott D Gordon8 Search for this author in: * NPG journals * PubMed * Google Scholar * Leanne Wallace1 Search for this author in: * NPG journals * PubMed * Google Scholar * Anjali K Henders1 Search for this author in: * NPG journals * PubMed * Google Scholar * Peter M Visscher5 Search for this author in: * NPG journals * PubMed * Google Scholar * Peter Kraft9, 10 Search for this author in: * NPG journals * PubMed * Google Scholar * Nicholas G Martin8 Search for this author in: * NPG journals * PubMed * Google Scholar * Andrew P Morris2 Search for this author in: * NPG journals * PubMed * Google Scholar * Susan A Treloar1, 11, 14 Search for this author in: * NPG journals * PubMed * Google Scholar * Stephen H Kennedy6, 14 Search for this author in: * NPG journals * PubMed * Google Scholar * Stacey A Missmer7, 9, 12, 14 Search for this author in: * NPG journals * PubMed * Google Scholar * Grant W Montgomery1, 14 Search for this author in: * NPG journals * PubMed * Google Scholar * Krina T Zondervan2, 6, 14 Contact Krina T Zondervan Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorsJournal name:Nature GeneticsVolume: 43,Pages:51–54Year published:(2011)DOI:doi:10.1038/ng.731Received14 May 2010Accepted17 November 2010Published online12 December 2010 Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Endometriosis is a common gynecological disease associated with pelvic pain and subfertility. We conducted a genome-wide association study (GWAS) in 3,194 individuals with surgically confirmed endometriosis (cases) and 7,060 controls from Australia and the UK. Polygenic predictive modeling showed significantly increased genetic loading among 1,364 cases with moderate to severe endometriosis. The strongest association signal was on 7p15.2 (rs12700667) for 'all' endometriosis (P = 2.6 × 10−7, odds ratio (OR) = 1.22, 95% CI 1.13–1.32) and for moderate to severe disease (P = 1.5 × 10−9, OR = 1.38, 95% CI 1.24–1.53). We replicated rs12700667 in an independent cohort from the United States of 2,392 self-reported, surgically confirmed endometriosis cases and 2,271 controls (P = 1.2 × 10−3, OR = 1.17, 95% CI 1.06–1.28), resulting in a genome-wide significant P value of 1.4 × 10−9 (OR = 1.20, 95% CI 1.13–1.27) for 'all' endometriosis in our combined datasets of 5,! 586 cases and 9,331 controls. rs12700667 is located in an intergenic region upstream of the plausible candidate genes NFE2L3 and HOXA10. View full text Figures at a glance * Figure 1: Allele-specific score prediction for endometriosis, using the Oxford population as the discovery dataset and the QIMR population as the target dataset. Results for 'all' endometriosis are shown in , and results for stage B endometriosis are shown in . The variance explained in the target dataset on the basis of allele-specific scores derived in the discovery dataset for eight significance thresholds (P < 0.01, P < 0.05, P < 0.1, P < 0.2, P < 0.3, P < 0.4, P < 0.5 and P < 0.75, plotted left to right in each study). The y axis indicates Nagelkerke's pseudo R2 representing the proportion of variance explained. The number above each bar is the P value for the target dataset analysis. This figure shows that the results were not driven by a few highly associated regions, indicating a substantial number of common variants underlying disease. * Figure 2: Evidence for association with endometriosis across the chromosome 7 region following imputation using HapMap 3 and 1000 Genomes Project CEU and TSI reference panels. Results for 'all' endometriosis are shown in , and results for stage B endometriosis are shown in . rs12700667 is represented by a purple diamond. All other SNPs are color coded according to the strength of LD (as measured by r2) with rs12700667. Author information * Author information * Supplementary information Primary authors * These authors contributed equally to this work. * Jodie N Painter, * Carl A Anderson & * Dale R Nyholt Affiliations * Molecular Epidemiology, Queensland Institute of Medical Research, Herston, Queensland, Australia. * Jodie N Painter, * Zhen Z Zhao, * Leanne Wallace, * Anjali K Henders, * Susan A Treloar & * Grant W Montgomery * Genetic and Genomic Epidemiology Unit, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. * Carl A Anderson, * Andrew P Morris & * Krina T Zondervan * Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK. * Carl A Anderson * Neurogenetics Laboratory, Queensland Institute of Medical Research, Herston, Queensland, Australia. * Dale R Nyholt * Queensland Statistical Genetics, Queensland Institute of Medical Research, Herston, Queensland, Australia. * Stuart Macgregor, * Sang Hong Lee & * Peter M Visscher * Nuffield Department of Obstetrics and Gynaecology, University of Oxford, John Radcliffe Hospital, Oxford, UK. * Jianghai Lin, * Ann Lambert, * Fenella Roseman, * Stephen H Kennedy & * Krina T Zondervan * Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. * Qun Guo & * Stacey A Missmer * Genetic Epidemiology, Queensland Institute of Medical Research, Herston, Queensland, Australia. * Scott D Gordon & * Nicholas G Martin * Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA. * Peter Kraft & * Stacey A Missmer * Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, USA. * Peter Kraft * Centre for Military and Veterans' Health, The University of Queensland, Mayne Medical School, Queensland, Australia. * Susan A Treloar * Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. * Stacey A Missmer * These authors jointly directed this work. * Susan A Treloar, * Stephen H Kennedy, * Stacey A Missmer, * Grant W Montgomery & * Krina T Zondervan Contributions The International Endogene Consortium J.N.P., C.A.A., D.R.N., S.M., S.H.L., P.M.V., P.K., N.G.M., A.P.M., S.A.T., S.H.K., S.A.M., G.W.M., K.T.Z. J.N.P., C.A.A., D.R.N., P.M.V., N.G.M., S.M., A.P.M., S.A.T., S.H.K., S.A.M., G.W.M., K.T.Z. J.N.P., J.L., A.L., F.R., L.W., A.K.H., N.G.M., S.A.T., S.H.K., G.W.M., K.T.Z. Q.G., P.K., S.A.M. Z.Z.Z., A.K.H., G.W.M. GWAS analysis subgroup: J.N.P., C.A.A., D.R.N., S.D.G., A.P.M., K.T.Z.; proportion of variance subgroup: S.H.L., P.M.V.; polygenic prediction analysis subgroup: S.M., P.M.V.; replication and meta-analysis subgroup: J.N.P., D.R.N., Q.G., P.K. S.A.M., G.W.M.; imputation: D.R.N., A.P.M.; bioinformatic analysis subgroup: J.N.P., G.W.M., K.T.Z. S.M., N.G.M., S.A.T., S.H.K., S.A.M., G.W.M., K.T.Z. Competing financial interests The authors declare no competing financial interests. Corresponding authors Correspondence to: * Krina T Zondervan or * Jodie N Painter Supplementary information * Author information * Supplementary information PDF files * Supplementary Text and Figures (944K) Supplemementary Note, Supplementary Tables 1–4 and Supplementary Figures 1–3 Additional data - Genome-wide association study identifies susceptibility loci for polycystic ovary syndrome on chromosome 2p16.3, 2p21 and 9q33.3
- Nat Genet 43(1):55-59 (2011)
Nature Genetics | Letter Genome-wide association study identifies susceptibility loci for polycystic ovary syndrome on chromosome 2p16.3, 2p21 and 9q33.3 * Zi-Jiang Chen1, 2 Contact Zi-Jiang Chen Search for this author in: * NPG journals * PubMed * Google Scholar * Han Zhao1, 2, 25 Search for this author in: * NPG journals * PubMed * Google Scholar * Lin He3, 4, 5, 25 Search for this author in: * NPG journals * PubMed * Google Scholar * Yuhua Shi1, 2, 25 Search for this author in: * NPG journals * PubMed * Google Scholar * Yingying Qin1, 2 Search for this author in: * NPG journals * PubMed * Google Scholar * Yongyong Shi4 Search for this author in: * NPG journals * PubMed * Google Scholar * Zhiqiang Li4 Search for this author in: * NPG journals * PubMed * Google Scholar * Li You1, 2 Search for this author in: * NPG journals * PubMed * Google Scholar * Junli Zhao6 Search for this author in: * NPG journals * PubMed * Google Scholar * Jiayin Liu7 Search for this author in: * NPG journals * PubMed * Google Scholar * Xiaoyan Liang8 Search for this author in: * NPG journals * PubMed * Google Scholar * Xiaoming Zhao9 Search for this author in: * NPG journals * PubMed * Google Scholar * Junzhao Zhao10 Search for this author in: * NPG journals * PubMed * Google Scholar * Yingpu Sun11 Search for this author in: * NPG journals * PubMed * Google Scholar * Bo Zhang12 Search for this author in: * NPG journals * PubMed * Google Scholar * Hong Jiang13 Search for this author in: * NPG journals * PubMed * Google Scholar * Dongni Zhao14 Search for this author in: * NPG journals * PubMed * Google Scholar * Yuehong Bian1, 2 Search for this author in: * NPG journals * PubMed * Google Scholar * Xuan Gao1, 2 Search for this author in: * NPG journals * PubMed * Google Scholar * Ling Geng1, 2 Search for this author in: * NPG journals * PubMed * Google Scholar * Yiran Li15, 16 Search for this author in: * NPG journals * PubMed * Google Scholar * Dongyi Zhu17 Search for this author in: * NPG journals * PubMed * Google Scholar * Xiuqin Sun18 Search for this author in: * NPG journals * PubMed * Google Scholar * Jin-e Xu19 Search for this author in: * NPG journals * PubMed * Google Scholar * Cuifang Hao20 Search for this author in: * NPG journals * PubMed * Google Scholar * Chun-e Ren16 Search for this author in: * NPG journals * PubMed * Google Scholar * Yajie Zhang21 Search for this author in: * NPG journals * PubMed * Google Scholar * Shiling Chen22 Search for this author in: * NPG journals * PubMed * Google Scholar * Wei Zhang23 Search for this author in: * NPG journals * PubMed * Google Scholar * Aijun Yang24 Search for this author in: * NPG journals * PubMed * Google Scholar * Junhao Yan1, 2 Search for this author in: * NPG journals * PubMed * Google Scholar * Yuan Li1, 2 Search for this author in: * NPG journals * PubMed * Google Scholar * Jinlong Ma1, 2 Search for this author in: * NPG journals * PubMed * Google Scholar * Yueran Zhao1, 2 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorJournal name:Nature GeneticsVolume: 43,Pages:55–59Year published:(2011)DOI:doi:10.1038/ng.732Received13 July 2010Accepted03 November 2010Published online12 December 2010 Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Polycystic ovary syndrome (PCOS) is a common metabolic disorder in women. To identify causative genes, we conducted a genome-wide association study (GWAS) of PCOS in Han Chinese. The discovery set included 744 PCOS cases and 895 controls; subsequent replications involved two independent cohorts (2,840 PCOS cases and 5,012 controls from northern Han Chinese; 498 cases and 780 controls from southern and central Han Chinese). We identified strong evidence of associations between PCOS and three loci: 2p16.3 (rs13405728; combined P-value by meta-analysis Pmeta = 7.55 × 10−21, odds ratio (OR) 0.71); 2p21 (rs13429458, Pmeta = 1.73 × 10−23, OR 0.67); and 9q33.3 (rs2479106, Pmeta = 8.12 × 10−19, OR 1.34). These findings provide new insight into the pathogenesis of PCOS. Follow-up studies of the candidate genes in these regions are recommended. View full text Figures at a glance * Figure 1: Genome-wide association scan for PCOS. Negative log10P-values adjusted by principal component analysis (PCA) are shown for SNPs that passed quality control. The red line (5 × 10−8) is the global significance level, whereas the blue line (5 × 10−6) is the threshold used in our study. Chr., chromosome. * Figure 2: Regional plots of the three newly discovered PCOS loci (2p16.3, 2p21 and 9q33.3). (–) Genotyped SNPs passing quality control measures in GWAS plotted with the P-values (as −log10 values) as a function of genomic position (in the University of California Santa Cruz March 2006 human reference sequence, hg18). () 2p16.3. () 2p21. () 9q33.3. PGWAS and Pmeta represent the P-values of GWAS and meta-analysis. In each panel, the index association SNP is represented by a diamond. Estimated recombination rates (taken from HapMap) are plotted to reflect the local LD structure. Color of the remaining SNPs (circles) indicates LD with the index SNP according to a scale from r2 = 0 to r2 = 1 based on pairwise r2 values from HapMap JPT (Japanese in Tokyo) + CHB; gray, no r2 value available. Gene annotations were taken from the University of California Santa Cruz genome browser. LD blocks were obtained from the HapMap project (release 22, CHB + JPT). Author information * Author information * Supplementary information Primary authors * These authors contributed equally to this work. * Han Zhao, * Lin He & * Yuhua Shi Affiliations * Center for Reproductive Medicine, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, China. * Zi-Jiang Chen, * Han Zhao, * Yuhua Shi, * Yingying Qin, * Li You, * Yuehong Bian, * Xuan Gao, * Ling Geng, * Junhao Yan, * Yuan Li, * Jinlong Ma & * Yueran Zhao * Shandong Key Laboratory of Reproductive Medicine, Jinan, Shandong, China. * Zi-Jiang Chen, * Han Zhao, * Yuhua Shi, * Yingying Qin, * Li You, * Yuehong Bian, * Xuan Gao, * Ling Geng, * Junhao Yan, * Yuan Li, * Jinlong Ma & * Yueran Zhao * Institutes of Biomedical Sciences, Fudan University, Shanghai, China. * Lin He * Bio-X Center, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China. * Lin He, * Yongyong Shi & * Zhiqiang Li * Institute for Nutritional Sciences, Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences, Shanghai, China. * Lin He * Affiliated Hospital of Ningxia Medical University, Ningxia, China. * Junli Zhao * The First Affiliated Hospital with Nanjing Medical University, Jiangsu, China. * Jiayin Liu * The Sixth Affiliated Hospital of Sun Yat-sen University, Guangdong, China. * Xiaoyan Liang * Renji Hospital Affiliated to Shanghai Jiaotong University, Shanghai, China. * Xiaoming Zhao * The First Affiliated Hospital of Wenzhou Medical College, Zhejiang, China. * Junzhao Zhao * The First Affiliated Hospital of Zhengzhou University, Henan, China. * Yingpu Sun * Maternal and Child Health Hospital in Guangxi, Guangxi, China. * Bo Zhang * 105th Hospital of People's Liberation Army, Anhui, China. * Hong Jiang * Shengjing Hospital of China Medical University, Liaoning, China. * Dongni Zhao * Qingdao Women & Children Medical Healthcare Center, Shandong, China. * Yiran Li * Affiliated Hospital of Weifang Medical College, Shandong, China. * Yiran Li & * Chun-e Ren * Linyi People's Hospital, Shandong, China. * Dongyi Zhu * Shandong Jingning First People's Hospital, Shandong, China. * Xiuqin Sun * The Affiliated Hospital of Medical College Qingdao University, Shandong, China. * Jin-e Xu * Yantai Yuhuangding Hospital, Shandong, China. * Cuifang Hao * Jinan Health Institute of Maternity and Infant, Shandong, China. * Yajie Zhang * Nanfang Hospital, Guangdong, China. * Shiling Chen * Obstetrics & Gynecology Hospital of Fudan University, Shanghai, China. * Wei Zhang * Affiliated Hospital of Jining Medical College, Shandong, China. * Aijun Yang Contributions Z.-J.C., L.H. and Yongyong Shi designed the study and revised the manuscript. Z.-J.C. supervised patients' diagnosis, subject recruitment and performance of experiments. Yongyong Shi supervised the experiments and data analysis. H.Z. and Z.L. conducted data analyses and drafted the manuscript. H.Z., Yuhua Shi, Y.Q., L.Y., L.G. and J.Y. recruited subjects. Junli Zhao, J.L., X.L., X.Z., Junzhao Zhao, Y. Sun, B.Z., H.J., D. Zhao, Yiran Li, D. Zhu, X.S., J.-e.X., C.H., C.-e.R., Y. Zhang, S.C., W.Z. and A.Y. coordinated and provided samples from different hospitals. L.Y., Y.B., Yuan Li, J.M. and Y. Zhao performed DNA extraction. X.G. performed endocrine biochemical examination. All authors critically reviewed the article and approved the final manuscript. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Zi-Jiang Chen Supplementary information * Author information * Supplementary information PDF files * Supplementary Text and Figures (2M) Supplementary Figures 1–5 and Supplementary Tables 1–7 Additional data - Genome-wide association study of renal cell carcinoma identifies two susceptibility loci on 2p21 and 11q13.3
- Nat Genet 43(1):60-65 (2011)
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this author in: * NPG journals * PubMed * Google Scholar * Doris Lechner3 Search for this author in: * NPG journals * PubMed * Google Scholar * Ivo Gut3 Search for this author in: * NPG journals * PubMed * Google Scholar * Simon Heath3 Search for this author in: * NPG journals * PubMed * Google Scholar * Hélène Blanche71 Search for this author in: * NPG journals * PubMed * Google Scholar * Amy Hutchinson1, 9 Search for this author in: * NPG journals * PubMed * Google Scholar * Gilles Thomas1, 9 Search for this author in: * NPG journals * PubMed * Google Scholar * Zhaoming Wang1, 9 Search for this author in: * NPG journals * PubMed * Google Scholar * Meredith Yeager1, 9 Search for this author in: * NPG journals * PubMed * Google Scholar * Joseph F Fraumeni Jr1 Search for this author in: * NPG journals * PubMed * Google Scholar * Konstantin G Skryabin4, 5, 73 Search for this author in: * NPG journals * PubMed * Google Scholar * James D McKay2, 73 Search for this author in: * NPG journals * PubMed * Google Scholar * Nathaniel Rothman1, 73 Search for this author in: * NPG journals * PubMed * Google Scholar * Stephen J Chanock1, 73 Contact Stephen J Chanock Search for this author in: * NPG journals * PubMed * Google Scholar * Mark Lathrop3, 73 Search for this author in: * NPG journals * PubMed * Google Scholar * Paul Brennan2, 73 Contact Paul Brennan Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorsJournal name:Nature GeneticsVolume: 43,Pages:60–65Year published:(2011)DOI:doi:10.1038/ng.723Received03 May 2010Accepted05 November 2010Published online05 December 2010 Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg We conducted a two-stage genome-wide association study of renal cell carcinoma (RCC) in 3,772 affected individuals (cases) and 8,505 controls of European background from 11 studies and followed up 6 SNPs in 3 replication studies of 2,198 cases and 4,918 controls. Two loci on the regions of 2p21 and 11q13.3 were associated with RCC susceptibility below genome-wide significance. Two correlated variants (r2 = 0.99 in controls), rs11894252 (P = 1.8 × 10−8) and rs7579899 (P = 2.3 × 10−9), map to EPAS1 on 2p21, which encodes hypoxia-inducible-factor-2 alpha, a transcription factor previously implicated in RCC. The second locus, rs7105934, at 11q13.3, contains no characterized genes (P = 7.8 × 10−14). In addition, we observed a promising association on 12q24.31 for rs4765623, which maps to SCARB1, the scavenger receptor class B, member 1 gene (P = 2.6 × 10−8). Our study reports previously unidentified genomic regions associated with RCC risk that may lead to new etiolog! ical insights. View full text Figures at a glance * Figure 1: Association results, recombination and linkage disequilibrium plots for regions below genome-wide significance (2p21 and 11q13.3) and a region with a promising association (12q24.31) to RCC susceptibility. Results of pooled IARC-CNG and NCI GWAS data (GWAS), for SNPs selected for replication in replication studies combined by meta-analysis (replication), and of all studies combined by meta-analysis (all combined). P values for log-additive association results (−log10) are shown with recombination rates (cm/Mb) based on HapMap phase II data, and pairwise r2 and superimposed D′ values are displayed below for all SNPs included in the GWAS analysis. Coordinates refer to genome build 36.1. () A depiction of the region of 2p21 including the EPAS1 gene region (46,353,240–46,498,984 