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Latest Articles Include:

• Crowdsourcing human mutations
  - Nat Genet 43(4):279 (2011)
  Nature Genetics | Editorial Crowdsourcing human mutations Journal name:Nature GeneticsVolume: 43,Page:279Year published:(2011)DOI:doi:10.1038/ng0411-279Published online29 March 2011 The first Human Variome microattribution review shows that data citation and publication credit can work as incentives for systematic curation of gene variant and phenotype data. Analysis of the formal assertions in both databases and journal articles argues for better separation of data structures from narrative so that they can better support one another to communicate meaning. View full text Additional data
• The value of data
  - Nat Genet 43(4):281-283 (2011)
  Nature Genetics | Commentary The value of data * Barend Mons1, 2, 3, 4 * Herman van Haagen1 * Christine Chichester2, 4 * Peter-Bram 't Hoen1, 4 * Johan T den Dunnen1 * Gertjan van Ommen1, 4 * Erik van Mulligen3, 4 * Bharat Singh2, 3 * Rob Hooft2, 4 * Marco Roos1, 2, 4 * Joel Hammond5 * Bruce Kiesel5 * Belinda Giardine6 * Jan Velterop4, 7 * Paul Groth4, 8 * Erik Schultes1, 4 * Affiliations * Contributions * Corresponding authorJournal name:Nature GeneticsVolume: 43,Pages:281–283Year published:(2011)DOI:doi:10.1038/ng0411-281Published online29 March 2011 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 Data citation and the derivation of semantic constructs directly from datasets have now both found their place in scientific communication. The social challenge facing us is to maintain the value of traditional narrative publications and their relationship to the datasets they report upon while at the same time developing appropriate metrics for citation of data and data constructs. View full text Figures at a glance * Figure 1: The current state of scholarly communication. Red ovals represent points where the current system is 'broken'. All predicates are represented as small ovals. An asterisk (yellow star in the figure) represents 'conditionality'. Illustrated concepts (large ovals) are discussed below in bold. produces . It also produces in which the of the experiments, methods and conclusions and some are presented. The that are too to be part of the itself are currently as . Unless (as indicated by stars) there is good data stewardship by the journal (and journal-governed storage), the link to these data is a in the system. Articles have a and can therefore be cited, and are possible. However, datasets and databases as well as figures and tables usually (as indicated by stars) do not have such a stable, . Neither do terms, thus, retrospectively mapping terms in the narrative, in tables and in figures to unambiguous is extremely hard, leaving these research objects suboptimal for and . Therefore, it becomes difficult to 'recover' original! from these research objects, and they cannot be properly . With as the primary focus of scholarly communication, (that is, deposition and sharing) and will remain invisible for mainstream and will not accrue the proper or . * Figure 2: A proposal for the future of scholarly communication. The concepts and predicates are represented as in Figure 1. By placing machine-readable at the core of communication and moving the slightly in the graph, many problems may be solved. First, , and the underlying data of (graphs), as well as their captions, can be represented as . Because all concepts in a graph, including those in the provenance and context parts, have a , they automatically link through the to their and their position in that source. The narrative article now becomes supplementary to the data: it provides the detailed description of the as well as the building the argument as to why the data are valid and the claims correct. Good news for publishers is that each in a conventional , a supplementary (for instance, for two co-expressing genes) or a related (for instance, for a variant-phenotype association) is now intrinsically , and (through the article in the provenance) to the . Therefore, will have the potential to increase the hit rate of an and will prom! ote proper citation of the in which the 'first' was made. As are now individually , are possible, and and can be traced back to the . Now, proper is possible by , and in the case of the simplest multiples, . Author information * Abstract * Author information * Supplementary information Affiliations * Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands. * Barend Mons, * Herman van Haagen, * Peter-Bram 't Hoen, * Johan T den Dunnen, * Gertjan van Ommen, * Marco Roos & * Erik Schultes * Netherlands Bioinformatics Center, Nijmegen, The Netherlands. * Barend Mons, * Christine Chichester, * Bharat Singh, * Rob Hooft & * Marco Roos * Department of Medical Informatics, Erasmus Medical Centre, Rotterdam, The Netherlands. * Barend Mons, * Erik van Mulligen & * Bharat Singh * Concept Web Alliance, Nijmegen, The Netherlands. * Barend Mons, * Christine Chichester, * Peter-Bram 't Hoen, * Gertjan van Ommen, * Erik van Mulligen, * Rob Hooft, * Marco Roos, * Jan Velterop, * Paul Groth & * Erik Schultes * Thomson Reuters, Philadelphia, Pennsylvania, USA. * Joel Hammond & * Bruce Kiesel * Center for Comparative Genomics and Bioinformatics, Pennsylvania State University, University Park, Pennsylvania, USA. * Belinda Giardine * Academic Concept Knowledge LTD., London, UK. * Jan Velterop * Free University, Amsterdam, The Netherlands. * Paul Groth Contributions B.M., J.T.d.D., G.v.O., J.H., B.K. and P.G. conceived of the experiment and supervised the research. H.v.H., C.C., P.-B.t.H., E.v.M., B.S. and E.S. performed the experiments. R.H., B.G., M.R. and J.V. commented on the experiments and the manuscript. Competing financial interests J.H., B.K. and J.V. are in a line of business that could engage in nanopublication-related models. Corresponding author Correspondence to: * Barend Mons Author Details * Barend Mons Contact Barend Mons Search for this author in: * NPG journals * PubMed * Google Scholar * Herman van Haagen Search for this author in: * NPG journals * PubMed * Google Scholar * Christine Chichester Search for this author in: * NPG journals * PubMed * Google Scholar * Peter-Bram 't Hoen Search for this author in: * NPG journals * PubMed * Google Scholar * Johan T den Dunnen Search for this author in: * NPG journals * PubMed * Google Scholar * Gertjan van Ommen Search for this author in: * NPG journals * PubMed * Google Scholar * Erik van Mulligen Search for this author in: * NPG journals * PubMed * Google Scholar * Bharat Singh Search for this author in: * NPG journals * PubMed * Google Scholar * Rob Hooft Search for this author in: * NPG journals * PubMed * Google Scholar * Marco Roos Search for this author in: * NPG journals * PubMed * Google Scholar * Joel Hammond Search for this author in: * NPG journals * PubMed * Google Scholar * Bruce Kiesel Search for this author in: * NPG journals * PubMed * Google Scholar * Belinda Giardine Search for this author in: * NPG journals * PubMed * Google Scholar * Jan Velterop Search for this author in: * NPG journals * PubMed * Google Scholar * Paul Groth Search for this author in: * NPG journals * PubMed * Google Scholar * Erik Schultes Search for this author in: * NPG journals * PubMed * Google Scholar Supplementary information * Abstract * Author information * Supplementary information Text files * Supplementary Table 1 (74K) * Supplementary Table 2 (1M) Additional data
• Personal genomics to the people
  - Nat Genet 43(4):285-286 (2011)
  Nature Genetics | Book Review Personal genomics to the people * Maynard Olson1Journal name:Nature GeneticsVolume: 43,Pages:285–286Year published:(2011)DOI:doi:10.1038/ng0411-285Published online29 March 2011 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. Here is a Human Being: At the Dawn of Personal Genomics Misha Angrist HarperCollins, 2010 352 pp., hardcover, $26.99 ISBN: 9780061628337 Buy this book: USUKJapan Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg In his 1999 Shattuck Lecture1, Francis Collins commented that "... many health care providers are probably still puzzled by how [gene-based medicine] will affect ... daily practice..." To help these providers visualize the coming revolution, Collins looked a decade ahead to a 2010 primary-care appointment in which a young, pack-a-day smoker with high cholesterol whose father had died of a heart attack at age 48 would undertake a battery of genetic tests. Collins envisioned the young man's physician, fortified by the test results, recommending that he take statins and quit smoking: good advice, no doubt, but indistinguishable from what he would have been told without the genetic tests. View full text Author information Affiliations * Maynard Olson is at the Department of Genome Sciences, University of Washington, Seattle, Washington, USA. Competing financial interests M.O. is a member of the Scientific Advisory Board of Illumina, Inc. Author Details * Maynard Olson Contact Maynard Olson Search for this author in: * NPG journals * PubMed * Google Scholar 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
• Next-generation association studies for complex traits
  - Nat Genet 43(4):287-288 (2011)
  Nature Genetics | News and Views Next-generation association studies for complex traits * Eleftheria Zeggini1Journal name:Nature GeneticsVolume: 43,Pages:287–288Year published:(2011)DOI:doi:10.1038/ng0411-287Published online29 March 2011 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. A new study successfully applies complementary whole-genome sequencing and imputation approaches to establish robust disease associations in an isolated population. This strategy is poised to help elucidate the role of variants at the low end of the allele frequency spectrum in the genetic architecture of complex traits. 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 * Eleftheria Zeggini is at the Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK. Competing financial interests The author declares no competing financial interests. Corresponding author Correspondence to: * Eleftheria Zeggini Author Details * Eleftheria Zeggini Contact Eleftheria Zeggini Search for this author in: * NPG journals * PubMed * Google Scholar 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
• Stopping RNA interference at the seed
  - Nat Genet 43(4):288-289 (2011)
  Nature Genetics | News and Views Stopping RNA interference at the seed * John J Rossi1Journal name:Nature GeneticsVolume: 43,Pages:288–289Year published:(2011)DOI:doi:10.1038/ng0411-288Published online29 March 2011 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. MicroRNAs (miRNAs) regulate expression of more than one half of the genes in the human genome. A study now reports a new method for selectively silencing whole families of miRNAs, thus providing a new paradigm for disease therapy. 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 * John J. Rossi is at the Department of Molecular and Cellular Biology, Beckman Research Institute of the City of Hope, Duarte, California, USA. Competing financial interests The author declares no competing financial interests. Corresponding author Correspondence to: * John J Rossi Author Details * John J Rossi Contact John J Rossi Search for this author in: * NPG journals * PubMed * Google Scholar 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
• DNMT3A mutations in acute myeloid leukemia
  - Nat Genet 43(4):289-290 (2011)
  Nature Genetics | News and Views DNMT3A mutations in acute myeloid leukemia * Mrinal Y Shah1 * Jonathan D Licht1 * Affiliations * Corresponding authorJournal name:Nature GeneticsVolume: 43,Pages:289–290Year published:(2011)DOI:doi:10.1038/ng0411-289Published online29 March 2011 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. New studies reveal that 20% of individuals with acute myeloid leukemia harbor somatic mutations in DNMT3A (encoding DNA methyltransferase 3A). Although these leukemias have some gene expression and DNA methylation changes, a direct link between mutant DNMT3A, epigenetic changes and pathogenesis remains to be established. 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 * Mrinal Y. Shah and Jonathan D. Licht are at the Division of Hematology and Oncology, Northwestern University, Chicago, Ilinois, USA. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Jonathan D Licht Author Details * Mrinal Y Shah Search for this author in: * NPG journals * PubMed * Google Scholar * Jonathan D Licht Contact Jonathan D Licht Search for this author in: * NPG journals * PubMed * Google Scholar 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(4):293 (2011)
  Nature Genetics | Research Highlights Research highlights Journal name:Nature GeneticsVolume: 43,Page:293Year published:(2011)DOI:doi:10.1038/ng0411-293Published online29 March 2011 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. Beach mouse coat color evolution Wild populations of deer mice (genus Peromyscus) vary in coat color, with mainland mice having a dark dorsum and a light ventrum. In contrast, recently colonized populations of beach mice have lighter coat colors and pigmentless faces, flanks and tails. Hopi Hoekstra and colleagues now report that Agouti, a well-known negative regulator of pigmentation, is the causal gene in coat color differences between mainland and beach mice (Science331, 1062, 2011). Previously, three quantitative trait loci, including a quantitative trait locus containing Agouti, were shown to explain most coat color variation between mainland and beach mice. As there are no coding differences between beach and mainland mice Agouti sequences, the authors examined allele-specific expression of Agouti in different tissues. In the ventral skin of F1 hybrids, the beach mouse allele is expressed 17-fold higher than the mainland mouse allele. However, no allele-specific expression differences were observed in! the testes, suggesting cis-regulatory mutations in Agouti are involved in coat color differences. Agouti was ectopically expressed in mainland beach embryos using ultrasound-assisted retroviral infection in utero. Although the effects on coat color in Peromyscus adults were not measured, ectopic expression of Agouti appeared to prevent the terminal differentiation of melanocytes and thus led to an absence of pigment production. PC Hedgehog signals in aggressive pontine glioma Diffuse intrinsic pontine glioma (DIPG) is an extremely aggressive and fatal cancer. DIPGs typically occur during a specific time in childhood and are restricted to the ventral pons. Due to the lack of tumor samples and an appropriate animal model, little is known about DIPG, and no advances in treatment have been made in 35 years. Now, Michelle Monje, Phillip Beachy and colleagues identify a population of OLIG2+ neural precursor-like cells in the ventral pons that is present at the appropriate time and place coincident with DIPG (Proc. Natl. Acad. Sci. U.S.A., published online, doi:10.1073/pnas.1101657108, 1 March 2011). Using DIPG tissue from a pediatric donor, the authors isolated Olig2+ cells consistent with the neural precursor-like cell type and transplanted them to mice. The resulting brain tumors had histopathology consistent with high-grade glioma. Similar to the unique biology of DIPG, infiltrating tumor cells were found in the brainstem. Using the same Olig2+ cell! s isolated from the donated tumor, the authors found evidence of active Hh signaling. Culturing these cells in the presence of an Hh antagonist reduced their self-renewal capacity, whereas activating Hh signaling appeared to increase self-renewal capacity. The authors suggest the Hh signaling pathway as a candidate therapeutic target in this deadly pediatric tumor. 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