bp). () A depiction of the region of 11q13.3 (68,852,465–69,037,945 bp). () A depiction of the region of 12q24.31 including the SCARB1 gene region (123,800,267–124,008,657 bp). * Figure 2: Forest plots for three SNPs showing significant or promising association to RCC susceptibility. Forest plots show stratified odds ratios (ORs) for SNPs selected for replication. The two highly correlated SNPs located at 2p21, rs7579899 and rs11894252, gave very similar results in the stratified analysis, and only the results from one of the SNPs (rs11894252) are shown in the figure. Apart from the ORs for heterozygous and homozygous individuals, ORs and 95% CIs were estimated by the per-rare-allele log-additive trend model. All models were adjusted for sex, study and country. The overall log-additive OR is shown by the broken vertical line. P values indicate heterogeneity for OR within each group. Author information * Author information * Supplementary information Primary authors * These authors contributed equally to this work. * Mark P Purdue, * Mattias Johansson, * Diana Zelenika, * Jorge R Toro, * Ghislaine Scelo, * Lee E Moore & * Egor Prokhortchouk Affiliations * Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department Health and Human Services, Bethesda, Maryland, USA. * Mark P Purdue, * Jorge R Toro, * Lee E Moore, * Kevin B Jacobs, * Wong-Ho Chow, * Joanne S Colt, * Ann W Hsing, * Demetrius Albanes, * Stephanie J Weinstein, * Amy Hutchinson, * Gilles Thomas, * Zhaoming Wang, * Meredith Yeager, * Joseph F Fraumeni Jr, * Nathaniel Rothman & * Stephen J Chanock * International Agency for Research on Cancer (IARC), Lyon, France. * Mattias Johansson, * Ghislaine Scelo, * Valerie Gaborieau, * Isabelle Romieu, * James D McKay & * Paul Brennan * Commissariat à l'énergie Atomique, Institut Genomique, Centre National de Genotypage, Evry, France. * Diana Zelenika, * Mario Foglio, * Doris Lechner, * Ivo Gut, * Simon Heath & * Mark Lathrop * Center 'Bioengineering' of Russian Academy of Sciences, Moscow, Russia. * Egor Prokhortchouk, * Alexander M Mazur, * Nikolai N Chekanov & * Konstantin G Skryabin * Kurchatov Scientific Center, Moscow, Russia. * Egor Prokhortchouk, * Alexander M Mazur, * Eugenia S Boulygina & * Konstantin G Skryabin * Department of Epidemiology, Division of Cancer Prevention and Population Sciences, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. * Xifeng Wu, * Yuanqing Ye & * Xia Pu * Department of Epidemiology, Biostatistics and Health Technology Assessment, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. * Lambertus A Kiemeney, * Sita H Vermeulen & * Katja K H Aben * Department of Urology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. * Lambertus A Kiemeney & * Egbert Oosterwijk * Core Genotyping Facility, SAIC-Frederick Inc., National Cancer Institute-Frederick, Frederick, Maryland, USA. * Kevin B Jacobs, * Amy Hutchinson, * Gilles Thomas, * Zhaoming Wang & * Meredith Yeager * Russian N.N. Blokhin Cancer Research Centre, Moscow, Russia. * David Zaridze, * Vsevolod Matveev, * Anush Mukeria & * Oxana Shangina * International Hereditary Cancer Center, Department of Genetics and Pathomorphology, Pomeranian Medical University, Szczecin, Poland. * Jan Lubinski & * Joanna Trubicka * Department of Epidemiology, Institute of Occupational Medicine, Lodz, Poland. * Neonila Szeszenia-Dabrowska * Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland. * Jolanta Lissowska * National Institute of Environmental Health, Department of Environmental Epidemiology, Budapest, Hungary. * Péter Rudnai * Regional Authority of Public Health, Banská Bystrica, Slovakia. * Eleonora Fabianova * Institute of Public Health, Bucharest, Romania. * Alexandru Bucur * Charles University in Prague, First Faculty of Medicine, Institute of Hygiene and Epidemiology, Prague, Czech Republic. * Vladimir Bencko * Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic. * Lenka Foretova * Palacky University, Olomouc, Czech Republic. * Vladimir Janout * The Tisch Cancer Institute, Mount Sinai School of Medicine, New York, New York, USA. * Paolo Boffetta * Division of Epidemiology and Biostatistics, School of Public Health, University of Illinois at Chicago, Chicago, Illinois, USA. * Faith G Davis * Karmanos Cancer Institute and Department of Family Medicine, Wayne State University, Detroit, Michigan, USA. * Kendra L Schwartz * Cancer Research UK Centre, Leeds Institute of Molecular Medicine, St James's University Hospital, Leeds, UK. * Rosamonde E Banks & * Peter J Selby * Department of Pathology, St James's University Hospital, Leeds, UK. * Patricia Harnden * Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, USA. * Christine D Berg * Division of Urologic Surgery, Washington University School of Medicine, St. Louis, Missouri, USA. * Robert L Grubb III * Department of Epidemiology, German Institute of Human Nutrition, Potsdam-Rehbruecke, Nuthetal, Germany. * Heiner Boeing * School of Public Health, Imperial College London, London, UK. * Paolo Vineis, * Petra H M Peeters & * Elio Riboli * Medical Research Council-Health Protection Agency (MRC-HPA) Centre for Environment and Health, Imperial College London, London, UK. * Paolo Vineis * Human Genetics Foundation (HuGeF), Torino, Italy. * Paolo Vineis * Inserm, Centre for Research in Epidemiology and Population Health, Institut Gustave Roussy, Villejuif, France. * Françoise Clavel-Chapelon * Paris South University, UMRS 1018, Villejuif, France. * Françoise Clavel-Chapelon * Molecular and Nutritional Epidemiology Unit Cancer Research and Prevention Institute-ISPO, Florence, Italy. * Domenico Palli * Cancer Registry, Azienda Ospedaliera 'Civile MP Arezzo', Ragusa, Italy. * Rosario Tumino * Nutritional Epidemiology Unit, Fondazione Istituto Di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale dei Tumori, Milano, Italy. * Vittorio Krogh * Department of Clinical and Experimental Medicine, Federico II University, Naples, Italy. * Salvatore Panico * Unit of Nutrition, Environment and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology (ICO-IDIBELL), Barcelona, Spain. * Eric J Duell * Jefe Sección Información Sanitaria, Consejería de Servicios Sociales, Principado de Asturias, Oviedo, Spain. * José Ramón Quirós * Andalusian School of Public Health, Granada, Spain. * Maria-José Sanchez * CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain. * Maria-José Sanchez, * Carmen Navarro, * Eva Ardanaz & * Miren Dorronsoro * Department of Epidemiology, Regional Council of Health and Consumer Affairs, Murcia, Spain. * Carmen Navarro * Public Health Institute of Navarra, Pamplona, Spain. * Eva Ardanaz * Public Health Division of Gipuzkoa, Basque Regional Health Department, San Sebastian, Spain. * Miren Dorronsoro * Department of Gerontology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. * Kay-Tee Khaw * Cancer Epidemiology Unit, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK. * Naomi E Allen * National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands. * H Bas Bueno-de-Mesquita * Julius Center for Health Sciences and Primary Care, University Medical Center, Utrecht, The Netherlands. * Petra H M Peeters * Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA. * Dimitrios Trichopoulos * Bureau of Epidemiologic Research, Academy of Athens, Athens, Greece. * Dimitrios Trichopoulos * Division of Cancer Epidemiology, German Cancer Research Centre, Heidelberg, Germany. * Jakob Linseisen * Institute of Epidemiology, Helmholtz Centre Munich, Munich, Germany. * Jakob Linseisen * Department of Surgical and Perioperative Sciences, Urology and Andrology, Umeå University, Umeå, Sweden. * Börje Ljungberg * Department of Epidemiology, School of Public Health, Aarhus University, Aarhus, Denmark. * Kim Overvad, * Victoria L Stevens & * W Ryan Diver * The Danish Cancer Society, Institute of Cancer Epidemiology, Copenhagen, Denmark. * Anne Tjønneland * Epidemiology Research Program, American Cancer Society, Atlanta, Georgia, USA. * Michael J Thun & * Susan M Gapstur * Department of Oncology, University of Cambridge, Cambridge, UK. * Paul D Pharoah & * Douglas F Easton * Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. * Paul D Pharoah & * Douglas F Easton * Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland. * Jarmo Virtamo * Department of Public Health, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway. * Lars Vatten & * Kristian Hveem * Department of Community Medicine, University of Tromsø, Tromsø, Norway. * Inger Njølstad * Department of Public Health and Primary Health Care, University of Bergen, Bergen, Norway. * Grethe S Tell * Division of Epidemiology, Norwegian Institute of Public Health, Oslo, Norway. * Camilla Stoltenberg * Division of Molecular Genetic Epidemiology, German Cancer Research Center, Im Neuenheimer Feld, Heidelberg, Germany. * Rajiv Kumar * Department of Environmental Hygiene, Regional Authority of Public Health, Banska Bystrica, Slovakia. * Kvetoslava Koppova * CeRePP, Tenon Hospital Assistance Publique Hôpitaux de Paris (APHP) (ER2-University Paris 6), Paris, France. * Olivier Cussenot * INSERM, U946, Fondation Jean Dausset-Centre d'Etude du Polymorphisme Humain (CEPH), Paris, France. * Simone Benhamou * Centre National de la Recherche Scientifique (CNRS) UMR8200, Institute Gustave Roussy, Villejuif, France. * Simone Benhamou * Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. * Sita H Vermeulen & * Saskia L van der Marel * Department of Cancer Registry and Research, Comprehensive Cancer Centre East, Nijmegen, The Netherlands. * Katja K H Aben * Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. * Christopher G Wood * Fondation Jean Dausset-CEPH, Paris, France. * Hélène Blanche * The authors jointly directed this work. * Konstantin G Skryabin, * James D McKay, * Nathaniel Rothman, * Stephen J Chanock, * Mark Lathrop & * Paul Brennan Contributions M.P.P., M.J., J.R.T., G.S., L.E.M., V.G., W.-H.C., J.D.M., N.R., S.J.C. and P. Brennan contributed to the design and execution of the overall study. M.P.P., M.J., J.R.T., G.S., L.E.M., L.A.K., X.W., V.G., K.B.J., J.D.M., N.R., S.J.C. and P. Brennan contributed to the statistical analyses. M.P.P., M.J., S.J.C. and P. Brennan wrote the first draft of the manuscript. D. Zelenika, E.P., L.A.K., X.W., K.B.J., S.H.V., S.L.v.d.M., Y.Y., A.M.M., E.S.B., N.N.C., M.F., D.L., I.G., S.H., H. Blanche, A.H., G.S.T., Z.W., M.Y., K.G.S., S.J.C. and M.L. supervised or conducted the genotyping. The remaining authors conducted the epidemiologic studies and contributed samples to the GWAS and/or replication studies. All authors contributed to the writing of the manuscript. Competing financial interests The authors declare no competing financial interests. Corresponding authors Correspondence to: * Stephen J Chanock or * Paul Brennan Supplementary information * Author information * Supplementary information Excel files * Supplementary Table 2 (7M) Association results for SNPs imputed on 2p21 (EPAS1), 11q13.3, and 12q24.31 (SCARB1), using data from 1000 Genomes as scaffold PDF files * Supplementary Text and Figures (680K) Supplementary Tables 1, 3 and 4, Supplementary Figures 1–3 and Supplementary Note Additional data - Common variants in P2RY11 are associated with narcolepsy
- Nat Genet 43(1):66-71 (2011)
Nature Genetics | Letter Common variants in P2RY11 are associated with narcolepsy * Birgitte R Kornum1, 2 Search for this author in: * NPG journals * PubMed * Google Scholar * Minae Kawashima1, 3 Search for this author in: * NPG journals * PubMed * Google Scholar * Juliette Faraco1 Search for this author in: * NPG journals * PubMed * Google Scholar * Ling Lin1 Search for this author in: * NPG journals * PubMed * Google Scholar * Thomas J Rico1 Search for this author in: * NPG journals * PubMed * Google Scholar * Stephanie Hesselson4 Search for this author in: * NPG journals * PubMed * Google Scholar * Robert C Axtell5 Search for this author in: * NPG journals * PubMed * Google Scholar * Hedwich Kuipers5 Search for this author in: * NPG journals * PubMed * Google Scholar * Karin Weiner1 Search for this author in: * NPG journals * PubMed * Google Scholar * Alexandra Hamacher6 Search for this author in: * NPG journals * PubMed * Google Scholar * Matthias U Kassack6 Search for this author in: * NPG journals * PubMed * Google Scholar * Fang Han7 Search for this author in: * NPG journals * PubMed * Google Scholar * Stine Knudsen2 Search for this author in: * NPG journals * PubMed * Google Scholar * Jing Li7 Search for this author in: * NPG journals * PubMed * Google Scholar * Xiaosong Dong7 Search for this author in: * NPG journals * PubMed * Google Scholar * Juliane Winkelmann8, 9, 10 Search for this author in: * NPG journals * PubMed * Google Scholar * Giuseppe Plazzi11 Search for this author in: * NPG journals * PubMed * Google Scholar * Sona Nevsimalova12 Search for this author in: * NPG journals * PubMed * Google Scholar * Seung-Chul Hong13 Search for this author in: * NPG journals * PubMed * Google Scholar * Yutaka Honda14 Search for this author in: * NPG journals * PubMed * Google Scholar * Makoto Honda15 Search for this author in: * NPG journals * PubMed * Google Scholar * Birgit Högl16 Search for this author in: * NPG journals * PubMed * Google Scholar * Thanh G N Ton17, 18 Search for this author in: * NPG journals * PubMed * Google Scholar * Jacques Montplaisir19 Search for this author in: * NPG journals * PubMed * Google Scholar * Patrice Bourgin20 Search for this author in: * NPG journals * PubMed * Google Scholar * David Kemlink12 Search for this author in: * NPG journals * PubMed * Google Scholar * Yu-Shu Huang21, 22 Search for this author in: * NPG journals * PubMed * Google Scholar * Simon Warby1 Search for this author in: * NPG journals * PubMed * Google Scholar * Mali Einen1 Search for this author in: * NPG journals * PubMed * Google Scholar * Jasmin L Eshragh4 Search for this author in: * NPG journals * PubMed * Google Scholar * Taku Miyagawa3 Search for this author in: * NPG journals * PubMed * Google Scholar * Alex Desautels19 Search for this author in: * NPG journals * PubMed * Google Scholar * Elisabeth Ruppert20 Search for this author in: * NPG journals * PubMed * Google Scholar * Per Egil Hesla23 Search for this author in: * NPG journals * PubMed * Google Scholar * Francesca Poli11 Search for this author in: * NPG journals * PubMed * Google Scholar * Fabio Pizza11 Search for this author in: * NPG journals * PubMed * Google Scholar * Birgit Frauscher16 Search for this author in: * NPG journals * PubMed * Google Scholar * Jong-Hyun Jeong13 Search for this author in: * NPG journals * PubMed * Google Scholar * Sung-Pil Lee13 Search for this author in: * NPG journals * PubMed * Google Scholar * Kingman P Strohl24 Search for this author in: * NPG journals * PubMed * Google Scholar * William T Longstreth Jr17, 18 Search for this author in: * NPG journals * PubMed * Google Scholar * Mark Kvale4 Search for this author in: * NPG journals * PubMed * Google Scholar * Marie Dobrovolna25 Search for this author in: * NPG journals * PubMed * Google Scholar * Maurice M Ohayon1 Search for this author in: * NPG journals * PubMed * Google Scholar * Gerald T Nepom26 Search for this author in: * NPG journals * PubMed * Google Scholar * H-Erich Wichmann27, 28 Search for this author in: * NPG journals * PubMed * Google Scholar * Guy A Rouleau29, 30 Search for this author in: * NPG journals * PubMed * Google Scholar * Christian Gieger28 Search for this author in: * NPG journals * PubMed * Google Scholar * Douglas F Levinson1 Search for this author in: * NPG journals * PubMed * Google Scholar * Pablo V Gejman31 Search for this author in: * NPG journals * PubMed * Google Scholar * Thomas Meitinger8, 9, 10 Search for this author in: * NPG journals * PubMed * Google Scholar * Paul Peppard32 Search for this author in: * NPG journals * PubMed * Google Scholar * Terry Young32 Search for this author in: * NPG journals * PubMed * Google Scholar * Poul Jennum2 Search for this author in: * NPG journals * PubMed * Google Scholar * Lawrence Steinman5 Search for this author in: * NPG journals * PubMed * Google Scholar * Katsushi Tokunaga3 Search for this author in: * NPG journals * PubMed * Google Scholar * Pui-Yan Kwok4 Search for this author in: * NPG journals * PubMed * Google Scholar * Neil Risch4, 33, 34 Search for this author in: * NPG journals * PubMed * Google Scholar * Joachim Hallmayer1 Search for this author in: * NPG journals * PubMed * Google Scholar * Emmanuel Mignot1 Contact Emmanuel Mignot Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorJournal name:Nature GeneticsVolume: 43,Pages:66–71Year published:(2011)DOI:doi:10.1038/ng.734Received20 July 2010Accepted19 November 2010Published online19 December 2010 Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Growing evidence supports the hypothesis that narcolepsy with cataplexy is an autoimmune disease. We here report genome-wide association analyses for narcolepsy with replication and fine mapping across three ethnic groups (3,406 individuals of European ancestry, 2,414 Asians and 302 African Americans). We identify a SNP in the 3′ untranslated region of P2RY11, the purinergic receptor subtype P2Y11 gene, which is associated with narcolepsy (rs2305795, combined P = 6.1 × 10−10, odds ratio = 1.28, 95% CI 1.19–1.39, n = 5689). The disease-associated allele is correlated with reduced expression of P2RY11 in CD8+ T lymphocytes (339% reduced, P = 0.003) and natural killer (NK) cells (P = 0.031), but not in other peripheral blood mononuclear cell types. The low expression variant is also associated with reduced P2RY11-mediated resistance to ATP-induced cell death in T lymphocytes (P = 0.0007) and natural killer cells (P = 0.001). These results identify P2RY11 as an important ! regulator of immune-cell survival, with possible implications in narcolepsy and other autoimmune diseases. View full text Figures at a glance * Figure 1: Risk locus on 19q13.2, showing gene organization and linkage disequilibrium in the region of interest (10,071,000–10,130,000 bp). At top, the D′ and LOD-based LD plot using data from the combined Chinese and Japanese populations (CHB/JPT). Below, the D′ and LOD-based LD plot for individuals of European ancestry only (CEU/TSI). We calculated D′ values from the HapMap v3R2 CHB, JPT, CEU and TSI populations. In addition, r2 values between the original marker, rs4804122 (green), and the best transethnic marker, rs2305795 (orange), derived from our own data are indicated. rs2305795 falls in the 3′UTR of P2RY11. * Figure 2: P2RY11 mRNA expression in PBMCs. () Expression in PBMCs from 116 subjects with various rs2305795 genotypes (mean + s.e.m., 60 cases and 56 controls; AA, n = 49; AG, n = 51; GG, n = 16). As we observed no direct effect of disease status on P2RY11 expression, subjects were grouped by genotype. The P2RY11 rs2305795 AA genotype resulted in a 53% reduction in P2RY11 expression compared to the rs2305795 GG genotype and was associated with increased risk of narcolepsy. () P2RY11 expression by rs2305795 genotype in various immune cell subsets (mean + s.e.m., n = 7–8 normal controls per genotype category). NK cells, CD56+ natural killer cells; B cells, CD19+ B cells; Monocy., CD14+ monocytes; DCs, myeloid/plasmacytoid dendritic cells. Shown are Bonferroni-corrected one-way analysis of variance (ANOVA) P values. * Figure 3: PBMC cell death induced by ATP was inhibited by the stimulation of P2RY11 and varied by rs2305795 