• Systematic documentation and analysis of human genetic variation in hemoglobinopathies using the microattribution approach
  - Nat Genet 43(4):295-301 (2011)
  Nature Genetics | Analysis Open Systematic documentation and analysis of human genetic variation in hemoglobinopathies using the microattribution approach * Belinda Giardine1, 37 * Joseph Borg2, 3, 4, 37 * Douglas R Higgs5 * Kenneth R Peterson6 * Sjaak Philipsen7 * Donna Maglott8 * Belinda K Singleton9 * David J Anstee9 * A Nazli Basak10 * Barnaby Clark11 * Flavia C Costa6 * Paula Faustino12 * Halyna Fedosyuk6 * Alex E Felice3, 4 * Alain Francina13 * Renzo Galanello14 * Monica V E Gallivan15 * Marianthi Georgitsi16 * Richard J Gibbons5 * Piero C Giordano17 * Cornelis L Harteveld17 * James D Hoyer18 * Martin Jarvis19 * Philippe Joly13 * Emmanuel Kanavakis20 * Panagoula Kollia21 * Stephan Menzel11 * Webb Miller1 * Kamran Moradkhani22 * John Old23 * Adamantia Papachatzopoulou24 * Manoussos N Papadakis25 * Petros Papadopoulos7 * Sonja Pavlovic26 * Lucia Perseu27 * Milena Radmilovic26 * Cathy Riemer1 * Stefania Satta14 * Iris Schrijver28 * Maja Stojiljkovic26 * Swee Lay Thein11 * Jan Traeger-Synodinos20 * Ray Tully8 * Takahito Wada29 * John S Waye30, 31 * Claudia Wiemann32 * Branka Zukic26 * David H K Chui33, 34 * Henri Wajcman22, 35 * Ross C Hardison1, 36 * George P Patrinos16 * Affiliations * Contributions * Corresponding authorJournal name:Nature GeneticsVolume: 43,Pages:295–301Year published:(2011)DOI:doi:10.1038/ng.785Received02 August 2010Accepted11 February 2011Published online20 March 2011Corrected online27 March 2011 Abstract * Abstract * Change history * 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 We developed a series of interrelated locus-specific databases to store all published and unpublished genetic variation related to hemoglobinopathies and thalassemia and implemented microattribution to encourage submission of unpublished observations of genetic variation to these public repositories. A total of 1,941 unique genetic variants in 37 genes, encoding globins and other erythroid proteins, are currently documented in these databases, with reciprocal attribution of microcitations to data contributors. Our project provides the first example of implementing microattribution to incentivise submission of all known genetic variation in a defined system. It has demonstrably increased the reporting of human variants, leading to a comprehensive online resource for systematically describing human genetic variation in the globin genes and other genes contributing to hemoglobinopathies and thalassemias. The principles established here will serve as a model for other systems an! d for the analysis of other common and/or complex human genetic diseases. View full text Figures at a glance * Figure 1: Graphical display of the HBB promoter variants recorded in HbVar, partitioned into unpublished variants contributed by investigators (blue) and published variants (purple). The genomic position, sequence change and associated phenotype (β+ or β0 thalassemia) are given for each variant. Known protein-binding sites in the DNA sequence are boxed, with the name of the site and the binding protein above it. The transcription start site (+1) is in reverse type. The reverse complement of the genomic sequence is shown so that the gene is in the conventional left-to-right transcriptional orientation. The image was generated by displaying the results of a query on HbVar in the Pennsylvania State University genome browser followed by editing for clarity. Variants are given using the conventional nomenclature. * Figure 2: Functional role of HBG1 and HBG2 promoter variants. () HBG1 promoter variants are confined to the upstream region and associated with HPFH. The top line gives a schematic view of previously described binding sites for transcription factors, including the TATA box, the stage-selector element (SSE), the CCAAT boxes, GATA motifs bound by GATA1, and an octamer motif (OCT), plus the response element (RE) defined by a cluster of HPFH mutations. Motifs in which variants have been found are colored gray. The transcription start site (+1) is in reverse type. The image was generated by displaying the results of a query on HbVar in the Pennsylvania State University genome browser followed by editing for clarity. Variants are given using the conventional nomenclature. () Flow cytometry analysis of γ-globin+ erythrocytes from adult HBG1 c.-248C>G HPFH β-YAC transgenic lines. A mouse monoclonal γ-globin antibody was used to determine the percentage of F cells. Line and individual numbers are indicated at the top of the panels. Percent �! �-globin–positive cells are indicated within each plot (see also Online Methods). Wild-type (wt) β-YAC mice served as negative controls, and HBG1 c.-170G>A HPFH β-YAC mice13 were used as positive controls. In parallel experiments, human β-globin was expressed in 92–97% of the cells analyzed for all lines (data not shown). () Human γ-globin gene expression in HBG1 c.-248C>G HPFH β-YAC transgenic lines. Percent γ-globin gene expression, copy number-corrected and normalized to per-copy mouse α-globin gene expression, is shown on the y axis. β-YAC construct and line numbers, where appropriate, are indicated at the bottom of the plot. Error bars represent standard deviation of triplicate experiments. * Figure 3: Correlation of the different KLF1 gene variants deposited into HbVar (shown as blue and red squares, depicting unpublished and published information, respectively) and their corresponding HbF levels (median value in cases of three or more individuals) compared to wild-type individuals (shown as green squares). KLF1 is not shown to scale. A simplified diagram depicting the KLF1 promoter and protein is shown underneath. The positions of the zinc fingers are indicated (F1, F2 and F3). For the exact HbF levels corresponding to each KLF1 gene variant, see Supplementary Table 2. Change history * Abstract * Change history * Author information * Supplementary informationCorrected online 27 March 2011In the version of this paper originally published online, Supplementary Table 1 was omitted. This error has been corrected as of 27 March 2011. Author information * Abstract * Change history * Author information * Supplementary information Primary authors * These authors contributed equally to this work. * Belinda Giardine & * Joseph Borg Affiliations * Pennsylvania State University, Center for Comparative Genomics and Bioinformatics, University Park, Philadelphia, Pennsylvania, USA. * Belinda Giardine, * Webb Miller, * Cathy Riemer & * Ross C Hardison * Department of Applied Biomedical Sciences, University of Malta, Msida, Malta. * Joseph Borg * Laboratory of Molecular Genetics, Department of Physiology and Biochemistry, University of Malta, Msida, Malta. * Joseph Borg & * Alex E Felice * Thalassemia Clinic, Section of Pathology, Mater Dei Hospital, Msida, Malta. * Joseph Borg & * Alex E Felice * Medical Research Council (MRC) Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Oxford, UK. * Douglas R Higgs & * Richard J Gibbons * University of Kansas Medical Center, Department of Biochemistry and Molecular Biology, Kansas City, Kansas, USA. * Kenneth R Peterson, * Flavia C Costa & * Halyna Fedosyuk * Erasmus University Medical Center, Faculty of Medicine and Health Sciences, Department of Cell Biology, Rotterdam, The Netherlands. * Sjaak Philipsen & * Petros Papadopoulos * National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland, USA. * Donna Maglott & * Ray Tully * Bristol Institute for Transfusion Sciences (BITS), National Health Service (NHS) Blood and Transplant, Bristol, UK. * Belinda K Singleton & * David J Anstee * Bogazici University, Department of Molecular Biology and Genetics, Istanbul, Turkey. * A Nazli Basak * King's College London, London, UK. * Barnaby Clark, * Stephan Menzel & * Swee Lay Thein * Unidade de Investigação e Desenvolvimento, Departamento de Genética, Instituto Nacional de Saúde Dr. Ricardo Jorge, Lisboa, Portugal. * Paula Faustino * Department of Biochemistry, Edouard Herriot University Hospital, Lyon Cedex, France. * Alain Francina & * Philippe Joly * Dipartimento di Scienze Biomediche e Biotecnologie, University of Cagliari, Cagliari, Sardinia, Italy. * Renzo Galanello & * Stefania Satta * Quest Diagnostics Nichols Institute, Chantilly, Virginia, USA. * Monica V E Gallivan * Department of Pharmacy, School of Health Sciences, University of Patras, Patras, Greece. * Marianthi Georgitsi & * George P Patrinos * Hemoglobinopathies Laboratory, Human and Clinical Genetics Department, Leiden University Medical Center, Leiden, The Netherlands. * Piero C Giordano & * Cornelis L Harteveld * Mayo Clinic, Division of Hematopathology, Rochester, Minnesota, USA. * James D Hoyer * North Middlesex University Hospital, London, UK. * Martin Jarvis * National and Kapodistrian University of Athens, School of Medicine, Medical Genetics, St. Sophia's Children's Hospital, Athens, Greece. * Emmanuel Kanavakis & * Jan Traeger-Synodinos * Department of Biology, National and Kapodistrian University of Athens, School of Physical Sciences, Athens, Greece. * Panagoula Kollia * Hospital Henri-Mondor and Albert-Chenevier Group, Department of Biochemistry and Genetics, Créteil, France. * Kamran Moradkhani & * Henri Wajcman * National Haemoglobinopathy Reference Laboratory, Oxford Haemophilia Centre, Churchill Hospital, Oxford, UK. * John Old * University of Patras, Faculty of Medicine, Laboratory of General Biology, Patras, Greece. * Adamantia Papachatzopoulou * Unit of Prenatal Diagnosis, Center for Thalassemia, Laikon General Hospital, Athens, Greece. * Manoussos N Papadakis * Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade, Serbia. * Sonja Pavlovic, * Milena Radmilovic, * Maja Stojiljkovic & * Branka Zukic * Istituto di Neurogenetica e Neurofarmacologia, National Research Council, Cagliari, Cagliari, Sardinia, Italy. * Lucia Perseu * Stanford University School of Medicine, Department of Pathology and Pediatrics, Stanford, California, USA. * Iris Schrijver * Division of Neurology, Kanagawa Children's Medical Center, Yokohama, Kanagawa, Japan. * Takahito Wada * Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada. * John S Waye * Molecular Diagnostic Genetics, Hamilton Regional Laboratory Program, Hamilton, Ontario, Canada. * John S Waye * Medizinisches Versorgungszentrum (MVZ), Laboratory Prof. Seelig, Karlsruhe, Germany. * Claudia Wiemann * Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA. * David H K Chui * Department of Pathology, Boston University School of Medicine, Boston, Massachusetts, USA. * David H K Chui * INSERM, U955, Créteil, France. * Henri Wajcman * Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, Philadelphia, Pennsylvania, USA. * Ross C Hardison Contributions B.G., J.B., R.C.H. and G.P.P. conceived and designed the study. B.G., J.B. and D.M. implemented the process, built and populated the databases. K.R.P., F.C.C. and H.F. performed experiments. B.K.S., D.J.A., A.N.B., B.C., P.F., A.E.F., A.F., R.G., M.V.E.G., M.G., R.J.G., P.C.G., C.L.H., J.D.H., M.J., P.J., E.K., P.K., S.M., K.M., J.O., A.P., M.N.P., P.P., S. Pavlovic, L.P., M.R., S.S., I.S., M.S., S.L.T., J.T.-S., R.T., T.W., J.S.W., C.W., B.Z. and G.P.P. contributed data. B.G., J.B., D.R.H. and S. Philipsen analyzed results. R.C.H. and G.P.P. supervised data analysis. D.M., W.M., C.R., D.H.K.C. and H.W. provided expertise and infrastructure. B.G., J.B., D.R.H., K.R.P., S. Philipsen, R.C.H. and G.P.P. wrote the paper. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * George P Patrinos Author Details * Belinda Giardine Search for this author in: * NPG journals * PubMed * Google Scholar * Joseph Borg Search for this author in: * NPG journals * PubMed * Google Scholar * Douglas R Higgs Search for this author in: * NPG journals * PubMed * Google Scholar * Kenneth R Peterson Search for this author in: * NPG journals * PubMed * Google Scholar * Sjaak Philipsen Search for this author in: * NPG journals * PubMed * Google Scholar * Donna Maglott Search for this author in: * NPG journals * PubMed * Google Scholar * Belinda K Singleton Search for this author in: * NPG journals * PubMed * Google Scholar * David J Anstee Search for this author in: * NPG journals * PubMed * Google Scholar * A Nazli Basak Search for this author in: * NPG journals * PubMed * Google Scholar * Barnaby Clark Search for this author in: * NPG journals * PubMed * Google Scholar * Flavia C Costa Search for this author in: * NPG journals * PubMed * Google Scholar * Paula Faustino Search for this author in: * NPG journals * PubMed * Google Scholar * Halyna Fedosyuk Search for this author in: * NPG journals * PubMed * Google Scholar * Alex E Felice Search for this author in: * NPG journals * PubMed * Google Scholar * Alain Francina Search for this author in: * NPG journals * PubMed * Google Scholar * Renzo Galanello Search for this author in: * NPG journals * PubMed * Google Scholar * Monica V E Gallivan Search for this author in: * NPG journals * PubMed * Google Scholar * Marianthi Georgitsi Search for this author in: * NPG journals * PubMed * Google Scholar * Richard J Gibbons Search for this author in: * NPG journals * PubMed * Google Scholar * Piero C Giordano Search for this author in: * NPG journals * PubMed * Google Scholar * Cornelis L Harteveld Search for this author in: * NPG journals * PubMed * Google Scholar * James D Hoyer Search for this author in: * NPG journals * PubMed * Google Scholar * Martin Jarvis Search for this author in: * NPG journals * PubMed * Google Scholar * Philippe Joly Search for this author in: * NPG journals * PubMed * Google Scholar * Emmanuel Kanavakis Search for this author in: * NPG journals * PubMed * Google Scholar * Panagoula Kollia Search for this author in: * NPG journals * PubMed * Google Scholar * Stephan Menzel Search for this author in: * NPG journals * PubMed * Google Scholar * Webb Miller Search for this author in: * NPG journals * PubMed * Google Scholar * Kamran Moradkhani Search for this author in: * NPG journals * PubMed * Google Scholar * John Old Search for this author in: * NPG journals * PubMed * Google Scholar * Adamantia Papachatzopoulou Search for this author in: * NPG journals * PubMed * Google Scholar * Manoussos N Papadakis Search for this author in: * NPG journals * PubMed * Google Scholar * Petros Papadopoulos Search for this author in: * NPG journals * PubMed * Google Scholar * Sonja Pavlovic Search for this author in: * NPG journals * PubMed * Google Scholar * Lucia Perseu Search for this author in: * NPG journals * PubMed * Google Scholar * Milena Radmilovic Search for this author in: * NPG journals * PubMed * Google Scholar * Cathy Riemer Search for this author in: * NPG journals * PubMed * Google Scholar * Stefania Satta Search for this author in: * NPG journals * PubMed * Google Scholar * Iris Schrijver Search for this author in: * NPG journals * PubMed * Google Scholar * Maja Stojiljkovic Search for this author in: * NPG journals * PubMed * Google Scholar * Swee Lay Thein Search for this author in: * NPG journals * PubMed * Google Scholar * Jan Traeger-Synodinos Search for this author in: * NPG journals * PubMed * Google Scholar * Ray Tully Search for this author in: * NPG journals * PubMed * Google Scholar * Takahito Wada Search for this author in: * NPG journals * PubMed * Google Scholar * John S Waye Search for this author in: * NPG journals * PubMed * Google Scholar * Claudia Wiemann Search for this author in: * NPG journals * PubMed * Google Scholar * Branka Zukic Search for this author in: * NPG journals * PubMed * Google Scholar * David H K Chui Search for this author in: * NPG journals * PubMed * Google Scholar * Henri Wajcman Search for this author in: * NPG journals * PubMed * Google Scholar * Ross C Hardison Search for this author in: * NPG journals * PubMed * Google Scholar * George P Patrinos Contact George P Patrinos Search for this author in: * NPG journals * PubMed * Google Scholar Supplementary information * Abstract * Change history * Author information * Supplementary information Excel files * Supplementary Table 1 (1.5M) Microattribution Tables PDF files * Supplementary Text and Figures (528K) Supplementary Figures 1–5, Supplementary Table 2 and Supplementary Note Creative Commons Attribution-Noncommercial-Share Alike 3.0 Licence This work is licensed under a Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. 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• Mutations in NOTCH2 cause Hajdu-Cheney syndrome, a disorder of severe and progressive bone loss
  - Nat Genet 43(4):303-305 (2011)
  Nature Genetics | Brief Communication Mutations in NOTCH2 cause Hajdu-Cheney syndrome, a disorder of severe and progressive bone loss * Michael A Simpson1, 14 * Melita D Irving1, 2, 14 * Esra Asilmaz1 * Mary J Gray3 * Dimitra Dafou1 * Frances V Elmslie4 * Sahar Mansour4 * Sue E Holder5 * Caroline E Brain6 * Barbara K Burton7 * Katherine H Kim7 * Richard M Pauli8 * Salim Aftimos9 * Helen Stewart10 * Chong Ae Kim11 * Muriel Holder-Espinasse12 * Stephen P Robertson3 * William M Drake13 * Richard C Trembath1 * Affiliations * Corresponding authorJournal name:Nature GeneticsVolume: 43,Pages:303–305Year published:(2011)DOI:doi:10.1038/ng.779Received27 October 2010Accepted04 February 2011Published online06 March 2011 Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg We used an exome-sequencing strategy and identified an allelic series of NOTCH2 mutations in Hajdu-Cheney syndrome, an autosomal dominant multisystem disorder characterized by severe and progressive bone loss. The Hajdu-Cheney syndrome mutations are predicted to lead to the premature truncation of NOTCH2 with either disruption or loss of the C-terminal proline-glutamate-serine-threonine-rich proteolytic recognition sequence, the absence of which has previously been shown to increase Notch signaling. View full text Author information * Author information * Supplementary information Primary authors * These authors contributed equally to this work. * Michael A Simpson & * Melita D Irving Affiliations * Division of Genetics and Molecular Medicine, King's College London School of Medicine, Guy's Hospital, London, UK. * Michael A Simpson, * Melita D Irving, * Esra Asilmaz, * Dimitra Dafou & * Richard C Trembath * Clinical Genetics, Guy's and St. Thomas' National Health Service (NHS) Foundation Trust, Guy's Hospital, London, UK. * Melita D Irving * Department of Paediatrics, Dunedin School of Medicine, Dunedin, New Zealand. * Mary J Gray & * Stephen P Robertson * South West Thames Regional Genetics Service, St. George's, University of London, London, UK. * Frances V Elmslie & * Sahar Mansour * North West Thames Regional Genetics Service, North West London Hospitals NHS Trust, Harrow, UK. * Sue E Holder * Department of Paediatric Endocrinology, Great Ormond Street Hospital For Children NHS Trust, London, UK. * Caroline E Brain * Department of Pediatrics and Division of Genetics, Northwestern University Feinberg School of Medicine, Children's Memorial Hospital, Chicago, Illinois, USA. * Barbara K Burton & * Katherine H Kim * Department of Medical Genetics, University of Wisconsin-Madison, Madison, Wisconsin, USA. * Richard M Pauli * Northern Regional Genetics Service, Auckland, New Zealand. * Salim Aftimos * Department of Clinical Genetics, Churchill Hospital, Old Road, Headington, Oxford, UK. * Helen Stewart * Genetics Unit, Instituto da Criança do Hospital das Clínicas—Faculdade de Medicinda a Universidade de São Paulo (FMUSP), São Paulo, Brazil. * Chong Ae Kim * Service de Génétique Clinique, Hôpital Jeanne de Flandre, Lille, France. * Muriel Holder-Espinasse * Department of Endocrinology, St. Bartholomew's Hospital, London, UK. * William M Drake Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Richard C Trembath Author Details * Michael A Simpson Search for this author in: * NPG journals * PubMed * Google Scholar * Melita D Irving Search for this author in: * NPG journals * PubMed * Google Scholar * Esra Asilmaz Search for this author in: * NPG journals * PubMed * Google Scholar * Mary J Gray Search for this author in: * NPG journals * PubMed * Google Scholar * Dimitra Dafou Search for this author in: * NPG journals * PubMed * Google Scholar * Frances V Elmslie Search for this author in: * NPG journals * PubMed * Google Scholar * Sahar Mansour Search for this author in: * NPG journals * PubMed * Google Scholar * Sue E Holder Search for this author in: * NPG journals * PubMed * Google Scholar * Caroline E Brain Search for this author in: * NPG journals * PubMed * Google Scholar * Barbara K Burton Search for this author in: * NPG journals * PubMed * Google Scholar * Katherine H Kim Search for this author in: * NPG journals * PubMed * Google Scholar * Richard M Pauli Search for this author in: * NPG journals * PubMed * Google Scholar * Salim Aftimos Search for this author in: * NPG journals * PubMed * Google Scholar * Helen Stewart Search for this author in: * NPG journals * PubMed * Google Scholar * Chong Ae Kim Search for this author in: * NPG journals * PubMed * Google Scholar * Muriel Holder-Espinasse Search for this author in: * NPG journals * PubMed * Google Scholar * Stephen P Robertson Search for this author in: * NPG journals * PubMed * Google Scholar * William M Drake Search for this author in: * NPG journals * PubMed * Google Scholar * Richard C Trembath Contact Richard C Trembath Search for this author in: * NPG journals * PubMed * Google Scholar Supplementary information * Author information * Supplementary information PDF files * Supplementary Text and Figures (610K) Supplementary Methods, Supplementary Tables 1–3 and Supplementary Figures 1–3. 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• Truncating mutations in the last exon of NOTCH2 cause a rare skeletal disorder with osteoporosis
  - Nat Genet 43(4):306-308 (2011)
  Nature Genetics | Brief Communication Truncating mutations in the last exon of NOTCH2 cause a rare skeletal disorder with osteoporosis * Bertrand Isidor1, 17 * Pierre Lindenbaum1, 2, 3, 17 * Olivier Pichon1 * Stéphane Bézieau1, 3 * Christian Dina2, 3, 4 * Sébastien Jacquemont5 * Dominique Martin-Coignard6 * Christel Thauvin-Robinet7, 8 * Martine Le Merrer9, 10, 11 * Jean-Louis Mandel12, 13, 14, 15, 16 * Albert David1 * Laurence Faivre7, 8 * Valérie Cormier-Daire9, 10, 11 * Richard Redon1, 2, 3 * Cédric Le Caignec1, 2, 3, 4 * Affiliations * Contributions * Corresponding authorJournal name:Nature GeneticsVolume: 43,Pages:306–308Year published:(2011)DOI:doi:10.1038/ng.778Received29 November 2010Accepted04 February 2011Published online06 March 2011 Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Hajdu-Cheney syndrome is a rare autosomal dominant skeletal disorder with facial anomalies, osteoporosis and acro-osteolysis. We sequenced the exomes of six unrelated individuals with this syndrome and identified heterozygous nonsense and frameshift mutations in NOTCH2 in five of them. All mutations cluster to the last coding exon of the gene, suggesting that the mutant mRNA products escape nonsense-mediated decay and that the resulting truncated NOTCH2 proteins act in a gain-of-function manner. View full text Accession codes * Accession codes * Author information * Supplementary information Referenced accessions Entrez Nucleotide * NM_024408.2 GenBank * NP_077719.2 Author information * Accession codes * Author information * Supplementary information Primary authors * These authors contributed equally to this work. * Bertrand Isidor & * Pierre Lindenbaum Affiliations * CHU Nantes, Service de Génétique Médicale, Nantes, France. * Bertrand Isidor, * Pierre Lindenbaum, * Olivier Pichon, * Stéphane Bézieau, * Albert David, * Richard Redon & * Cédric Le Caignec * INSERM, UMR915, L'Institut du Thorax, Nantes, France. * Pierre Lindenbaum, * Christian Dina, * Richard Redon & * Cédric Le Caignec * Université de Nantes, Nantes, France. * Pierre Lindenbaum, * Stéphane Bézieau, * Christian Dina, * Richard Redon & * Cédric Le Caignec * CNRS, ERL3147, Nantes, France. * Christian Dina & * Cédric Le Caignec * Centre Hospitalier Universitaire Vaudois (CHUV), Service de Génétique Médicale, Lausanne, Switzerland. * Sébastien Jacquemont * Unité de Génétique Clinique, Centre Hospitalier du Mans, Le Mans, France. * Dominique Martin-Coignard * Centre de Génétique, Centre de Référence Maladies Rares 'Anomalies du développement et syndromes malformatifs de l'interrégion Est' Hôpital d'Enfants, CHU, Dijon, France. * Christel Thauvin-Robinet & * Laurence Faivre * Université de Bourgogne, Dijon, France. * Christel Thauvin-Robinet & * Laurence Faivre * INSERM U781, Paris, France. * Martine Le Merrer & * Valérie Cormier-Daire * Département de Génétique, Hôpital Necker-Enfants Malades, Paris, France. * Martine Le Merrer & * Valérie Cormier-Daire * Université Paris Descartes, Paris, France. * Martine Le Merrer & * Valérie Cormier-Daire * Translational Medicine and Neurogenetics Program, Institut de Génétique et de Biologie, Moléculaire et Cellulaire (IGBMC), Collège de France, Illkirch, France. * Jean-Louis Mandel * INSERM U964, Illkirch, France. * Jean-Louis Mandel * CNRS UMR 7104, Illkirch, France. * Jean-Louis Mandel * Université de Strasbourg, Illkirch, France. * Jean-Louis Mandel * CHU de Strasbourg, Strasbourg, France. * Jean-Louis Mandel Contributions C.L.C., B.I., S.B., V.C.-D., L.F. and A.D. conceived the project and planned the experiments. B.I., V.C.-D., L.F., M.L.M., S.J., D.M.-C., C.T.-R. and A.D. clinically characterized the HCS cases and collected blood samples. O.P. performed validation experiments. P.L., C.D., R.R., B.I., J.-L.M. and C.L.C. analyzed and interpreted the exome data. C.L.C., B.I., R.R., J.-L.M. and S.J. wrote the manuscript. All authors contributed to the final manuscript. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Cédric Le Caignec Author Details * Bertrand Isidor Search for this author in: * NPG journals * PubMed * Google Scholar * Pierre Lindenbaum Search for this author in: * NPG journals * PubMed * Google Scholar * Olivier Pichon Search for this author in: * NPG journals * PubMed * Google Scholar * Stéphane Bézieau Search for this author in: * NPG journals * PubMed * Google Scholar * Christian Dina Search for this author in: * NPG journals * PubMed * Google Scholar * Sébastien Jacquemont Search for this author in: * NPG journals * PubMed * Google Scholar * Dominique Martin-Coignard Search for this author in: * NPG journals * PubMed * Google Scholar * Christel Thauvin-Robinet Search for this author in: * NPG journals * PubMed * Google Scholar * Martine Le Merrer Search for this author in: * NPG journals * PubMed * Google Scholar * Jean-Louis Mandel Search for this author in: * NPG journals * PubMed * Google Scholar * Albert David Search for this author in: * NPG journals * PubMed * Google Scholar * Laurence Faivre Search for this author in: * NPG journals * PubMed * Google Scholar * Valérie Cormier-Daire Search for this author in: * NPG journals * PubMed * Google Scholar * Richard Redon Search for this author in: * NPG journals * PubMed * Google Scholar * Cédric Le Caignec Contact Cédric Le Caignec Search for this author in: * NPG journals * PubMed * Google Scholar Supplementary information * Accession codes * Author information * Supplementary information PDF files * Supplementary Text and Figures (479K) Supplementary Tables 1–5, Supplementary Figures 1–3 and Supplementary Methods. Additional data
• Exome sequencing identifies somatic mutations of DNA methyltransferase gene DNMT3A in acute monocytic leukemia
  - Nat Genet 43(4):309-315 (2011)