genotype. () The effect of ATP on cell viability and the dose response of co-incubation with the P2RY11-specific agonist NF546 and the antagonist NF340 (mean + s.e.m., n = 7–8 rs2305795 AG control subjects). Overall one-way ANOVA P values are shown, with Tukey's post test. *, significantly different from control with no ATP, P < 0.01; #, significantly different from treatment with 100 μM ATP but no NF546, P < 0.01; $, significantly different from treatment with 100 μM ATP and 100 μM NF546, P < 0.01. () Effect of the rs2305795 genotype on the percent of cells rescued from ATP-induced cell death by P2RY11 stimulation. Ten micromolar NF546 has a less potent effect on cell survival after ATP-induced cell death with the rs2305795 AA genotype compared to the rs2305795 GG genotype. Heterozygote subjects fall in between. Mean + s.e.m., n = 9 subjects in each group. * Figure 4: Effect of ATP and P2RY11 co-stimulation on different immune cell subtypes. PBMCs were co-incubated with 100 μM ATP and the P2RY11-specific agonist NF546 in different doses and the effect on different cell fractions was determined by FACS. We saw an effect from the rs2305795 genotype in T lymphocytes and natural killer (NK) cells but not in B lymphocytes and monocytes. Shown are mean + s.e.m., n = 8 per column and P values are from one-way ANOVAs. Dashed lines represent 100% survival. Accession codes * Accession codes * Author information * Supplementary information Referenced accessions Entrez Nucleotide * NM_002566.4 * NM_020230.4 * NM_003755.3 * NM_001130823.1 Author information * Accession codes * Author information * Supplementary information Affiliations * Center for Sleep Sciences and Department of Psychiatry, Stanford University School of Medicine, Palo Alto, California, USA. * Birgitte R Kornum, * Minae Kawashima, * Juliette Faraco, * Ling Lin, * Thomas J Rico, * Karin Weiner, * Simon Warby, * Mali Einen, * Maurice M Ohayon, * Douglas F Levinson, * Joachim Hallmayer & * Emmanuel Mignot * Danish Center for Sleep Medicine, University of Copenhagen, Glostrup Hospital, Glostrup, Denmark. * Birgitte R Kornum, * Stine Knudsen & * Poul Jennum * Department of Human Genetics, University of Tokyo, Tokyo, Japan. * Minae Kawashima, * Taku Miyagawa & * Katsushi Tokunaga * Institute for Human Genetics, University of California San Francisco School of Medicine, San Francisco, California, USA. * Stephanie Hesselson, * Jasmin L Eshragh, * Mark Kvale, * Pui-Yan Kwok & * Neil Risch * Department of Neurology and Neurological Sciences, Stanford University, Stanford, California, USA. * Robert C Axtell, * Hedwich Kuipers & * Lawrence Steinman * Institute of Pharmaceutical and Medicinal Chemistry, Pharmaceutical Biochemistry, Heinrich-Heine-University of Düsseldorf, Düsseldorf, Germany. * Alexandra Hamacher & * Matthias U Kassack * Department of Pulmonary Medicine, The People's Hospital, Beijing University, Beijing, China. * Fang Han, * Jing Li & * Xiaosong Dong * Institute for Human Genetics, Technische Universität München, Munich, Germany. * Juliane Winkelmann & * Thomas Meitinger * Department of Neurology, Technische Universität München, Munich, Germany. * Juliane Winkelmann & * Thomas Meitinger * Institute of Human Genetics, Helmholtz Zentrum München—German Research Center for Environmental Health, Neuherberg, Germany. * Juliane Winkelmann & * Thomas Meitinger * Department of Neurological Sciences, University of Bologna, Bologna, Italy. * Giuseppe Plazzi, * Francesca Poli & * Fabio Pizza * Department of Neurology, 1st Faculty of Medicine, Charles University in Prague and General University Hospital, Prague, Czech Republic. * Sona Nevsimalova & * David Kemlink * Department of Neuropsychiatry, St. Vincent's Hospital, The Catholic University of Korea, Suwon, Korea. * Seung-Chul Hong, * Jong-Hyun Jeong & * Sung-Pil Lee * Japan Somnology Center, Neuropsychiatric Research Institute, Tokyo, Japan. * Yutaka Honda * Tokyo Institute of Psychiatry, Tokyo Metropolitan Organization for Medical Research, Tokyo, Japan. * Makoto Honda * Department of Neurology, Innsbruck Medical University, Innsbruck, Austria. * Birgit Högl & * Birgit Frauscher * Department of Neurology, University of Washington, Seattle, Washington, USA. * Thanh G N Ton & * William T Longstreth Jr * Department of Epidemiology, University of Washington, Seattle, Washington, USA. * Thanh G N Ton & * William T Longstreth Jr * Sleep Disorders Center, Université de Montréal, Montréal, Québec, Canada. * Jacques Montplaisir & * Alex Desautels * Sleep Clinic, Hôpital Civil, Louis Pasteur University, Strasbourg, France. * Patrice Bourgin & * Elisabeth Ruppert * Department of Child Psychiatry, Chang Gung Memorial University Hospital, Taipei, Taiwan. * Yu-Shu Huang * Department of Sleep Medicine, Chang Gung Memorial University Hospital, Taipei, Taiwan. * Yu-Shu Huang * Electroencephalography (EEG) Laboratory, Medical Section, Coliseum on Majorstua Clinic, Oslo, Norway. * Per Egil Hesla * Division of Pulmonary and Critical Care Medicine, Veterans Administation Medical Center, Cleveland, Ohio, USA. * Kingman P Strohl * HLA Typing Lab, National Reference Laboratory for DNA Diagnostics, Institute of Hematology and Blood Transfusion, Prague, Czech Republic. * Marie Dobrovolna * The Benaroya Research Institute at Virginia Mason, Seattle, Washington, USA. * Gerald T Nepom * Institute of Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Munich, Germany. * H-Erich Wichmann * Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians—Universität, Munich, Germany. * H-Erich Wichmann & * Christian Gieger * Center of Excellence in Neuromics, Centre de recherche du Centre hospitalier de l'Université de Montréal, Montréal, Québec, Canada. * Guy A Rouleau * Department of Medicine, Université de Montréal, Montréal, Québec, Canada. * Guy A Rouleau * Department of Psychiatry and Behavioral Sciences, Evanston Northwestern Healthcare Research Institute, Evanston, Illinois, USA. * Pablo V Gejman * Department of Population Health Sciences, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA. * Paul Peppard & * Terry Young * Kaiser Permanente Northern California Division of Research, Oakland, California, USA. * Neil Risch * Department of Epidemiology and Biostatistics, University of California San Francisco School of Medicine, San Francisco, California, USA. * Neil Risch Contributions E.M., B.R.K., J.H. and N.R. designed the study with valuable input from R.C.A., H.K., L.S., K.T. and P.Y.K. B.R.K., M. Kawashima, L.L., S.H., R.C.A., H.K., K.W., J.L.E. and T. Miyagawa generated molecular data. A.H. and M.U.K. provided the P2RY11 agonist and antagonist. B.R.K., J.F., J.H., E.M. and N.R. participated in the data analysis. B.R.K. and E.M. wrote the manuscript. J.F., S.W., M. Kvale, D.F.L., N.R. and J.H. read and substantially commented on the manuscript. E.M., F.H., S.K., J.L., X.D., G.P., S.N., S.C.H., Y.H., M.H., B.H., J.M., P.B., D.K., Y.S.H., M.E., A.D., E.R., P.E.H., F. Poli, F. Pizza, B.F., J.H.J., S.-P.L., K.P.S., W.T.L., M.M.O. and P.J. contributed narcolepsy samples. T.J.R., J.W., T.G.N.T., M.D., G.T.N., H.-E.W., G.A.R., C.G., T. Meitinger, P.P. and T.Y. provided samples and/or genotypes. E.M. provided financial support. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Emmanuel Mignot Supplementary information * Accession codes * Author information * Supplementary information PDF files * Supplementary Text and Figures (120K) Supplementary Tables 1–3 Additional data - CCDC39 is required for assembly of inner dynein arms and the dynein regulatory complex and for normal ciliary motility in humans and dogs
- Nat Genet 43(1):72-78 (2011)
Nature Genetics | Letter CCDC39 is required for assembly of inner dynein arms and the dynein regulatory complex and for normal ciliary motility in humans and dogs * Anne-Christine Merveille1, 24 Search for this author in: * NPG journals * PubMed * Google Scholar * Erica E Davis2, 24 Search for this author in: * NPG journals * PubMed * Google Scholar * Anita Becker-Heck3, 4, 5, 24 Search for this author in: * NPG journals * PubMed * Google Scholar * Marie Legendre6, 24 Search for this author in: * NPG journals * PubMed * Google Scholar * Israel Amirav7, 8 Search for this author in: * NPG journals * PubMed * Google Scholar * Géraldine Bataille1 Search for this author in: * NPG journals * PubMed * Google Scholar * John Belmont9 Search for this author in: * NPG journals * PubMed * Google Scholar * Nicole Beydon10 Search for this author in: * NPG journals * PubMed * Google Scholar * Frédéric Billen11 Search for this author in: * NPG journals * PubMed * Google Scholar * Annick Clément12 Search for this author in: * NPG journals * PubMed * Google Scholar * Cécile Clercx11 Search for this author in: * NPG journals * PubMed * Google Scholar * André Coste13 Search for this author in: * NPG journals * PubMed * Google Scholar * Rachelle Crosbie14 Search for this author in: * NPG journals * PubMed * Google Scholar * Jacques de Blic15 Search for this author in: * NPG journals * PubMed * Google Scholar * Stephane Deleuze11 Search for this author in: * NPG journals * PubMed * Google Scholar * Philippe Duquesnoy6 Search for this author in: * NPG journals * PubMed * Google Scholar * Denise Escalier6 Search for this author in: * NPG journals * PubMed * Google Scholar * Estelle Escudier6 Search for this author in: * NPG journals * PubMed * Google Scholar * Manfred Fliegauf3 Search for this author in: * NPG journals * PubMed * Google Scholar * Judith Horvath3 Search for this author in: * NPG journals * PubMed * Google Scholar * Kent Hill14 Search for this author in: * NPG journals * PubMed * Google Scholar * Mark Jorissen16 Search for this author in: * NPG journals * PubMed * Google Scholar * Jocelyne Just17 Search for this