  Nature Genetics | Article Exome sequencing identifies somatic mutations of DNA methyltransferase gene DNMT3A in acute monocytic leukemia * Xiao-Jing Yan1, 2, 4 * Jie Xu1, 4 * Zhao-Hui Gu3, 4 * Chun-Ming Pan1, 4 * Gang Lu1, 4 * Yang Shen1 * Jing-Yi Shi1 * Yong-Mei Zhu1 * Lin Tang1 * Xiao-Wei Zhang1 * Wen-Xue Liang1 * Jian-Qing Mi1 * Huai-Dong Song1 * Ke-Qin Li1 * Zhu Chen1, 3 * Sai-Juan Chen1, 3 * Affiliations * Contributions * Corresponding authorsJournal name:Nature GeneticsVolume: 43,Pages:309–315Year published:(2011)DOI:doi:10.1038/ng.788Received13 October 2010Accepted15 February 2011Published online13 March 2011 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 Abnormal epigenetic regulation has been implicated in oncogenesis. We report here the identification of somatic mutations by exome sequencing in acute monocytic leukemia, the M5 subtype of acute myeloid leukemia (AML-M5). We discovered mutations in DNMT3A (encoding DNA methyltransferase 3A) in 23 of 112 (20.5%) cases. The DNMT3A mutants showed reduced enzymatic activity or aberrant affinity to histone H3 in vitro. Notably, there were alterations of DNA methylation patterns and/or gene expression profiles (such as HOXB genes) in samples with DNMT3A mutations as compared with those without such changes. Leukemias with DNMT3A mutations constituted a group of poor prognosis with elderly disease onset and of promonocytic as well as monocytic predominance among AML-M5 individuals. Screening other leukemia subtypes showed Arg882 alterations in 13.6% of acute myelomonocytic leukemia (AML-M4) cases. Our work suggests a contribution of aberrant DNA methyltransferase activity to the pa! thogenesis of acute monocytic leukemia and provides a useful new biomarker for relevant cases. View full text Figures at a glance * Figure 1: Locations of DNMT3A mutations and structure of DNMT3A protein. () Genomic organization of DNMT3A locus, alternative exons and protein domain structure. Locations of the mutations affecting Arg478 in exon 12, Gly543 in exon 14, Arg882 and Val897 in exon 23 of the DNMT3A gene (top) and protein (bottom) are indicated with arrows and red asterisks, respectively. () Structural prediction of DNMT3A alterations. The structure of DNMT3A dimer is shown in cyan, the structure of two DNMT3L molecules bound to both sides of the DNMT3A dimer (3A-3A) is shown in blue, and the DNA double helix is shown in orange. Purple ribbons, histone H3 N-peptide. Rainbow ribbons, SAM cofactor. Red stick residues, mutations in AML-M5 leukemia. Mutation residues are involved in 3A-3A dimerization or DNA binding (Arg882), SAM cofactor binding (Val897), protein-protein interaction (Arg478), and histone H3 peptide binding (Gly543). Arg882 is near the 3A-3A interface with two pairs of salt bridges formed between Arg885 and Asp876 (counterparts in mouse protein, Arg881 a! nd Asp872, respectively) and very close to the DNA double helix (enlarged). * Figure 2: Functional analysis of DNMT3A mutants. () In vitro methyltransferase activity of DNMT3A mutants in AML-M5. DNMT3A, D3A; DNMT3L, D3L. Data for incorporation in counts per minute (c.p.m.) are mean ± standard deviation (s.d.) for three independent experiments. () Interaction of the p.Gly543Cys mutant with histone H3. Histone H3 in core histone was pulled down by His-labeled DNMT3A (top). His-labeled DNMT3A was pulled down by GST-labeled N-terminal histone H3 (bottom). WT, wild type. () Cell proliferation assay. 32D cells overexpressing WT, p.Arg882His or p.Arg882Cys DNMT3A grew in 12-well plates with (left) or without (right) IL-3. Cell numbers were counted at indicated time points, beginning at 24 h after transfection. *P ≤ 0.05. Results are mean ± s.d. from three independent experiments. * Figure 3: Analysis of gene expression and DNA methylation in individuals with AML-M5. () Gene expression. Real-time PCR of mRNA levels of HOXB2–HOXB5, HOXB7 and IDH1 in individuals without (WT) and with DNMT3A mutations (mutants). Results are the average of three independent experiments. () CpG islands adjacent to HOXB2 were hypomethylated in samples from individuals with DNMT3A mutations. Each horizontal line represents methylation status of one individual sample detected by Sequenom EpiTYPER DNA methylation analysis. * Figure 4: Kaplan-Meier analysis of the survival of individuals with AML-M5. () Overall survival (OS) and TTF of individuals with or without DNMT3A mutations. Individuals with DNMT3A mutations had a poorer overall survival or TTF than those without the mutations. () Overall survival and TTF of individuals with or without MLL mutations. MLL mutations did not influence overall survival or TTF of individuals with AML-M5. Mon, months. Author information * Abstract * Author information * Supplementary information Primary authors * These authors contributed equally to this work. * Xiao-Jing Yan, * Jie Xu, * Zhao-Hui Gu, * Chun-Ming Pan & * Gang Lu Affiliations * State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. * Xiao-Jing Yan, * Jie Xu, * Chun-Ming Pan, * Gang Lu, * Yang Shen, * Jing-Yi Shi, * Yong-Mei Zhu, * Lin Tang, * Xiao-Wei Zhang, * Wen-Xue Liang, * Jian-Qing Mi, * Huai-Dong Song, * Ke-Qin Li, * Zhu Chen & * Sai-Juan Chen * Department of Hematology, The First Hospital of China Medical University, Shenyang, China. * Xiao-Jing Yan * Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, China. * Zhao-Hui Gu, * Zhu Chen & * Sai-Juan Chen Contributions S.-J.C. and Z.C. were the principal investigators who conceived the study. S.-J.C., Z.C. and X.-J.Y. coordinated and oversaw the study. X.-J.Y. and J.X. carried out most of the experiments. Z.-H.G. and G.L. were responsible for bioinformatics investigation. C.-M.P. and H.-D.S. carried out the exome sequencing and participated in the validation experiments. J.-Q.M. and L.T. participated in the preparation of biological samples. Y.S. helped gather detailed clinical information for the study and helped to carry out clinical analysis. Y.-M.Z. and J.-Y.S. participated in the PCR assay and Sequenom analysis. X.-W.Z. and W.-X.L. helped to carry out the biochemical experiments. K.-Q.L. carried out the structural analysis and guided the biochemical experiments. Z.C., S.-J.C. and X.-J.Y. wrote the manuscript. Competing financial interests The authors declare no competing financial interests. Corresponding authors Correspondence to: * Zhu Chen or * Sai-Juan Chen Author Details * Xiao-Jing Yan Search for this author in: * NPG journals * PubMed * Google Scholar * Jie Xu Search for this author in: * NPG journals * PubMed * Google Scholar * Zhao-Hui Gu Search for this author in: * NPG journals * PubMed * Google Scholar * Chun-Ming Pan Search for this author in: * NPG journals * PubMed * Google Scholar * Gang Lu Search for this author in: * NPG journals * PubMed * Google Scholar * Yang Shen Search for this author in: * NPG journals * PubMed * Google Scholar * Jing-Yi Shi Search for this author in: * NPG journals * PubMed * Google Scholar * Yong-Mei Zhu Search for this author in: * NPG journals * PubMed * Google Scholar * Lin Tang Search for this author in: * NPG journals * PubMed * Google Scholar * Xiao-Wei Zhang Search for this author in: * NPG journals * PubMed * Google Scholar * Wen-Xue Liang Search for this author in: * NPG journals * PubMed * Google Scholar * Jian-Qing Mi Search for this author in: * NPG journals * PubMed * Google Scholar * Huai-Dong Song Search for this author in: * NPG journals * PubMed * Google Scholar * Ke-Qin Li Search for this author in: * NPG journals * PubMed * Google Scholar * Zhu Chen Contact Zhu Chen Search for this author in: * NPG journals * PubMed * Google Scholar * Sai-Juan Chen Contact Sai-Juan Chen Search for this author in: * NPG journals * PubMed * Google Scholar Supplementary information * Abstract * Author information * Supplementary information PDF files * Supplementary Text and Figures (8M) Supplementary Figures 1–11 and Supplementary Tables 1–11. 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• A rare variant in MYH6 is associated with high risk of sick sinus syndrome
  - Nat Genet 43(4):316-320 (2011)
  Nature Genetics | Article A rare variant in MYH6 is associated with high risk of sick sinus syndrome * Hilma Holm1, 9 * Daniel F Gudbjartsson1, 9 * Patrick Sulem1 * Gisli Masson1 * Hafdis Th Helgadottir1 * Carlo Zanon1 * Olafur Th Magnusson1 * Agnar Helgason1 * Jona Saemundsdottir1 * Arnaldur Gylfason1 * Hrafnhildur Stefansdottir2 * Solveig Gretarsdottir1 * Stefan E Matthiasson3 * Gu∂mundur Thorgeirsson2, 4 * Aslaug Jonasdottir1 * Asgeir Sigurdsson1 * Hreinn Stefansson1 * Thomas Werge5 * Thorunn Rafnar1 * Lambertus A Kiemeney6, 7 * Babar Parvez8 * Raafia Muhammad8 * Dan M Roden8 * Dawood Darbar8 * Gudmar Thorleifsson1 * G Bragi Walters1 * Augustine Kong1 * Unnur Thorsteinsdottir1, 4 * David O Arnar2, 4 * Kari Stefansson1, 4 * Affiliations * Contributions * Corresponding authorsJournal name:Nature GeneticsVolume: 43,Pages:316–320Year published:(2011)DOI:doi:10.1038/ng.781Received20 December 2010Accepted10 February 2011Published online06 March 2011 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 Through complementary application of SNP genotyping, whole-genome sequencing and imputation in 38,384 Icelanders, we have discovered a previously unidentified sick sinus syndrome susceptibility gene, MYH6, encoding the alpha heavy chain subunit of cardiac myosin. A missense variant in this gene, c.2161C>T, results in the conceptual amino acid substitution p.Arg721Trp, has an allelic frequency of 0.38% in Icelanders and associates with sick sinus syndrome with an odds ratio = 12.53 and P = 1.5 × 10−29. We show that the lifetime risk of being diagnosed with sick sinus syndrome is around 6% for non-carriers of c.2161C>T but is approximately 50% for carriers of the c.2161C>T variant. View full text Figures at a glance * Figure 1: Study design and outcomes. The white boxes describe study actions performed. The blue boxes describe results from preceding actions. SSS, sick sinus syndrome. * Figure 2: An overview of the region around c.2161C>T. The black circles show −log10P for association with sick sinus syndrome for imputed SNPs based on whole-genome sequencing as a function of their build 36 coordinates. The orange crosses show results conditional on the effect of c.2161C>T. Neighboring genes are shown in blue. Recombination rates are reported in cM/Mb. * Figure 3: Penetrance of sick sinus syndrome among carriers and non-carriers of c.2161C>T. The red crosses represent observed penetrance of sick sinus syndrome for 10-year birth cohorts among heterozygous carriers of c.2161C>T. The red line represents the fit of the logistic model to the c.2161C>T carrier data. The blue line and crosses represent the same information for non-carriers of c.2161C>T. SSS, sick sinus syndrome. Author information * Abstract * Author information * Supplementary information Primary authors * These authors contributed equally to this work. * Hilma Holm & * Daniel F Gudbjartsson Affiliations * deCODE genetics, Sturlugata 8, Reykjavik, Iceland. * Hilma Holm, * Daniel F Gudbjartsson, * Patrick Sulem, * Gisli Masson, * Hafdis Th Helgadottir, * Carlo Zanon, * Olafur Th Magnusson, * Agnar Helgason, * Jona Saemundsdottir, * Arnaldur Gylfason, * Solveig Gretarsdottir, * Aslaug Jonasdottir, * Asgeir Sigurdsson, * Hreinn Stefansson, * Thorunn Rafnar, * Gudmar Thorleifsson, * G Bragi Walters, * Augustine Kong, * Unnur Thorsteinsdottir & * Kari Stefansson * Department of Medicine, Landspitali University Hospital, Reykjavik, Iceland. * Hrafnhildur Stefansdottir, * Gu∂mundur Thorgeirsson & * David O Arnar * Laekning, Medical Clinics, Reykjavik, Iceland. * Stefan E Matthiasson * University of Iceland, Faculty of Medicine, Reykjavik, Iceland. * Gu∂mundur Thorgeirsson, * Unnur Thorsteinsdottir, * David O Arnar & * Kari Stefansson * Research Institute of Biological Psychiatry, Mental Health Centre Sct. Hans, Copenhagen University Hospital, Roskilde, Denmark. * Thomas Werge * Department of Epidemiology, Biostatistics and Health Technology Assessment, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. * Lambertus A Kiemeney * Department of Urology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. * Lambertus A Kiemeney * Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA. * Babar Parvez, * Raafia Muhammad, * Dan M Roden & * Dawood Darbar Contributions The study was designed and results interpreted by H. Holm, D.F.G., D.O.A., P.S., U.T. and K.S. O.M., J.S., A.J., A.S., G.B.W. and H. Helgadottir managed and contributed to sequencing and genotyping. Data alignment, imputation and statistical analysis was carried out by D.F.G., G.M., A.G., P.S., G. Thorleifsson and A.K. Additional analyses were performed by A.H. and C.Z. D.O.A., H. Holm, G. Thorgeirsson, S.E.M. and H. Stefansson collected the Icelandic data. Foreign data was collected and supervised by H. Stefansson, T.W., T.R., L.A.K., B.P., R.M., D.M.R. and D.D. H. Holm, D.F.G., D.O.A., U.T. and K.S. wrote the first draft of the paper. All authors contributed to the final version of the manuscript. Competing financial interests The authors that are affiliated with deCODE genetics are all employees of deCODE, a biotechnology company that provides genetic testing services, and some own stocks or stock options in the company. Corresponding authors Correspondence to: * Hilma Holm or * Kari Stefansson Author Details * Hilma Holm Contact Hilma Holm Search for this author in: * NPG journals * PubMed * Google Scholar * Daniel F Gudbjartsson Search for this author in: * NPG journals * PubMed * Google Scholar * Patrick Sulem Search for this author in: * NPG journals * PubMed * Google Scholar * Gisli Masson Search for this author in: * NPG journals * PubMed * Google Scholar * Hafdis Th Helgadottir Search for this author in: * NPG journals * PubMed * Google Scholar * Carlo Zanon Search for this author in: * NPG journals * PubMed * Google Scholar * Olafur Th Magnusson Search for this author in: * NPG journals * PubMed * Google Scholar * Agnar Helgason Search for this author in: * NPG journals * PubMed * Google Scholar * Jona Saemundsdottir Search for this author in: * NPG journals * PubMed * Google Scholar * Arnaldur Gylfason Search for this author in: * NPG journals * PubMed * Google Scholar * Hrafnhildur Stefansdottir Search for this author in: * NPG journals * PubMed * Google Scholar * Solveig Gretarsdottir Search for this author in: * NPG journals * PubMed * Google Scholar * Stefan E Matthiasson Search for this author in: * NPG journals * PubMed * Google Scholar * Gu∂mundur Thorgeirsson Search for this author in: * NPG journals * PubMed * Google Scholar * Aslaug Jonasdottir Search for this author in: * NPG journals * PubMed * Google Scholar * Asgeir Sigurdsson Search for this author in: * NPG journals * PubMed * Google Scholar * Hreinn Stefansson Search for this author in: * NPG journals * PubMed * Google Scholar * Thomas Werge Search for this author in: * NPG journals * PubMed * Google Scholar * Thorunn Rafnar Search for this author in: * NPG journals * PubMed * Google Scholar * Lambertus A Kiemeney Search for this author in: * NPG journals * PubMed * Google Scholar * Babar Parvez Search for this author in: * NPG journals * PubMed * Google Scholar * Raafia Muhammad Search for this author in: * NPG journals * PubMed * Google Scholar * Dan M Roden Search for this author in: * NPG journals * PubMed * Google Scholar * Dawood Darbar Search for this author in: * NPG journals * PubMed * Google Scholar * Gudmar Thorleifsson Search for this author in: * NPG journals * PubMed * Google Scholar * G Bragi Walters Search for this author in: * NPG journals * PubMed * Google Scholar * Augustine Kong Search for this author in: * NPG journals * PubMed * Google Scholar * Unnur Thorsteinsdottir Search for this author in: * NPG journals * PubMed * Google Scholar * David O Arnar Search for this author in: * NPG journals * PubMed * Google Scholar * Kari Stefansson Contact Kari Stefansson Search for this author in: * NPG journals * PubMed * Google Scholar Supplementary information * Abstract * Author information * Supplementary information PDF files * Supplementary Text and Figures (1M) Supplementary Tables 1–8 and Supplementary Figures 1–4. 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• Genome-wide association study identifies susceptibility loci for IgA nephropathy
  - Nat Genet 43(4):321-327 (2011)
  Nature Genetics | Article Genome-wide association study identifies susceptibility loci for IgA nephropathy * Ali G Gharavi1 * Krzysztof Kiryluk1 * Murim Choi2 * Yifu Li1 * Ping Hou1, 3 * Jingyuan Xie1, 4 * Simone Sanna-Cherchi1 * Clara J Men2 * Bruce A Julian5 * Robert J Wyatt6 * Jan Novak5 * John C He7 * Haiyan Wang3 * Jicheng Lv3 * Li Zhu3 * Weiming Wang4 * Zhaohui Wang4 * Kasuhito Yasuno2 * Murat Gunel2 * Shrikant Mane2, 8 * Sheila Umlauf2, 8 * Irina Tikhonova2, 8 * Isabel Beerman2 * Silvana Savoldi9 * Riccardo Magistroni10 * Gian Marco Ghiggeri11 * Monica Bodria11 * Francesca Lugani1, 11 * Pietro Ravani12 * Claudio Ponticelli13 * Landino Allegri14 * Giuliano Boscutti15 * Giovanni Frasca16 * Alessandro Amore17 * Licia Peruzzi17 * Rosanna Coppo17 * Claudia Izzi18 * Battista Fabio Viola19 * Elisabetta Prati20 * Maurizio Salvadori21 * Renzo Mignani22 * Loreto Gesualdo23 * Francesca Bertinetto24 * Paola Mesiano24 * Antonio Amoroso24 * Francesco Scolari18 * Nan Chen4 * Hong Zhang3 * Richard P Lifton2 * Affiliations * Contributions * Corresponding authorsJournal name:Nature GeneticsVolume: 43,Pages:321–327Year published:(2011)DOI:doi:10.1038/ng.787Received08 October 2010Accepted15 February 2011Published online13 March 2011 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 We carried out a genome-wide association study of IgA nephropathy, a major cause of kidney failure worldwide. We studied 1,194 cases and 902 controls of Chinese Han ancestry, with targeted follow up in Chinese and European cohorts comprising 1,950 cases and 1,920 controls. We identified three independent loci in the major histocompatibility complex, as well as a common deletion of CFHR1 and CFHR3 at chromosome 1q32 and a locus at chromosome 22q12 that each surpassed genome-wide significance (P values for association between 1.59 × 10−26 and 4.84 × 10−9 and minor allele odds ratios of 0.63–0.80). These five loci explain 4–7% of the disease variance and up to a tenfold variation in interindividual risk. Many of the alleles that protect against IgA nephropathy impart increased risk for other autoimmune or infectious diseases, and IgA nephropathy risk allele frequencies closely parallel the variation in disease prevalence among Asian, European and African populations, ! suggesting complex selective pressures. View full text Figures at a glance * Figure 1: Manhattan plot of P values for SNP associations to IgA nephropathy. Observed P values versus chromosomal location; highlighted are the ten independent loci followed up in additional cohorts. Dashed line, follow-up threshold. * Figure 2: High-resolution view of MHC locus. x axes, physical distance (kb); left y axes, −log P for association statistics. The −log P values in the discovery and combined cohorts are blue circles and red diamonds, respectively. Right y axes, average recombination rates based on the phased HapMap haplotypes. Recombination rates, light blue lines. () The three intervals associated with IgA nephropathy reside within a 0.54 Mb segment on chromosome 6. Shaded areas correspond to regional plots in –. () Regional plot for interval containing HLA-DQB1, HLA-DQA1 and HLA-DRB1. The classical HLA alleles imputed in the discovery cohort (green triangles) formed a protective haplotype, DQB1*0602-DQA1*0102-DRB1*1501. () Regional plot for the second MHC interval: SNPs typed in the combined cohorts reside within PSMB8. () Regional plot for the HLA-DPB2, HLA-DPB1 and HLA-DPA1 interval. Bottom of –, LD heat maps (D′) calculated based on the genotype data of the Beijing cohort. * Figure 3: Analysis of the chromosome 1 and chromosome 22 loci. () Regional association plot of the chromosome 1q32 locus; although the most strongly associated SNP resides within CFH, it is a perfect proxy for CFHR1,3Δ. Bottom, LD heat map (D′) calculated based on the genotype data of the Beijing cohort. () Haplotype analysis indicated five common haplotypes (H-1 to H-5) in the Beijing discovery cohort (frequency (freq.) > 0.01). The haplotype frequencies, corresponding tag SNPs and reported disease associations are shown22, 23, 24, 36, 37, 41, 43. The H2 haplotype perfectly tags CFHR1,3Δ. The ORs and 95% CIs are calculated in reference to H-1, which has an identical frequency among cases and controls. ***P = 7.7 × 10−6 for comparison of H-2 versus all other haplotypes. () Regional association plot of the chromosome 22 locus: the strongest association stems from the SNPs residing within HORMAD2, but the area of association spans a region over ~0.7 Mb containing multiple genes. * Figure 4: Differences in the distributions of protective alleles by subject ancestry. () Distributions of protective alleles by subject ancestry and case-control status. Numbers of protective alleles were scored for the combined Asian (n = 3,556) and European (n = 2,410) cohorts. Europeans harbor much greater numbers of protective alleles. The differences in the distribution of protective alleles between Asians and Europeans are highly significant within both case and control groups (χ2P = 4.9 × 10−72 and P = 6.4 × 10−60 for cases and controls, respectively). () Distributions of protective alleles among the three HapMap populations: there were highly significant differences between Asian (CHB+JPT) and European (CEU, P = 1.3 × 10−3) and Asian and Yoruban (YRI, P = 7.1 × 10−6) populations. Author information * Abstract * Author information * Supplementary information Affiliations * Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York, USA. * Ali G Gharavi, * Krzysztof Kiryluk, * Yifu Li, * Ping Hou, * Jingyuan Xie, * Simone Sanna-Cherchi & * Francesca Lugani * Department of Genetics, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut, USA. * Murim Choi, * Clara J Men, * Kasuhito Yasuno, * Murat Gunel, * Shrikant Mane, * Sheila Umlauf, * Irina Tikhonova, * Isabel Beerman & * Richard P Lifton * Renal Division, Peking University First Hospital, Peking University, Institute of Nephrology, Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China. * Ping Hou, * Haiyan Wang, * Jicheng Lv, * Li Zhu & * Hong Zhang * Department of Nephrology, Ruijin Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai, China. * Jingyuan Xie, * Weiming Wang, * Zhaohui Wang & * Nan Chen * Departments of Microbiology and Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA. * Bruce A Julian & * Jan Novak * Children's Foundation Research Center at the Le Bonheur Children's Hospital, and the Division of Pediatric Nephrology, University of Tennessee Health Sciences Center, Memphis, Tennessee, USA. * Robert J Wyatt * Department of Medicine, Mount Sinai School of Medicine, New York, New York, USA. * John C He * Yale Center for Genome Analysis, Yale University School of Medicine, New Haven, Connecticut, USA. * Shrikant Mane, * Sheila Umlauf & * Irina Tikhonova * Nephrology and Dialysis Unit, Ciriè Hospital, Torino, Italy. * Silvana Savoldi * Divisione di Nefrologia Dialisi e Trapianto, Azienda Ospedaliero-Universitaria Policlinico di Modena, Modena, Italy. * Riccardo Magistroni * Laboratory on Pathophysiology, Uremia Istituto Giannina Gaslini, Genova, Italy. * Gian Marco Ghiggeri, * Monica Bodria & * Francesca Lugani * University of Calgary, Alberta, Canada. * Pietro Ravani * Divisione di Nefrologia e Dialisi, Istituto Scientifico Humanitas, Milan, Italy. * Claudio Ponticelli * Department of Clinical Medicine, Nephrology and Health Science, Section of Nephrology, University of Parma, Parma, Italy. * Landino Allegri * Department of Nephrology, Ospedale di Gorizia, Gorizia, Italy. * Giuliano Boscutti * Nephrology and Dialysis Unit, Ospedali Riuniti, Ancona, Italy. * Giovanni Frasca * Nephrology, Dialysis and Transplantation, Regina Margherita University Hospital, Turin, Italy. * Alessandro Amore, * Licia Peruzzi & * Rosanna Coppo * University of Brescia and Second Division of Nephrology, Montichiari Hospital, Montichiari, Italy. * Claudia Izzi & * Francesco Scolari * Division of Nephrology, Spedali Civili, Brescia, Brescia Italy. * Battista Fabio Viola * Dialysis Center, Ospedale di Desenzano, Desenzano del Garda, Italy. * Elisabetta Prati * Renal Unit Careggi University Hospital, Florence, Italy. * Maurizio Salvadori * Division of Nephrology, Ospedale degli Infermi, Rimini, Italy. * Renzo Mignani * Department of Biomedical Sciences, University of Foggia, Foggia, Italy. * Loreto Gesualdo * Department of Genetics, Biology and Biochemistry, University of Torino, Torino, Italy. * Francesca Bertinetto, * Paola Mesiano & * Antonio Amoroso Contributions P.H., J.X., S.S.C., B.A.J., R.J.W., J.N., J.C.H., H.W., J.L., L.Z., W.W., Z.W., S.S., R. Magistroni, G.M.G., M.B., P.R., C.P., L.A., G.B., G.F., A. Amore, L.P., R.C., C.I., B.F.V., E.P., M.S., R. Mignani, L.G., F.B., P.M., A. Amoroso, F.S., N.C. and H.Z. : Y.L., P.H., J.X., F.L., I.B., K.K., C.J.M. and M.C. : S.M., S.U., I.T., C.J.M., M.C., P.H., J.X. and Y.L. K.K., Y.L., S.S.C. and M.C. K.K., M.C., A.G.G. and R.P.L. K.Y. and M.G. : A.G.G., K.K., M.C. and R.P.L. A.G.G. and R.P.L. Competing financial interests The authors declare no competing financial interests. Corresponding authors Correspondence to: * Ali G Gharavi or * Richard P Lifton Author Details * Ali G Gharavi Contact Ali G Gharavi Search for this author in: * NPG journals * PubMed * Google Scholar * Krzysztof Kiryluk Search for this author in: * NPG journals * PubMed * Google Scholar * Murim Choi Search for this author in: * NPG journals * PubMed * Google Scholar * Yifu Li Search for this author in: * NPG journals * PubMed * Google Scholar * Ping Hou Search for this author in: * NPG journals * PubMed * Google Scholar * Jingyuan Xie Search for this author in: * NPG journals * PubMed * Google Scholar * Simone Sanna-Cherchi Search for this author in: * NPG journals * PubMed * Google Scholar * Clara J Men Search for this author in: * NPG journals * PubMed * Google Scholar * Bruce A Julian Search for this author in: * NPG journals * PubMed * Google Scholar * Robert J Wyatt Search for this author in: * NPG journals * PubMed * Google Scholar * Jan Novak Search for this author in: * NPG journals * PubMed * Google Scholar * John C He Search for this author in: * NPG journals * PubMed * Google Scholar * Haiyan Wang Search for this author in: * NPG journals * PubMed * Google Scholar * Jicheng Lv Search for this author in: * NPG journals * PubMed * Google Scholar * Li Zhu Search for this author in: * NPG journals * PubMed * Google Scholar * Weiming Wang Search for this author in: * NPG journals * PubMed * Google Scholar * Zhaohui Wang Search for this author in: * NPG journals * PubMed * Google Scholar * Kasuhito Yasuno Search for this author in: * NPG journals * PubMed * Google Scholar * Murat Gunel Search for this author in: * NPG journals * PubMed * Google Scholar * Shrikant Mane Search for this author in: * NPG journals * PubMed * Google Scholar * Sheila Umlauf Search for this author in: * NPG journals * PubMed * Google Scholar * Irina Tikhonova Search for this author in: * NPG journals * PubMed * Google Scholar * Isabel Beerman Search for this author in: * NPG journals * PubMed * Google Scholar * Silvana Savoldi Search for this author in: * NPG journals * PubMed * Google Scholar * Riccardo Magistroni Search for this author in: * NPG journals * PubMed * Google Scholar * Gian Marco Ghiggeri Search for this author in: * NPG journals * PubMed * Google Scholar * Monica Bodria Search for this author in: * NPG journals * PubMed * Google Scholar * Francesca Lugani Search for this author in: * NPG journals * PubMed * Google Scholar * Pietro Ravani Search for this author in: * NPG journals * PubMed * Google Scholar * Claudio Ponticelli Search for this author in: * NPG journals * PubMed * Google Scholar * Landino Allegri Search for this author in: * NPG journals * PubMed * Google Scholar * Giuliano Boscutti Search for this author in: * NPG journals * PubMed * Google Scholar * Giovanni Frasca Search for this author in: * NPG journals * PubMed * Google Scholar * Alessandro Amore Search for this author in: * NPG journals * PubMed * Google Scholar * Licia Peruzzi Search for this author in: * NPG journals * PubMed * Google Scholar * Rosanna Coppo Search for this author in: * NPG journals * PubMed * Google Scholar * Claudia Izzi Search for this author in: * NPG journals * PubMed * Google Scholar * Battista Fabio Viola Search for this author in: * NPG journals * PubMed * Google Scholar * Elisabetta Prati Search for this author in: * NPG journals * PubMed * Google Scholar * Maurizio Salvadori Search for this author in: * NPG journals * PubMed * Google Scholar * Renzo Mignani Search for this author in: * NPG journals * PubMed * Google Scholar * Loreto Gesualdo Search for this author in: * NPG journals * PubMed * Google Scholar * Francesca Bertinetto Search for this author in: * NPG journals * PubMed * Google Scholar * Paola Mesiano Search for this author in: * NPG journals * PubMed * Google Scholar * Antonio Amoroso Search for this author in: * NPG journals * PubMed * Google Scholar * Francesco Scolari Search for this author in: * NPG journals * PubMed * Google Scholar * Nan Chen Search for this author in: * NPG journals * PubMed * Google Scholar * Hong Zhang Search for this author in: * NPG journals * PubMed * Google Scholar * Richard P Lifton Contact Richard P Lifton Search for this author in: * NPG journals * PubMed * Google Scholar Supplementary information * Abstract * Author information * Supplementary information PDF files * Supplementary Text and Figures (2M) Supplementary Note, Supplementary Tables 1–17 and Supplementary Figures 1–8. 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• Genome-wide association study identifies 12 new susceptibility loci for primary biliary cirrhosis