author in: * NPG journals * PubMed * Google Scholar * Andreas Kispert18 Search for this author in: * NPG journals * PubMed * Google Scholar * Mark Lathrop19 Search for this author in: * NPG journals * PubMed * Google Scholar * Niki Tomas Loges3, 5 Search for this author in: * NPG journals * PubMed * Google Scholar * June K Marthin20 Search for this author in: * NPG journals * PubMed * Google Scholar * Yukihide Momozawa1 Search for this author in: * NPG journals * PubMed * Google Scholar * Guy Montantin6 Search for this author in: * NPG journals * PubMed * Google Scholar * Kim G Nielsen21 Search for this author in: * NPG journals * PubMed * Google Scholar * Heike Olbrich3, 6 Search for this author in: * NPG journals * PubMed * Google Scholar * Jean-François Papon6, 13 Search for this author in: * NPG journals * PubMed * Google Scholar * Isabelle Rayet20 Search for this author in: * NPG journals * PubMed * Google Scholar * Gilles Roger22 Search for this author in: * NPG journals * PubMed * Google Scholar * Miriam Schmidts3 Search for this author in: * NPG journals * PubMed * Google Scholar * Henrique Tenreiro6 Search for this author in: * NPG journals * PubMed * Google Scholar * Jeffrey A Towbin9 Search for this author in: * NPG journals * PubMed * Google Scholar * Diana Zelenika19 Search for this author in: * NPG journals * PubMed * Google Scholar * Hanswalter Zentgraf23 Search for this author in: * NPG journals * PubMed * Google Scholar * Michel Georges1 Contact Michel Georges Search for this author in: * NPG journals * PubMed * Google Scholar * Anne-Sophie Lequarré1, 25 Search for this author in: * NPG journals * PubMed * Google Scholar * Nicholas Katsanis2, 25 Search for this author in: * NPG journals * PubMed * Google Scholar * Heymut Omran3, 5, 25 Search for this author in: * NPG journals * PubMed * Google Scholar * Serge Amselem6, 25 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorJournal name:Nature GeneticsVolume: 43,Pages:72–78Year published:(2011)DOI:doi:10.1038/ng.726Received04 June 2010Accepted10 November 2010Published online05 December 2010 Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Primary ciliary dyskinesia (PCD) is an inherited disorder characterized by recurrent infections of the upper and lower respiratory tract, reduced fertility in males and situs inversus in about 50% of affected individuals (Kartagener syndrome). It is caused by motility defects in the respiratory cilia that are responsible for airway clearance, the flagella that propel sperm cells and the nodal monocilia that determine left-right asymmetry1. Recessive mutations that cause PCD have been identified in genes encoding components of the outer dynein arms, radial spokes and cytoplasmic pre-assembly factors of axonemal dyneins, but these mutations account for only about 50% of cases of PCD. We exploited the unique properties of dog populations to positionally clone a new PCD gene, CCDC39. We found that loss-of-function mutations in the human ortholog underlie a substantial fraction of PCD cases with axonemal disorganization and abnormal ciliary beating. Functional analyses indicated ! that CCDC39 localizes to ciliary axonemes and is essential for assembly of inner dynein arms and the dynein regulatory complex. View full text Figures at a glance * Figure 1: Positional identification of CCDC39 as the gene that underlies PCD in Bobtails. () Old English Sheepdog (Bobtail). Representative TEM images of disorganized cilia identified in nasal mucosal biopsies of cases (PCD) and normal cilia from a healthy dog (CTR). () Positional identification of the p.Arg96X alteration in CCDC39. Homozygosity mapping identified a genome-wide significant signal on chromosome CFA34, corresponding to a 15-Mb segment shared homozygous-by-descent by 5 affected animals and encompassing 151 annotated protein-coding genes, of which 10 were included in the ciliome or cilia proteome database (or both). Sequencing CCDC39 in affected individuals revealed a C>T transition in the third exon of the main isoform, creating a stop codon that causes nonsense-mediated RNA decay. d, disease. * Figure 2: Expression and functional studies in mouse and zebrafish. () Whole-mount in situ hybridization analysis of mouse Ccdc39 in mouse embryos. Ccdc39 expression is restricted to the node in embryos at embryonic day (E) 7.75–8.0 (arrowheads). In E16.5 mouse embryonic sections, Ccdc39 (arrowheads) is expressed in ciliated cells of the upper and lower airways. () Dose-response curve of ccdc39 translation-blocking morpholino (tb-MO). Wildtype zebrafish embryos were injected with increasing concentrations of tb-MO and were scored live at 36 h post fertilization for heart looping (left, right, no loop). () Dose-response curve of ccdc39 splice-blocking MO. Scoring was conducted as in . () Quantification of spaw staining in embryo batches injected with 4 ng ccdc39 morpholino or 4 ng ccdc39 morpholino plus 25 pg wildtype (WT) human CCDC39 mRNA (n = 24–30 embryos per injection). () Representative spaw RNA in situ staining in 14 somite-stage embryos. In wildtype embryos, spaw is expressed in the left lateral plate mesoderm (lpm; left); however! , ccdc39 morphant embryos showed bilateral (center) or, in most cases, undetectable spaw expression (right). * Figure 3: Ultrastructural and mutational analysis of human PCD cases with axonemal disorganization. () Electron microscopy of respiratory cilia from an individual (DCP85) who is homozygous for the CCDC39 mutation resulting in the p.Glu731AsnfsX31 alteration. It shows the absence of inner dynein arms in all ciliary sections, associated with a range of other, heterogeneous defects: isolated absence of the nine inner dynein arms (1), axonemal disorganization with mislocalized peripheral doublet associated with either a displacement of the central pair (2), an absence of the central pair (3), or supernumerary central pairs (4). Magnification of the axoneme from a normal cilium is shown in the upper right panel with presence of inner dynein arms (black arrow), nexin links (white arrow) and radial spokes (short arrow). The axonemal disorganization found in cases is associated with defects of inner dynein arms (black flash), nexin links (white flash) and radial spokes (star) that are better seen after magnification (lower right panel). Scale bar, 0.2 μm. () Unambiguous disease-c! ausing CCDC39 mutations detected in PCD cases with axonemal disorganization. Exonic organization of the human CCDC39 cDNA (top) and domain organization model of the corresponding protein (bottom). The 20 coding exons are indicated by empty or hashed boxes, depicting translated or untranslated sequences, respectively. 'SMC_N' and 'SMC_Prok_B' refer to domains homologous to the N terminus of SMC (structural maintenance of chromosomes) proteins and to the common bacterial type SMC protein, respectively. The predicted coiled-coil domains of the protein are indicated by green rectangles. The canine p.Arg96X alteration is shown in green. The splice mutation leading to the inclusion of pseudo-exon 9 is underlined. * Figure 4: Subcellular localization of CCDC39 in respiratory epithelial cells from individuals with PCD carrying CCDC39 mutations. Axoneme-specific antibodies against acetylated α-tubulin (green) were used as the control. Nuclei were stained with Hoechst 33342 (blue). () In respiratory epithelial cells from healthy probands, CCDC39 (red) localized predominantly along the entire length of the axonemes, as well as to the apical cytoplasm. () In respiratory epithelial cells from individuals OP-736 II2 (), OP-736 II1 (), OP-122 () and OP-18 II1 () carrying CCDC39 loss-of function mutations, CCDC39 was absent from the axoneme and markedly reduced in the apical cytoplasm. White scale bars, 5 μm. * Figure 5: Subcellular localization of DNAH5, DNALI1 and GAS11 in respiratory epithelial cells from individuals with PCD carrying CCDC39 mutations. Immunofluorescence analyses of human respiratory epithelial cells using antibodies to the outer dynein arm heavy chain DNAH5 (), the inner dynein arm component DNALI1 () and the DRC component GAS11 (). Axoneme-specific antibodies to acetylated α-tubulin () or α/β-tubulin () were used as controls. Nuclei were stained with Hoechst 33342 (blue). The localization of DNAH5 (red) in respiratory epithelial cells from case OP-736 II1 was unchanged (). DNALI1 (green) localized along the entire length of the axonemes of respiratory epithelial cells from healthy probands (). In epithelial cells from case OP-736 II1, DNALI1 (green) was absent from the ciliary axonemes (). In respiratory epithelial cells from healthy probands, GAS11 (green) localizes along the entire length of the axonemes (). In respiratory epithelial cells from case OP-736 II1, GAS11 (green) was targeted to the ciliary base, where it accumulated (). White scale bars, 5 μm. Accession codes * Accession codes * Author information * Supplementary information Referenced accessions Entrez Nucleotide * XM_545213.2 * NM_181426.1 * NM_026222.2 * XM_677617.4 Author information * Accession codes * Author information * Supplementary information Primary authors * These authors contributed equally to this work. * Anne-Christine Merveille, * Erica E Davis, * Anita Becker-Heck & * Marie Legendre Affiliations * Unit of Animal Genomics, Groupe Interdisciplinaire de Genomique Appliquee-Recherche (GIGA-R) and Faculty of Veterinary Medicine, University of Liège (B34), Liège, Belgium. * Anne-Christine Merveille, * Géraldine Bataille, * Yukihide Momozawa, * Michel Georges & * Anne-Sophie Lequarré * Center for Human Disease Modeling, Department of Cell Biology, Duke University Medical Center, Durham, North Carolina, USA. * Erica E Davis & * Nicholas Katsanis * Department of