  - Nat Genet 43(4):329-332 (2011)
  Nature Genetics | Letter Genome-wide association study identifies 12 new susceptibility loci for primary biliary cirrhosis * George F Mells1, 2, 11 * James A B Floyd3, 11 * Katherine I Morley3, 4, 11 * Heather J Cordell5 * Christopher S Franklin3 * So-Youn Shin3 * Michael A Heneghan6 * James M Neuberger7 * Peter T Donaldson8 * Darren B Day1 * Samantha J Ducker8 * Agnes W Muriithi1 * Elizabeth F Wheater1 * Christopher J Hammond9 * Muhammad F Dawwas2 * The UK PBC Consortium * The Wellcome Trust Case Control Consortium 3 * David E Jones8 * Leena Peltonen3 * Graeme J Alexander2 * Richard N Sandford1, 12 * Carl A Anderson3, 12 * Affiliations * Contributions * Corresponding authorsJournal name:Nature GeneticsVolume: 43,Pages:329–332Year published:(2011)DOI:doi:10.1038/ng.789Received19 August 2010Accepted15 February 2011Published online13 March 2011 Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg In addition to the HLA locus, six genetic risk factors for primary biliary cirrhosis (PBC) have been identified in recent genome-wide association studies (GWAS). To identify additional loci, we carried out a GWAS using 1,840 cases from the UK PBC Consortium and 5,163 UK population controls as part of the Wellcome Trust Case Control Consortium 3 (WTCCC3). We followed up 28 loci in an additional UK cohort of 620 PBC cases and 2,514 population controls. We identified 12 new susceptibility loci (at a genome-wide significance level of P < 5 × 10−8) and replicated all previously associated loci. We identified three further new loci in a meta-analysis of data from our study and previously published GWAS results. New candidate genes include STAT4, DENND1B, CD80, IL7R, CXCR5, TNFRSF1A, CLEC16A and NFKB1. This study has considerably expanded our knowledge of the genetic architecture of PBC. View full text Author information * Author information * Supplementary information Primary authors * These authors contributed equally to this work. * George F Mells, * James A B Floyd & * Katherine I Morley Affiliations * Academic Department of Medical Genetics, Cambridge University, Cambridge, UK. * George F Mells, * Darren B Day, * Agnes W Muriithi, * Elizabeth F Wheater & * Richard N Sandford * Department of Hepatology, Cambridge University Hospitals National Health Service (NHS) Foundation Trust, Cambridge, UK. * George F Mells, * Muhammad F Dawwas & * Graeme J Alexander * Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK. * James A B Floyd, * Katherine I Morley, * Christopher S Franklin, * So-Youn Shin, * Leena Peltonen & * Carl A Anderson * Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, School of Population Health, University of Melbourne, Melbourne, Australia. * Katherine I Morley * Institute of Human Genetics, Newcastle University, Newcastle upon Tyne, UK. * Heather J Cordell * Institute of Liver Studies, King's College Hospital NHS Foundation Trust, Denmark Hill, London, UK. * Michael A Heneghan * The Liver Unit, Queen Elizabeth Hospital, Birmingham, UK. * James M Neuberger * Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle upon Tyne, UK. * Peter T Donaldson, * Samantha J Ducker & * David E Jones * Department of Twin Research and Genetic Epidemiology, King's College London, London, UK. * Christopher J Hammond * A full list of members is provided in the Supplementary Note. * Christopher J Hammond & * Christopher J Hammond * These authors jointly directed this work. * Richard N Sandford & * Carl A Anderson Contributions G.F.M., H.J.C., M.A.H., J.M.N., P.T.D., the WTCCC3 management committee (see Supplementary Note), L.P., D.E.J., G.J.A., R.N.S., C.A.A. G.F.M., D.B.D., S.J.D., A.W.M., E.F.W., R.N.S. G.F.M., D.B.D., S.J.D., A.W.M., E.F.W., M.F.D., The UK PBC Consortium (see Supplementary Note), D.E.J., G.J.A., R.N.S. The UK Blood Service Controls group (see Supplementary Note), The 1958 Birth Cohort Controls group (see Supplementary Note), C.J.H., C.A.A. The WTCCC3 DNA, Genotyping and Informatics group (see Supplementary Note). J.A.B.F., K.I.M., H.J.C., C.S.F., S.-Y.S., The WTCCC3 data analysis group (see Supplementary Note), C.A.A. G.F.M., J.A.B.F., K.I.M., H.J.C., D.E.J., G.J.A., R.N.S., C.A.A. Competing financial interests The authors declare no competing financial interests. Corresponding authors Correspondence to: * Richard N Sandford or * Carl A Anderson Author Details * George F Mells Search for this author in: * NPG journals * PubMed * Google Scholar * James A B Floyd Search for this author in: * NPG journals * PubMed * Google Scholar * Katherine I Morley Search for this author in: * NPG journals * PubMed * Google Scholar * Heather J Cordell Search for this author in: * NPG journals * PubMed * Google Scholar * Christopher S Franklin Search for this author in: * NPG journals * PubMed * Google Scholar * So-Youn Shin Search for this author in: * NPG journals * PubMed * Google Scholar * Michael A Heneghan Search for this author in: * NPG journals * PubMed * Google Scholar * James M Neuberger Search for this author in: * NPG journals * PubMed * Google Scholar * Peter T Donaldson Search for this author in: * NPG journals * PubMed * Google Scholar * Darren B Day Search for this author in: * NPG journals * PubMed * Google Scholar * Samantha J Ducker Search for this author in: * NPG journals * PubMed * Google Scholar * Agnes W Muriithi Search for this author in: * NPG journals * PubMed * Google Scholar * Elizabeth F Wheater Search for this author in: * NPG journals * PubMed * Google Scholar * Christopher J Hammond Search for this author in: * NPG journals * PubMed * Google Scholar * Muhammad F Dawwas Search for this author in: * NPG journals * PubMed * Google Scholar * The UK PBC Consortium * The Wellcome Trust Case Control Consortium 3 * David E Jones Search for this author in: * NPG journals * PubMed * Google Scholar * Leena Peltonen Search for this author in: * NPG journals * PubMed * Google Scholar * Graeme J Alexander Search for this author in: * NPG journals * PubMed * Google Scholar * Richard N Sandford Contact Richard N Sandford Search for this author in: * NPG journals * PubMed * Google Scholar * Carl A Anderson Contact Carl A Anderson Search for this author in: * NPG journals * PubMed * Google Scholar Supplementary information * Author information * Supplementary information PDF files * Supplementary Text and Figures (3M) Supplementary Tables 1–10, Supplementary Figures 1–7 and Supplementary Note. 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• Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease
  - Nat Genet 43(4):333-338 (2011)
  Nature Genetics | Letter Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease * Heribert Schunkert1, 119 * Inke R König2, 119 * Sekar Kathiresan3, 4, 5, 119 * Muredach P Reilly6, 119 * Themistocles L Assimes7, 119 * Hilma Holm8, 119 * Michael Preuss1, 2 * Alexandre F R Stewart9 * Maja Barbalic10 * Christian Gieger11 * Devin Absher12 * Zouhair Aherrahrou1 * Hooman Allayee13 * David Altshuler5, 14 * Sonia S Anand15 * Karl Andersen16, 17 * Jeffrey L Anderson18 * Diego Ardissino19 * Stephen G Ball20, 21 * Anthony J Balmforth22 * Timothy A Barnes23 * Diane M Becker24 * Lewis C Becker24 * Klaus Berger25 * Joshua C Bis26 * S Matthijs Boekholdt27, 28 * Eric Boerwinkle10 * Peter S Braund23 * Morris J Brown29 * Mary Susan Burnett30 * Ian Buysschaert31, 32 * Cardiogenics * John F Carlquist18 * Li Chen33 * Sven Cichon34, 35, 36 * Veryan Codd23 * Robert W Davies37 * George Dedoussis38 * Abbas Dehghan39, 40 * Serkalem Demissie41, 42 * Joseph M Devaney30 * Patrick Diemert1 * Ron Do43 * Angela Doering11 * Sandra Eifert44 * Nour Eddine El Mokhtari45 * Stephen G Ellis46 * Roberto Elosua47 * James C Engert43, 48 * Stephen E Epstein30 * Ulf de Faire49, 50 * Marcus Fischer51 * Aaron R Folsom52 * Jennifer Freyer1 * Bruna Gigante49, 50 * Domenico Girelli53 * Solveig Gretarsdottir8 * Vilmundur Gudnason17, 54 * Jeffrey R Gulcher8 * Eran Halperin55, 56, 57 * Naomi Hammond58 * Stanley L Hazen59 * Albert Hofman39 * Benjamin D Horne18 * Thomas Illig11 * Carlos Iribarren60 * Gregory T Jones61 * J Wouter Jukema62, 63 * Michael A Kaiser23 * Lee M Kaplan64 * John J P Kastelein65 * Kay-Tee Khaw66 * Joshua W Knowles7 * Genovefa Kolovou67 * Augustine Kong8 * Reijo Laaksonen68 * Diether Lambrechts32 * Karin Leander49 * Guillaume Lettre69, 70 * Mingyao Li71 * Wolfgang Lieb1 * Christina Loley1, 2 * Andrew J Lotery72, 73 * Pier M Mannucci74 * Seraya Maouche1 * Nicola Martinelli53 * Pascal P McKeown75 * Christa Meisinger11 * Thomas Meitinger76, 77 * Olle Melander78 * Pier Angelica Merlini79 * Vincent Mooser80 * Thomas Morgan81 * Thomas W Mühleisen34, 35 * Joseph B Muhlestein18 * Thomas Münzel82 * Kiran Musunuru3, 4, 5 * Janja Nahrstaedt1, 2 * Christopher P Nelson22 * Markus M Nöthen34, 35 * Oliviero Olivieri53 * Riyaz S Patel83, 84 * Chris C Patterson75 * Annette Peters11 * Flora Peyvandi85 * Liming Qu71 * Arshed A Quyyumi83 * Daniel J Rader6, 86 * Loukianos S Rallidis87 * Catherine Rice58 * Frits R Rosendaal88, 89, 90 * Diana Rubin91 * Veikko Salomaa92 * M Lourdes Sampietro93 * Manj S Sandhu94, 95 * Eric Schadt96, 97 * Arne Schäfer98 * Arne Schillert2 * Stefan Schreiber98 * Jürgen Schrezenmeir99, 100 * Stephen M Schwartz26 * David S Siscovick26 * Mohan Sivananthan101 * Suthesh Sivapalaratnam27 * Albert Smith17, 54 * Tamara B Smith102 * Jaapjan D Snoep88 * Nicole Soranzo58 * John A Spertus103 * Klaus Stark51 * Kathy Stirrups58 * Monika Stoll104 * W H Wilson Tang46 * Stephanie Tennstedt1 * Gudmundur Thorgeirsson16, 17 * Gudmar Thorleifsson8 * Maciej Tomaszewski23, 105 * Andre G Uitterlinden39, 40, 106 * Andre M van Rij61 * Benjamin F Voight4, 5, 107 * Nick J Wareham108 * George A Wells37 * H-Erich Wichmann11, 44, 109 * Philipp S Wild82 * Christina Willenborg1, 2 * Jaqueline C M Witteman39, 40 * Benjamin J Wright110 * Shu Ye111 * Tanja Zeller82 * Andreas Ziegler2 * Francois Cambien112 * Alison H Goodall23, 105 * L Adrienne Cupples41, 42 * Thomas Quertermous7 * Winfried März113, 114, 115 * Christian Hengstenberg51 * Stefan Blankenberg82 * Willem H Ouwehand58, 116 * Alistair S Hall21 * Panos Deloukas58 * John R Thompson117 * Kari Stefansson8, 17 * Robert Roberts9 * Unnur Thorsteinsdottir8, 17 * Christopher J O'Donnell42, 119 * Ruth McPherson9, 118, 119 * Jeanette Erdmann1, 119 * Nilesh J Samani23, 105, 119 * for the CARDIoGRAM Consortium120 * Affiliations * Contributions * Corresponding authorsJournal name:Nature GeneticsVolume: 43,Pages:333–338Year published:(2011)DOI:doi:10.1038/ng.784Received10 August 2010Accepted10 February 2011Published online06 March 2011 Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg We performed a meta-analysis of 14 genome-wide association studies of coronary artery disease (CAD) comprising 22,233 individuals with CAD (cases) and 64,762 controls of European descent followed by genotyping of top association signals in 56,682 additional individuals. This analysis identified 13 loci newly associated with CAD at P < 5 × 10−8 and confirmed the association of 10 of 12 previously reported CAD loci. The 13 new loci showed risk allele frequencies ranging from 0.13 to 0.91 and were associated with a 6% to 17% increase in the risk of CAD per allele. Notably, only three of the new loci showed significant association with traditional CAD risk factors and the majority lie in gene regions not previously implicated in the pathogenesis of CAD. Finally, five of the new CAD risk loci appear to have pleiotropic effects, showing strong association with various other human diseases or traits. View full text Figures at a glance * Figure 1: Graphical summary (Manhattan plot) of genome-wide association results. The x axis represents the genome in physical order; the y axis shows −log10P for all SNPs. Data from the discovery phase are shown in circles, and data from the combined discovery and replication phases are shown in stars. Genes at the significant loci are listed above the signals. Known loci are shown in red and newly discovered loci are shown in blue. * Figure 2: Example of overlapping association signals for multiple traits at the ABO gene region on chromosome 9q34. In the upper panel, the association signal for coronary disease at the ABO gene region in CARDIoGRAM and the positions and rs numbers of SNPs in this region are shown. The size of the boxes illustrates the number of individuals available for this respective SNP. In the lower panel, all SNPs with P values at the genome-wide significance level of P < 5 × 10−8 based on the National Human Genome Research Institute GWAS catalog (accessed on 28 June 2010) for all diseases and traits are shown. The degree of linkage disequilibrium (r2) between the lead SNPs for coronary disease and the other traits is reflected by the color of the squares (upper panel) and the small bars (lower panel), from dark red (high LD) to faint red (low LD). SI/CH, sitosterol normalized to cholesterol; CA/CH, campesterol normalized to cholesterol; ALP, alkaline phosphatase; ACE, angiotensin converting enzyme; FVIII, coagulation factor VIII; vWF, von Willebrand factor. Author information * Author information * Supplementary information Primary authors * These authors contributed equally to this work. * Heribert Schunkert, * Inke R König, * Sekar Kathiresan, * Muredach P Reilly, * Themistocles L Assimes, * Hilma Holm, * Christopher J O'Donnell, * Ruth McPherson, * Jeanette Erdmann & * Nilesh J Samani Affiliations * Universität zu Lübeck, Medizinische Klinik II, Lübeck, Germany. * Heribert Schunkert, * Michael Preuss, * Zouhair Aherrahrou, * Patrick Diemert, * Jennifer Freyer, * Wolfgang Lieb, * Christina Loley, * Seraya Maouche, * Janja Nahrstaedt, * Stephanie Tennstedt, * Christina Willenborg & * Jeanette Erdmann * Institut für Medizinische Biometrie und Statistik, Universität zu Lübeck, Lübeck, Germany. * Inke R König, * Michael Preuss, * Christina Loley, * Janja Nahrstaedt, * Arne Schillert, * Christina Willenborg & * Andreas Ziegler * Cardiovascular Research Center and Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts, USA. * Sekar Kathiresan & * Kiran Musunuru * Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA. * Sekar Kathiresan, * Kiran Musunuru & * Benjamin F Voight * Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. * Sekar Kathiresan, * David Altshuler, * Kiran Musunuru & * Benjamin F Voight * The Cardiovascular Institute, University of Pennsylvania, Philadelphia, Pennsylvania, USA. * Muredach P Reilly & * Daniel J Rader * Department of Medicine, Stanford University School of Medicine, Stanford, California, USA. * Themistocles L Assimes, * Joshua W Knowles & * Thomas Quertermous * deCODE genetics, Reykjavik, Iceland. * Hilma Holm, * Solveig Gretarsdottir, * Jeffrey R Gulcher, * Augustine Kong, * Gudmar Thorleifsson, * Kari Stefansson & * Unnur Thorsteinsdottir * The John and Jennifer Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute, Ottawa, Ontario, Canada. * Alexandre F R Stewart, * Robert Roberts & * Ruth McPherson * University of Texas Health Science Center, Human Genetics Center, Houston, Texas, USA. * Maja Barbalic & * Eric Boerwinkle * Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany. * Christian Gieger, * Angela Doering, * Thomas Illig, * Christa Meisinger, * Annette Peters & * H-Erich Wichmann * Hudson Alpha Institute, Huntsville, Alabama, USA. * Devin Absher * Department of Preventive Medicine, University of Southern California, Los Angeles, California, USA. * Hooman Allayee * Department of Molecular Biology and Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA. * David Altshuler * Population Health Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, Ontario, Canada. * Sonia S Anand * Department of Medicine, Landspitali University Hospital, Reykjavik, Iceland. * Karl Andersen & * Gudmundur Thorgeirsson * University of Iceland, Faculty of Medicine, Reykjavik, Iceland. * Karl Andersen, * Vilmundur Gudnason, * Albert Smith, * Gudmundur Thorgeirsson, * Kari Stefansson & * Unnur Thorsteinsdottir * Cardiovascular Department, Intermountain Medical Center, Cardiology Division, University of Utah, Salt Lake City, Utah, USA. * Jeffrey L Anderson, * John F Carlquist, * Benjamin D Horne & * Joseph B Muhlestein * Division of Cardiology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy. * Diego Ardissino * LIGHT Research Institute, Faculty of Medicine and Health, University of Leeds, Leeds, UK. * Stephen G Ball * Division of Cardiovascular and Neuronal Remodelling, Multidisciplinary Cardiovascular Research Centre, Leeds Institute of Genetics, Health and Therapeutics, University of Leeds, Leeds, UK. * Stephen G Ball & * Alistair S Hall * Division of Cardiovascular and Diabetes Research, Multidisciplinary Cardiovascular Research Centre, Leeds Institute of Genetics, Health and Therapeutics, University of Leeds, Leeds, UK. * Anthony J Balmforth & * Christopher P Nelson * Department of Cardiovascular Sciences, University of Leicester, Clinical Sciences Wing, Glenfield Hospital, Leicester, UK. * Timothy A Barnes, * Peter S Braund, * Veryan Codd, * Michael A Kaiser, * Maciej Tomaszewski, * Alison H Goodall & * Nilesh J Samani * The Johns Hopkins University School of Medicine, Division of General Internal Medicine, Baltimore, Maryland, USA. * Diane M Becker & * Lewis C Becker * Institute of Epidemiology and Social Medicine, University of Münster, Münster, Germany. * Klaus Berger * Cardiovascular Health Resarch Unit and Department of Medicine, University of Washington, Seattle, Washington, USA. * Joshua C Bis, * Stephen M Schwartz & * David S Siscovick * Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands. * S Matthijs Boekholdt & * Suthesh Sivapalaratnam * Department of Cardiology, Academic Medical Center, Amsterdam, The Netherlands. * S Matthijs Boekholdt * Clinical Pharmacology Unit, University of Cambridge, Cambridge, UK. * Morris J Brown * Cardiovascular Research Institute, Medstar Health Research Institute, Washington Hospital Center, Washington, DC, USA. * Mary Susan Burnett, * Joseph M Devaney & * Stephen E Epstein * Department of Cardiology, University Hospital Gasthuisberg, Leuven, Belgium. * Ian Buysschaert * Vesalius Research Center, VIB-K.U.Leuven, Leuven, Belgium. * Ian Buysschaert & * Diether Lambrechts * Cardiovascular Research Methods Centre, University of Ottawa Heart Institute, Ottawa, Ontario, Canada. * Li Chen * Institute of Human Genetics, University of Bonn, Bonn, Germany. * Sven Cichon, * Thomas W Mühleisen & * Markus M Nöthen * Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany. * Sven Cichon, * Thomas W Mühleisen & * Markus M Nöthen * Institute of Neuroscience and Medicine (INM-1), Research Center Juelich, Juelich, Germany. * Sven Cichon * The Cardiovascular Research Methods, University of Ottawa Heart Institute, Ottawa, Ontario, Canada. * Robert W Davies & * George A Wells * Department of Dietetics-Nutrition, Harokopio University, Athens, Greece. * George Dedoussis * Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands. * Abbas Dehghan, * Albert Hofman, * Andre G Uitterlinden & * Jaqueline C M Witteman * Member of Netherlands Consortium for Healthy Aging (NCHA) sponsored by Netherlands Genomics Initiative (NGI), Leiden, The Netherlands. * Abbas Dehghan, * Andre G Uitterlinden & * Jaqueline C M Witteman * Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA. * Serkalem Demissie & * L Adrienne Cupples * National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, USA. * Serkalem Demissie, * L Adrienne Cupples & * Christopher J O'Donnell * Department of Human Genetics, McGill University, Montreal, Quebec, Canada. * Ron Do & * James C Engert * Klinikum Grosshadern, Munich, Germany. * Sandra Eifert & * H-Erich Wichmann * Klinik für Innere Medizin, Kreiskrankenhaus Rendsburg, Rendsburg, Germany. * Nour Eddine El Mokhtari * Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio, USA. * Stephen G Ellis & * W H Wilson Tang * Cardiovascular Epidemiology and Genetics Group, Institut Municipal d'Investigació Mèdica, Ciber Epidemiología y Salud Pública (CIBERSP), Barcelona, Spain. * Roberto Elosua * Department of Medicine, McGill University, Montreal, Canada. * James C Engert * Division of Cardiovascular Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden. * Ulf de Faire, * Bruna Gigante & * Karin Leander * Department of Cardiology, Karolinska University Hospital, Stockholm, Sweden. * Ulf de Faire & * Bruna Gigante * Klinik und Poliklinik für Innere Medizin II, Regensburg, Germany. * Marcus Fischer, * Klaus Stark & * Christian Hengstenberg * University of Minnesota School of Public Health, Division of Epidemiology and Community Health, School of Public Health (A.R.F.), Minneapolis, Minnesota, USA. * Aaron R Folsom * Department of Medicine, University of Verona, Verona, Italy. * Domenico Girelli, * Nicola Martinelli & * Oliviero Olivieri * Icelandic Heart Association, Kopavogur, Iceland. * Vilmundur Gudnason & * Albert Smith * The Blavatnik School of Computer Science, Tel-Aviv University, Tel-Aviv, Israel. * Eran Halperin * Department of Molecular Microbiology and Biotechnology, Tel-Aviv University, Tel-Aviv, Israel. * Eran Halperin * International Computer Science Institute, Berkeley, California, USA. * Eran Halperin * Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK. * Naomi Hammond, * Catherine Rice, * Nicole Soranzo, * Kathy Stirrups, * Willem H Ouwehand & * Panos Deloukas * Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA. * Stanley L Hazen * Division of Research, Kaiser Permanente of Northern California, Oakland, California, USA. * Carlos Iribarren * Surgery Department, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand. * Gregory T Jones & * Andre M van Rij * Department of Cardiology C5-P, Leiden University Medical Center, Leiden, The Netherlands. * J Wouter Jukema * Durrer Center for Cardiogenetic Research, Amsterdam, The Netherlands. * J Wouter Jukema * Massachusetts General Hospital, Boston, Massachusetts, USA. * Lee M Kaplan * Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. * John J P Kastelein * Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge, Cambridge, UK. * Kay-Tee Khaw * 1st Cardiology Department, Onassis Cardiac Surgery Center, Athens, Greece. * Genovefa Kolovou * Science Center, Tampere University Hospital, Tampere, Finland. * Reijo Laaksonen * Montreal Heart Institute, Montréal, Québec, Canada. * Guillaume Lettre * Département de Médecine, Université de Montréal, succursale Centre-ville, Montréal, Québec, Canada. * Guillaume Lettre * Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA. * Mingyao Li & * Liming Qu * Clinical Neurosciences Division, School of Medicine, University of Southampton, Southampton, UK. * Andrew J Lotery * Southampton Eye Unit, Southampton General Hospital, Southampton, UK. * Andrew J Lotery * Scientific Direction, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Fondazione Cà Granda, Ospedale Maggiore Policlinico, Milano, Italy. * Pier M Mannucci * Centre for Public Health, Queen's University Belfast, Institute of Clinical Science, Belfast, Ireland, UK. * Pascal P McKeown & * Chris C Patterson * Institute of Human Genetics, Helmholtz Zentrum München, Deutsches Forschungszentrum für Umwelt und Gesundheit, Neuherberg, Germany. * Thomas Meitinger * Institute of Human Genetics, Technische Universität München, Klinikum rechts der Isar, Munich, Germany. * Thomas Meitinger * Department of Clinical Sciences, Hypertension and Cardiovascular Diseases, Scania University Hospital, Lund University, Malmö, Sweden. * Olle Melander * Division of Cardiology, Azienda Ospedaliera Niguarda Ca'Granda, Milan, Italy. * Pier Angelica Merlini * Genetics Division and Drug Discovery, GlaxoSmithKline, King of Prussia, Pennsylvania, USA. * Vincent Mooser * Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA. * Thomas Morgan * Medizinische Klinik und Poliklinik, Universitätsmedizin Mainz, Johannes-Gutenberg Universität Mainz, Germany. * Thomas Münzel, * Philipp S Wild, * Tanja Zeller & * Stefan Blankenberg * Emory University School of Medicine, Atlanta, Georgia, USA. * Riyaz S Patel & * Arshed A Quyyumi * Cardiff University, Cardiff, Wales, UK. * Riyaz S Patel * A. Bianchi Bonomi Hemophilia and Thrombosis Center, Department of Medicine and Medical Specialties, Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico, Università degli Studi di Milano and Luigi Villa Foundation, Milan, Italy. * Flora Peyvandi * The Institute for Translational Medicine and Therapeutics, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. * Daniel J Rader * Second Department of Cardiology, Attikon Hospital, School of Medicine, University of Athens, Athens, Greece. * Loukianos S Rallidis * Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands. * Frits R Rosendaal & * Jaapjan D Snoep * Department of Thrombosis and Haemostasis, Leiden University Medical Center, Leiden, The Netherlands. * Frits R Rosendaal * Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands. * Frits R Rosendaal * Medizinische Klinik I, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Kiel, Germany. * Diana Rubin * Chronic Disease Epidemiology and Prevention Unit, Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland. * Veikko Salomaa * Department of Human Genetics and Cardiology, Leiden University Medical Center, Leiden, The Netherlands. * M Lourdes Sampietro * Manjinder S. Sandhu, Genetic Epidemiology Group, Wellcome Trust Sanger Institute, Cambridge, UK. * Manj S Sandhu * Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge, Cambridge, UK. * Manj S Sandhu * Pacific Biosciences, Menlo Park, California, USA. * Eric Schadt * Sage Bionetworks, Palo Alto, California, USA. * Eric Schadt * Institut für Klinische Molekularbiologie, Christian-Albrechts Universität, Kiel, Germany. * Arne Schäfer & * Stefan Schreiber * Institute of Physiology and Biochemistry of Nutrition, Max Rubner-Institute, Kiel, Germany. * Jürgen Schrezenmeir * Clinical Research Center Kiel, Kiel Innovation and Technology Center, Kiel, Germany. * Jürgen Schrezenmeir * Cardiology Division, Leeds Teaching Hospitals National Health Service Trust, Leeds, UK. * Mohan Sivananthan * Laboratory of Epidemiology, Demography and Biometry, Intramural Research Program, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA. * Tamara B Smith * Mid America Heart Institute and University of Missouri-Kansas City, Kansas City, Missouri, USA. * John A Spertus * Leibniz-Institute for Arteriosclerosis Research, University of Münster, Münster, Germany. * Monika Stoll * Leicester National Institute for Health Research Biomedical Research Unit in Cardiovascular Disease, Glenfield Hospital, Leicester, UK. * Maciej Tomaszewski, * Alison H Goodall & * Nilesh J Samani * Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands. * Andre G Uitterlinden * Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA. * Benjamin F Voight * Medical Research Council Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK. * Nick J Wareham * Institute of Medical Information Science, Biometry and Epidemiology, Ludwig-Maximilians-Universität München, München, Germany. * H-Erich Wichmann * Department of Cardiovascular Surgery, University of Leicester, Leicester, UK. * Benjamin J Wright * William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK. * Shu Ye * INSERM UMRS 937, Pierre and Marie Curie University, Université Pierre et Marie Curie (UPMC)-Paris 6, Faculté de Médecine Pierre et Marie Curie, Paris, France. * Francois Cambien * Synlab Center of Laboratory Diagnostics Heidelberg, Heidelberg, Germany. * Winfried März * Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria. * Winfried März * Institute of Public Health, Social and Preventive Medicine, Medical Faculty Manneim, University of Heidelberg, Heidelberg, Germany. * Winfried März * Department of Haematology, University of Cambridge and NHS Blood and Transplant, Cambridge, UK. * Willem H Ouwehand * Department of Health Sciences, University of Leicester, Leicester, UK. * John R Thompson * Atherogenomics Laboratory, University of Ottawa Heart Institute, Ottawa, Ontario, Canada. * Ruth McPherson * A full list of members is provided in the Supplementary Note. * the CARDIoGRAM Consortium Consortia * the CARDIoGRAM Consortium * Nilesh J Samani Contributions H.S., I.R.K., S.K., M.P.R., T.L.A., H.H., A.F.R.S., P. Deloukas, R.R., R.M., J.E., N.J.S. H.S., I.R.K., S.K., M.P.R., T.L.A., H.H., M.P., A.F.R.S., M.B., C.G., D. Absher, D. Ardissino, K.A., S.G.B., A.J.B., J.C.B., E.B., P.S.B., M.S.B., L.C., A. Deghan, S.D., P. Diemert, J.D., A. Doering, N.E.E.M., R.E., S.E., M.F., A.R.F., S.G., J.R.G., E.H., A.H., T.I., C.I., M.A.K., J.W.K., A.K., R.L., M.L., W.L., C.L., C.M., T. Meitinger, O.M., V.M., K.M., T. Morgan, J.N., C.P.N., A.P., L.Q., D.J.R., V.S., A. Schäfer, A. Schillert, S.S., J.S., S.M.S., D.S.S., K.S., G. Thorgeirsson, G. Thorleifsson, M.T., A.G.U., B.F.V., G.A.W., H.E.W., C.W., P.S.W., J.C.M.W., B.J.W., T.Z., A.Z., F.C., L.A.C., T.Q., W.M., C.H., S.B., A.S.H., P.D., U.T., R.R., J.R.T., C.J.O., R.M., J.E., N.J.S. H.S., I.R.K., S.K., M.P.R., H.H., M.P., H.A., S.A., K.A., T.L.A., J.L.A., D. Ardissino, D. Absher, T.A.B., L.C.B, D.M.B., K.B., S.M.B., M.J.B., I.B., J.F.C., R.W.D., G.D., R.D., S.G.E., J.C.E., U.d.F., B.G., D.G., V.G., N.H., S.L.H., B.D.H., C.I., G.T.J., J.W.J., L.M.K., J.W.K., J.J.P.K., K.-T.K., G.K., D.L., K.L., P.L.-N., A.J.L., P.M.M., N.M., P.P.M., P.A.M., T. Morgan, T. Meitinger, T.W.M., J.B.M., S.C., M.M.N., O.O., F.P., R.S.P., C.C.P., A.A.Q., L.S.R., F.R.R., D.R., M.L.S., M.S.S., S. Sivapalaratnam, T.B.S., J.D.S., N.S., J.A.S., T.Q., K. Stark, K. Stirrups, M. Stoll, W.H.W.T., A.M.v.R., N.J.W., S.Y., P.D., U.T., R.R., R.M., J.E., N.J.S. I.R.K., M.P., D. Absher, L.C., E.H., M.L., K.M., A. Schillert, G. Thorleifsson, B.F.V., G.A.W., L.A.C., J.R.T. H.S., T.L.A., H.H., M.B., C.G., Z.A., P.S.B., V.C., J.F., S.G., P.L.-N., G.L., S.M., C.R., E.S., M.T., F.C., A.H.G., T.Q., C.H., W.H.O., P.D., U.T., J.E., N.J.S. H.S., S.K., M.P.R., J.E., N.J.S. H.S., I.R.K., S.K., M.P.R., T.L.A., E.B., R.L., A.Z., C.H., A.S.H., U.T., J.R.T., R.M., J.E., N.J.S. Competing financial interests Genotyping of PennCATH and Medstar was supported by GlaxoSmithKline. D.M.W., M.C.W. and V.M. are employees of GlaxoSmithKline. H.H., S.G., J.R.G., A.K., K.S., G.T. and U.T. are employees of and/or own stock or stock options in deCODE genetics. 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• A genome-wide association study in Europeans and South Asians identifies five new loci for coronary artery disease