Pediatrics and Adolescent Medicine, University Hospital Freiburg, Freiburg, Germany. * Anita Becker-Heck, * Manfred Fliegauf, * Judith Horvath, * Niki Tomas Loges, * Heike Olbrich, * Miriam Schmidts & * Heymut Omran * Faculty of Biology, Albert-Ludwigs-University, Freiburg, Germany. * Anita Becker-Heck * Department of General Pediatrics, University Children's Hospital Münster, Münster, Germany. * Anita Becker-Heck, * Niki Tomas Loges & * Heymut Omran * Institut National de la Santé et de la Recherche Médicale (INSERM) U.933, Université Pierre et Marie Curie-Paris 6 and Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Armand-Trousseau, Paris, France. * Marie Legendre, * Philippe Duquesnoy, * Denise Escalier, * Estelle Escudier, * Guy Montantin, * Heike Olbrich, * Jean-François Papon, * Henrique Tenreiro & * Serge Amselem * Department of Pediatrics, Ziv Medical Center, Safed, Israel. * Israel Amirav * Rapaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel. * Israel Amirav * Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA. * John Belmont & * Jeffrey A Towbin * AP-HP, Hôpital Armand-Trousseau, Service d′explorations fonctionnelles respiratoires, Paris, France. * Nicole Beydon * Department of Clinical Sciences, Faculty of Veterinary Medicine, University of Liège, Belgium. * Frédéric Billen, * Cécile Clercx & * Stephane Deleuze * AP-HP, Hôpital Armand-Trousseau, Unité de pneumologie pédiatrique, Centre de Référence des Maladies Respiratoires Rares, Paris, France. * Annick Clément * AP-HP, Hôpital Intercommunal et Groupe Hospitalier Henri Mondor-Albert Chenevier, Service d'ORL et de chirurgie cervico-faciale, Créteil, France. * André Coste & * Jean-François Papon * Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, California, USA. * Rachelle Crosbie & * Kent Hill * AP-HP, Groupe Hospitalier Necker-Enfants Malades, Service de pneumologie et d'allergologie pédiatriques, Paris, France. * Jacques de Blic * Department of Otorhinolaryngology, Head and Neck Surgery, University Hospitals Leuven, Leuven, Belgium. * Mark Jorissen * AP-HP, Hôpital Armand-Trousseau, Centre d'investigation de l'asthme et des allergies, Paris, France. * Jocelyne Just * Institut für Molekularbiologie, Medizinische Hochschule Hannover, Hannover, Germany. * Andreas Kispert * Centre National de Génotypage, Evry, France. * Mark Lathrop & * Diana Zelenika * Hôpital Nord, Service de réanimation pédiatrique, Centre Hospitalier Universitaire de Saint-Etienne, Saint-Etienne, France. * June K Marthin & * Isabelle Rayet * Copenhagen University Hospital, Rigshospitalet, Danish Primary Ciliary Dyskinesia Center, Pediatric Pulmonary Service, Copenhagen, Denmark. * Kim G Nielsen * AP-HP, Hôpital Armand-Trousseau, Service d'ORL et de chirurgie cervico-faciale pédiatrique, Paris, France. * Gilles Roger * Department of Tumor Virology, German Cancer Research Center, Heidelberg, Germany. * Hanswalter Zentgraf * These authors jointly supervised this work. * Anne-Sophie Lequarré, * Nicholas Katsanis, * Heymut Omran & * Serge Amselem Contributions The positional cloning of CCDC39 in the dog was performed by A.-C.M. and G.B. Genome-wide SNP genotyping was conducted at CNG under supervision of M. Lathrop and D.Z. Mining the ciliome databases was conducted by E.E.D. Experiments in the zebrafish were conducted by E.E.D. In situ hybridization in the mouse was conducted by A.K. and H.O. qRT-PCR on human samples was conducted by M. Legendre, P.D., G.M. and H.T. Sequencing of CCDC39 in human subjects, including high-throughput sequencing, was conducted by A.-C.M., G.B., Y.M., A.B.-H., M. Legendre, E.E., P.D., G.M. and H.T. Identifying the p.Glu390SerfsX6 mutation was realized by M. Legendre, P.D., G.M. and H.T. Haplotype analysis to determine founder status of CCDC39 mutations was conducted by M. Legendre and P.D. TEM analysis was conducted by M.J. (dog), E.E. and D.E. (French cohort), and by K.G.N., J.K.M., H.O. and routine laboratories (German cohort). High-resolution immunofluorescence analyses were done by A.B.-H., M.F., ! J.H. and N.T.L. Immunoblotting analyses were done by A.B.-H. High-speed video analyses were conducted by H.O., N.T.L. and A.B.-H. Monoclonal anti-GAS11 antibody was produced by A.B.-H. and H.Z. Polyclonal anti-GAS11 antibodies were provided by K.H. and R.C. Clinical examination and collection of the canine PCD cases was conducted by F.B., C.C. and S.D. M.G., A.-S.L., N.K., H.O. and S.A. designed experiments, analyzed data and wrote the manuscript. All remaining authors as well as H.O., K.G.N. and J.K.M. examined and contributed samples from individuals with PCD or heterotaxia. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Michel Georges Supplementary information * Accession codes * Author information * Supplementary information Movies * Supplemental Video 1 (1M) Ciliary beating pattern of PCD patient OP122 with CCDC39 mutations assessed by high-speed videomicroscopy analyses of respiratory cells obtained by nasal brushing biopsy * Supplemental Video 2 (4M) Ciliary beating pattern of a healthy control individual assessed by high-speed videomicroscopy analyses of respiratory cells obtained by nasal brushing biopsy PDF files * Supplementary Text and Figures (4M) Supplementary Note, Supplementary Figures 1–9 and Supplementary Table 1 Additional data - The coiled-coil domain containing protein CCDC40 is essential for motile cilia function and left-right axis formation
- Nat Genet 43(1):79-84 (2011)
Nature Genetics | Letter The coiled-coil domain containing protein CCDC40 is essential for motile cilia function and left-right axis formation * Anita Becker-Heck1, 2, 3, 14 Search for this author in: * NPG journals * PubMed * Google Scholar * Irene E Zohn4, 5, 14 Search for this author in: * NPG journals * PubMed * Google Scholar * Noriko Okabe6, 14 Search for this author in: * NPG journals * PubMed * Google Scholar * Andrew Pollock4, 14 Search for this author in: * NPG journals * PubMed * Google Scholar * Kari Baker Lenhart6 Search for this author in: * NPG journals * PubMed * Google Scholar * Jessica Sullivan-Brown6 Search for this author in: * NPG journals * PubMed * Google Scholar * Jason McSheene6 Search for this author in: * NPG journals * PubMed * Google Scholar * Niki T Loges1, 2 Search for this author in: * NPG journals * PubMed * Google Scholar * Heike Olbrich2 Search for this author in: * NPG journals * PubMed * Google Scholar * Karsten Haeffner1 Search for this author in: * NPG journals * PubMed * Google Scholar * Manfred Fliegauf1 Search for this author in: * NPG journals * PubMed * Google Scholar * Judith Horvath1, 7 Search for this author in: * NPG journals * PubMed * Google Scholar * Richard Reinhardt8 Search for this author in: * NPG journals * PubMed * Google Scholar * Kim G Nielsen9 Search for this author in: * NPG journals * PubMed * Google Scholar * June K Marthin9 Search for this author in: * NPG journals * PubMed * Google Scholar * Gyorgy Baktai10 Search for this author in: * NPG journals * PubMed * Google Scholar * Kathryn V Anderson11 Search for this author in: * NPG journals * PubMed * Google Scholar * Robert Geisler12, 13 Search for this author in: * NPG journals * PubMed * Google Scholar * Lee Niswander4, 15 Contact Lee Niswander Search for this author in: * NPG journals * PubMed * Google Scholar * Heymut Omran1, 2, 15 Contact Heymut Omran Search for this author in: * NPG journals * PubMed * Google Scholar * Rebecca D Burdine6, 15 Contact Rebecca D Burdine Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorsJournal name:Nature GeneticsVolume: 43,Pages:79–84Year published:(2011)DOI:doi:10.1038/ng.727Received08 June 2010Accepted12 November 2010Published online05 December 2010 Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Primary ciliary dyskinesia (PCD) is a genetically heterogeneous autosomal recessive disorder characterized by recurrent infections of the respiratory tract associated with the abnormal function of motile cilia. Approximately half of individuals with PCD also have alterations in the left-right organization of their internal organ positioning, including situs inversus and situs ambiguous (Kartagener's syndrome). Here, we identify an uncharacterized coiled-coil domain containing a protein, CCDC40, essential for correct left-right patterning in mouse, zebrafish and human. In mouse and zebrafish, Ccdc40 is expressed in tissues that contain motile cilia, and mutations in Ccdc40 result in cilia with reduced ranges of motility. We further show that CCDC40 mutations in humans result in a variant of PCD characterized by misplacement of the central pair of microtubules and defective assembly of inner dynein arms and dynein regulatory complexes. CCDC40 localizes to motile cilia and the ! apical cytoplasm and is required for axonemal recruitment of CCDC39, disruption of which underlies a similar variant of PCD. View full text Subject terms: * Developmental biology Figures at a glance * Figure 1: Mutation of Ccdc40 in lnks mice results in laterality defects. (–) Heart, lung and stomach (S) from E13.5 (,) and E12.5 (,) wild-type (,) embryos exhibiting normal situs (NS) and lnks mutant viscera exhibiting left isomerism (, LI) or situs inversus (, SI). RV, right ventricle. The heart is outlined in black, and the left and right lung lobes are outlined in yellow and red, respectively. () Genetic map of the lnks interval on mouse chromosome 11. The number of recombination events over the number of opportunities for recombination is indicated for each polymorphic marker. D11ski16 never separated from the lnks phenotype. Within this interval are four transcription units: Tbc1d16 (TBC1 domain family, member 16), Ccdc40 (Coiled-coil domain containing 40), Gaa (Glucosidase, alpha, acid) and Eif4a3 (Eukaryotic translation initiation factor 4A3). (–) Ccdc40 expression in wild-type E8.0 (), E8.25 (), E8.5 () and E9.5 () embryos as detected by RNA in situ hybridization. Strong staining was detected in the node. () The lnks ENU-induced muta! tion results in a C>A transversion (green asterisk) in the Ccdc40 coding sequence, introducing a nonsense mutation that changes Ser792 to a stop codon. Mouse Ccdc40 is 63% identical and 78% similar to human CCDC40. () The lnks mutation truncates the Ccdc40 protein within the coiled-coil domain (red). The green box indicates the peptide used to generate the Ccdc40 antibody. * Figure 2: Mutation of zebrafish ccdc40 in lok mutants or knockdown of ccdc40 in morpholino-injected embryos produces laterality defects. (–) Expression of the ccdc40 transcript in wild-type zebrafish embryos at 75% epiboly () and six somites (,). Staining was detected in the dorsal forerunner cells (arrow in ), the pronephric tubules (arrows in ) and the otic vesicles (arrows in ). () The predicted domain structure of the 941-amino-acid zebrafish Ccdc40 protein. The lok mutation introduces a stop codon at position 778, producing a protein with a truncated C-terminal domain. Zebrafish ccdc40 is 39% and 36% identical and 60% and 58% similar to the human and mouse genes, respectively. (–) Phenotypes of lok mutant and ccdc40MO-injected embryos at 3 days post fertilization. A lok mutant embryo () displays the curly-tail phenotype compared to an unaffected sibling (). An embryo injected with ccdc40MO1 also displays the curly-tail phenotype () which can be rescued by co-injection of ccdc40 mRNA (). Insets in and indicate that fluorescein-labeled MO was injected into both embryos. () Quantification of left-right ! organ patterning in lok mutant and ccdc40MO-injected embryos. SS, situs solitus; SI, situs inversus; HTX, heterotaxia (that is, any organ pattern that is not SS or SI). () Rescue of MO phenotypes by co-injection of ccdc40 mRNA. Heart looping was scored as an indication of left-right patterning. RLoop, rightward looping of the heart; NLoop, no heart looping (midline); LLoop, leftward looping of the heart. Curly tail down (CTD) indicates a strong phenotype such as that pictured in . +/++ indicates tails that were slightly kinked or bent. WT indicates results indistinguishable from those of uninjected embryos (compare tail in to that in ). * Figure 3: Loss of Ccdc40 results in ciliary defects. (,,,) Scanning electron microscopy showing morphology of node cilia in E8.0 wild type (,) and lnks mutant (,) mouse embryos. Panels and are higher magnification views of and ; scale bars are indicated. (,,,) Cilia imaging in zebrafish pronephric tubules (,) and Kuppfer's vesicle (,). Loss of Ccdc40 function in mouse (,) and zebrafish embryos (,) results in significantly shorter cilia relative to controls. In Kupffer's vesicle, cilia length in uninjected controls averaged 5.2 μm (standard deviation (s.d.) = 1.486, n = 589 cilia), whereas cilia in MO-injected embryos were consistently shorter, averaging 3.6 μm (s.d. = 1.20, n = 511 cilia, P = 6 × 10−73 by one-tailed Student's t test). Shorter cilia were also reported in lok mutants11, 12. (–) Transmission electron microscopy analysis of cilia in the pronephros of lok mutant embyos shows defects in central pair positioning (,) or number of cilia () compared to controls (). Note that outer dynein arms are not affected. (�! ��) Immunofluorescence analysis showing localization of endogenous Ccdc40 protein (,,,) and acetylated tubulin (,,,) in the nodes of E8.0 wild-type () and lnks mutant (–) embryos and in P21 wild-type trachea (–) and lnks mutant trachea (–) (overlay including visualization of nuclei (Hoechst staining) in ,,,). Arrow in points to a node cilium that was not recognized by the Ccdc40 antibody. Note that Ccdc40 is not readily detectable in the 9+0 node cilium but is present in the axonemes of multiciliated tracheal cells. Arrow in shows axonemal localization of Ccdc40 in 9+2 tracheal cells. The motility of node cilia was not evaluated. * Figure 4: Localization of DNAH5, GAS11 and DNALI1 in respiratory epithelial cells from individuals with PCD carrying CCDC40 mutations. (–) Immunofluorescence analyses of human respiratory epithelial cells using specific antibodies directed against the outer dynein arm heavy chain DNAH5 (), the dynein regulating complex component GAS11 () and the inner dynein arm component DNALI1 (). As controls, we used axoneme-specific antibodies against acetylated α-tubulin () or α/β-tubulin (,). We stained the nuclei with Hoechst 33342 (blue). () In respiratory epithelial cells from healthy probands, DNAH5 (red) localized along the entire length of the axonemes. In respiratory epithelial cells from subject OP-799 carrying compound heterozygous CCDC40 mutations, cilia were shorter, but DNAH5 (red) was localized along the entire length of the axonome, as in the healthy control. (,) Similarly, GAS11 (, green) and DNALI1 (, green) localized along the entire length of the axonemes in the healthy control, whereas in respiratory epithelial cells from subject OP-712II1, GAS11 (green), and from subject OP-799, DNALI1 (green)! , are absent from the ciliary axonemes. White scale bars (–), 5 μm. (–) Transmission electron microscopy of respiratory cilia showing normal axonemal structure in the control () and cilia with abnormal tubular organization in subject OP-712II2, carrying a homozygous loss-of-function mutation in CCDC40 (–), and subject OP-43II1, carrying compound heterozygous CCDC40 mutations (–). Black scale bars (–), 0.1 μm. * Figure 5: CCDC40 mutations affect localization of CCDC39 in respiratory cells. Subcellular localization of CCDC39 in respiratory epithelial cells from individuals with PCD carrying CCDC40 loss-of-function mutations. As a control, we used axoneme-specific antibodies against acetylated α-tubulin (green). () We stained the nuclei with Hoechst 33342 (blue). In respiratory epithelial cells from healthy probands (), CCDC39 (red) localized along the entire length of the axonemes and, to a weaker degree, in the apical cytoplasm. (–) In respiratory epithelial cells from individuals carrying CCDC40 loss-of function mutations, OP-799 (), OP-712 II1 (), OP-741 () and OP-659 (), CCDC39 was either markedly reduced or was absent in ciliary axonemes and instead accumulated at the ciliary base. White scale bars (–), 5 μm. Accession codes * Accession codes * Author information * Supplementary information Referenced accessions Entrez Nucleotide * NM_017950 * NM_175430 GenBank * NP_060420 * NP_780639 * XM_691926 * XP_697018 Author information * Accession codes * Author information * Supplementary information Primary authors * These authors contributed equally to this work. * Anita Becker-Heck, * Irene E Zohn, * Noriko Okabe & * Andrew Pollock Affiliations * Department of Pediatrics, University Hospital Freiburg, Freiburg, Germany. * Anita Becker-Heck, * Niki T Loges, * Karsten Haeffner, * Manfred Fliegauf, * Judith Horvath & * Heymut Omran * Klinik und Poliklinik für Kinder-und Jugendmedizin-Allgemeine Pädiatrie, Universitätsklinikum Münster, Münster, Germany. * Anita Becker-Heck, * Niki T Loges, * Heike Olbrich & * Heymut Omran * Faculty of Biology, Albert-Ludwigs-University Freiburg, Freiburg, Germany. * Anita Becker-Heck * Howard Hughes Medical Institute, Department of Pediatrics, University of Colorado Denver, Aurora, Colorado, USA. * Irene E Zohn, * Andrew Pollock & * Lee Niswander * Center for Neuroscience Research, Children's Research Institute, Children's National Medical Center, Washington, DC, USA. * Irene E Zohn * Department of Molecular Biology, Princeton University, Princeton, New Jersey, USA. * Noriko Okabe, * Kari Baker Lenhart, * Jessica Sullivan-Brown, * Jason McSheene & * Rebecca D Burdine * National Medical Center, Budapest, Hungary. * Judith Horvath * Genome Centre Cologne at Max Planck Institute for Plant Breeding Research, Köln, Germany. * Richard Reinhardt * Pediatric Pulmonary Service and Cystic Fibrosis Centre Copenhagen University Hospital, Copenhagen, Denmark. * Kim G Nielsen & * June K Marthin * Pediatric Institute Svabhegy, Budapest, Hungary. * Gyorgy Baktai * Developmental Biology Program, Sloan-Kettering Institute, New York, New York, USA. * Kathryn V Anderson * Max Planck Institute for Developmental Biology, Department of Genetics, Tübingen, Germany. * Robert Geisler * Present address: Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, Eggenstein-Leopoldshafen, Germany. * Robert Geisler * These authors jointly directed this work. * Lee Niswander, * Heymut Omran & * Rebecca D Burdine Contributions Studies in mice were conducted by I.E.Z., A.P., A.B.-H., H. Omran, K.V.A. and L.N. Studies in zebrafish were conducted by N.O., K.B.L., J.S.-B., J.M., R.G. and R.D.B. Studies with human samples were conducted by A.B.-H., N.T.L., H. Olbrich, K.H., M.F., J.H., R.R., K.G.N., J.K.M., G.B. and H. Omran. The manuscript was prepared by A.B.-H., I.E.Z., L.N., H. Omran and R.D.B. Competing financial interests The authors declare no competing financial interests. Corresponding authors Correspondence to: * Lee Niswander or * Heymut Omran or * Rebecca D Burdine Supplementary information * Accession codes * Author information * Supplementary information Movies * Supplementary Video 1 (3M) Cilia motility in control cells from a nasal brush biopsy * Supplementary Video 2 (2M) Defective cilia motility in patient OP76II1 * Supplementary Video 3 (6M) Defective cilia motility in patient OP82II1 * Supplementary Video 4 (3M) Defective cilia motility in patient OP87II2 PDF files * Supplementary Text and Figures (10M) Supplementary Figures 1–8 and Supplementary Table 1 Additional data
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