  - Nat Genet 43(4):339-344 (2011)
  Nature Genetics | Letter A genome-wide association study in Europeans and South Asians identifies five new loci for coronary artery disease * The Coronary Artery Disease (C4D) Genetics Consortium * Affiliations * Contributions * Corresponding authorsJournal name:Nature GeneticsVolume: 43,Pages:339–344Year published:(2011)DOI:doi:10.1038/ng.782Received22 July 2010Accepted10 February 2011Published online06 March 2011 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 have identified 11 common variants convincingly associated with coronary artery disease (CAD)1, 2, 3, 4, 5, 6, 7, a modest number considering the apparent heritability of CAD8. All of these variants have been discovered in European populations. We report a meta-analysis of four large genome-wide association studies of CAD, with ~575,000 genotyped SNPs in a discovery dataset comprising 15,420 individuals with CAD (cases) (8,424 Europeans and 6,996 South Asians) and 15,062 controls. There was little evidence for ancestry-specific associations, supporting the use of combined analyses. Replication in an independent sample of 21,408 cases and 19,185 controls identified five loci newly associated with CAD (P < 5 × 10−8 in the combined discovery and replication analysis): LIPA on 10q23, PDGFD on 11q22, ADAMTS7-MORF4L1 on 15q25, a gene rich locus on 7q22 and KIAA1462 on 10p11. The CAD-associated SNP in the PDGFD locus showed tissue-specific cis exp! ression quantitative trait locus effects. These findings implicate new pathways for CAD susceptibility. View full text Figures at a glance * Figure 1: Studies contributing to the discovery and replication meta-analyses. aIncludes 2,133 cases who are either full or half siblings of another case. bIncludes 2,697 controls from the National Blood Service. cIncludes 2,887 controls from the 1958 British Birth cohort. dIncludes 5,157 controls from the UK Twins study and 2,535 additional independent PROCARDIS controls not used in the discovery analysis. * Figure 2: Genome-wide Manhattan plot of P values for all studies (European and South Asian). The −log10P for 574,919 SNPs from the meta-analysis of the PROCARDIS, HPS, PROMIS and LOLIPOP studies. The y axis is truncated at −log10P of 12; rs9349379 at the PHACTR1 locus (P = 5.8 × 10−19) and 15 SNPs at the 9p21 locus (7.9 × 10−13 > P > 1.3 × 10−25) exceed the truncation. SNP associations with CAD that exceeded the genome-wide significance threshold (P < 5.0 × 10−8) are shown in magenta; P values between P = 4.5 × 10−5 and P = 5.0 × 10−8 are shown in blue. The locations of the new replicated loci are annotated in black and previously reported CAD loci (Table 1) with P < 4.0 × 10−5 in the meta-analysis of all studies together are annotated in gray. * Figure 3: Newly identified loci and variants associated with CAD in European, South Asian and all studies. Odds ratios per copy of the risk allele are indicated by squares (size inversely proportional to the variance), with horizontal lines indicating 95% CIs. Odds ratios and 95% CIs for all participants are indicated by diamonds. Allele frequencies (allele freq) are given for the risk allele. P values for heterogeneity between European and South Asian (S Asian) results are reported (ethnic Phet). *The South Asian only discovery P value for rs4380028 was P = 3.6 × 10−6. * Figure 4: Regional plots for significant associations with CAD. Regional association plots of the discovery meta-analysis from which each replicated SNP was selected; that is, the European and South Asian discovery meta-analysis (, and ,) and South Asian meta-analysis (). Each panel shows SNPs plotted by position on the chromosome against –log10P, with estimated recombination rates from HapMap release 27 (CEU, YRI and JPT+CHB populations) plotted in light blue to reflect the local LD structure on a secondary y axis. The most significant lead SNP (red diamond) at each locus is annotated with its discovery P value, and flanking SNPs are color-coded to represent the pairwise r2 measure of LD with the lead SNP: blue, r2 ≥ 0.8; green, 0.5 ≤ r2 < 0.8; orange, 0.2 ≤ r2 ≤ 0.5; gray, r2 < 0.2. , and , report r2 values calculated from HapMap2 CEU reference samples, and reports r2 values calculated from HapMap2 GIH reference samples. Green bars represent RefSeq genes in the region. All positions are on NCBI build 36. The purple star in re! presents significant eQTL association in aortic media. The black arrowhead in represents the South Asian only meta-analysis P value. Author information * Author information * Supplementary information Primary authors * These authors contributed equally to this work. * John F Peden, * Jemma C Hopewell, * Danish Saleheen, * John C Chambers, * Jorg Hager, * Nicole Soranzo, * Rory Collins, * John Danesh, * Paul Elliott, * Martin Farrall, * Kathy Stirrups, * Weihua Zhang, * Anders Hamsten, * Sarah Parish, * Mark Lathrop, * Hugh Watkins (Chair), * Robert Clarke, * Panos Deloukas & * Jaspal S Kooner Affiliations * Department of Cardiovascular Medicine, The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. * John F Peden, * Martin Farrall, * Hugh Watkins, * Anuj Goel, * Halit Ongen, * Anna Helgadottir, * Shapour Jalilzadeh & * Theodosios Kyriakou * Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford, UK. * John F Peden, * Martin Farrall, * Hugh Watkins, * Anuj Goel, * Halit Ongen, * Anna Helgadottir, * Shapour Jalilzadeh, * Theodosios Kyriakou & * Peter Sleight * Clinical Trial Service Unit, University of Oxford, Oxford, UK. * Jemma C Hopewell, * Rory Collins, * Sarah Parish, * Robert Clarke, * Alison Offer, * Louise Bowman, * Jane Armitage, * Richard Peto, * Pamela Linksted & * Derrick Bennett * Center for Non-Communicable Diseases Pakistan, Karachi, Pakistan. * Danish Saleheen, * Asif Rasheed, * Moazzam Zaidi, * Nabi Shah, * Maria Samuel & * Philippe M Frossard * Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK. * Danish Saleheen & * John Danesh * Epidemiology and Biostatistics, Imperial College London, Norfolk Place, London, UK. * John C Chambers, * Paul Elliott & * Weihua Zhang * Cardiology, Ealing Hospital National Health Service (NHS) Trust, Middlesex, UK. * John C Chambers, * Weihua Zhang & * Jaspal S Kooner * Commissariat à l′Energie Atomique (CEA) Genomics Institute-Centre National de Génotypage, Evry Cedex, France. * Jorg Hager, * Mark Lathrop, * Simon Heath & * Marc Delepine * Human Genetics, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK. * Nicole Soranzo, * Kathy Stirrups, * Panos Deloukas, * Muhammed Murtaza & * Leena Peltonen * Medical Research Council-Health Protection Agency (MRC-HPA) Centre for Environment and Health, Imperial College London, London, UK. * Paul Elliott * Atherosclerosis Research Unit, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden. * Anders Hamsten, * Rona J Strawbridge, * Anders Mälarstig, * John Öhrvik, * Lasse Folkersen, * Per Eriksson, * Angela Silveira & * Ferdinand M van 't Hooft * Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden. * Anders Hamsten, * Rona J Strawbridge, * Anders Mälarstig, * John Öhrvik, * Lasse Folkersen, * Per Eriksson, * Angela Silveira & * Ferdinand M van 't Hooft * National Heart and Lung Institute, Imperial College London, London, UK. * Jaspal S Kooner, * James Scott & * Joban Sehmi * Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK. * Simon Potter, * Sarah E Hunt, * Rhian Gwilliam, * Suzannah Bumpstead, * Emma Gray & * Sarah Edkins * Department of Medical Sciences, Molecular Medicine, Uppsala University, Uppsala, Sweden. * Tomas Axelsson & * Ann-Christine Syvanen * Thoracic Surgery Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden. * Anders Franco-Cereceda * Cardiology Unit, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden. * Anders Gabrielsen * Gesellschaft für Arterioskleroseforschung e.V., Leibniz-Institut für Arterioskleroseforschung an der Universität Münster (LIFA), Münster, Germany. * Udo Seedorf, * Stephan Rust & * Gerd Assmann * Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA. * Goncalo Abecasis * Cardiology, Ealing Hospital NHS Trust, Middlesex, UK. * Nabeel Ahmed & * Angad S Kooner * William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK. * Mark Caulfield * Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. * Peter Donnelly & * Mark I McCarthy * Department of Statistics, Oxford University, Oxford, UK. * Peter Donnelly * Genomic Medicine, Imperial College London, London, UK. * Philippe Froguel * Oxford Centre for Diabetes, Endocrinology and Metabolism, Oxford University, Oxford, UK. * Mark I McCarthy * Oxford National Institute of Health Research (NIHR) Biomedical Research Centre, Churchill Hospital, Headington, UK. * Mark I McCarthy * Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Leicester, UK. * Nilesh J Samani * Leicester NIHR Biomedical Research Unit in Cardiovascular Disease, Glenfield Hospital, Leicester, UK. * Nilesh J Samani * Cardiology Unit, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden. * Mai-Lis Hellénius * Cardiovascular Drug Research at the Department of Medicine, Solna, Sweden. * Gunnar Olsson * Cardiovascular and Gastrointestinal Innovative Medicines, Global Research and Development, AstraZeneca, Sweden. * Gunnar Olsson * Department of Cardiovascular Research, Istituto Mario Negri, Milano, Italy. * Simona Barlera, * Gianni Tognoni, * Maria Grazia Franzosi, * Silvia Pietri & * Francesca Gori * Consorzio Mario Negri Sud, Santa Maria Imbaro (Chieti), Italy. * Gianni Tognoni * Biochemical Sciences Division, Faculty of Health and Medical Sciences, University of Surrey, Guilford, UK. * Fiona R Green * Department of Cardiology, Punjab Institute of Cardiology, Jail Road, Lahore, Pakistan. * Nadeem H Mallick & * Muhammad Azhar * Department of Cardiology, National Institute of Cardiovascular Diseases, Karachi, Pakistan. * Khan S Zaman * Department of Cardiology, Karachi Institute of Heart Diseases, Federal B. Area, Karachi, Pakistan. * Abdus Samad & * Mohammad Ishaq * Department of Cardiology, Ch. Pervaiz Elahi Institute Of Cardiology, Multan, Pakistan. * Ali R Gardezi * Department of Cardiology, Red Crescent Institute of Cardiology, Latifabad, Hyderabad, Pakistan. * Fazal-ur-Rehman Memon * Department of Twin Research and Genetic Epidemiology, Kings College London, London, UK. * Tim Spector * Department of Medical Genetics, University of Helsinki and the Helsinki University Central Hospital, Helsinki, Finland. * Leena Peltonen * Division of Cardiology, Helsinki University Central Hospital, Helsinki, Finland. * Markku S Nieminen * University Central Hospital, Cardiovascular Laboratory, Helsinki, Finland. * Juha Sinisalo * National Institute for Health and Welfare, Helsinki, Finland. * Veikko Salomaa & * Samuli Ripatti * Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland. * Leena Peltonen & * Samuli Ripatti * Cardiovascular Epidemiology Unit, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden. * Karin Leander, * Bruna Gigante & * Ulf de Faire * Laboratory of Clinical Epidemiology of Cardiovascular Disease, Consorzio Mario Negri Sud, Santa Maria Imbaro, Italy. * Roberto Marchioli * Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. * Suthesh Sivapalaratnam, * John J P Kastelein & * Mieke D Trip * Department of Dietetics-Nutrition, Harokopio University, Athens, Greece. * Eirini V Theodoraki & * George V Dedoussis * McGill University Department of Medicine, Montreal, Quebec, Canada. * Jamie C Engert * McGill University Department of Human Genetics, Montreal, Quebec, Canada. * Jamie C Engert * Population Health Research Institute, Hamilton Health Sciences, McMaster University, Hamilton, Canada. * Salim Yusuf & * Sonia S Anand * Department of Medicine, McMaster University, Hamilton, Canada. * Sonia S Anand Consortia * The Coronary Artery Disease (C4D) Genetics Consortium * Steering and Writing committee * John F Peden, * Jemma C Hopewell, * Danish Saleheen, * John C Chambers, * Jorg Hager, * Nicole Soranzo, * Rory Collins, * John Danesh, * Paul Elliott, * Martin Farrall, * Kathy Stirrups, * Weihua Zhang, * Anders Hamsten, * Sarah Parish, * Mark Lathrop, * Hugh Watkins (Chair), * Robert Clarke, * Panos Deloukas & * Jaspal S Kooner * Statistical genetics and bioinformatics * Anuj Goel, * Halit Ongen, * Rona J Strawbridge, * Simon Heath, * Anders Mälarstig, * Anna Helgadottir, * John Öhrvik, * Muhammed Murtaza, * Simon Potter & * Sarah E Hunt * Genotyping * Marc Delepine, * Shapour Jalilzadeh, * Tomas Axelsson, * Ann-Christine Syvanen, * Rhian Gwilliam, * Suzannah Bumpstead, * Emma Gray & * Sarah Edkins * Expression QTL analyses * Lasse Folkersen, * Theodosios Kyriakou, * Anders Franco-Cereceda, * Anders Gabrielsen, * Udo Seedorf, * Per Eriksson & * the MuTHER consortium * Discovery cohorts * Alison Offer, * Louise Bowman, * Peter Sleight, * Jane Armitage, * Richard Peto, * Goncalo Abecasis, * Nabeel Ahmed, * Mark Caulfield, * Peter Donnelly, * Philippe Froguel, * Angad S Kooner, * Mark I McCarthy, * Nilesh J Samani, * James Scott, * Joban Sehmi, * Angela Silveira, * Mai-Lis Hellénius, * Ferdinand M van 't Hooft, * Gunnar Olsson, * Stephan Rust, * Gerd Assmann, * Simona Barlera, * Gianni Tognoni, * Maria Grazia Franzosi, * Pamela Linksted, * Fiona R Green, * Asif Rasheed, * Moazzam Zaidi, * Nabi Shah, * Maria Samuel, * Nadeem H Mallick, * Muhammad Azhar, * Khan S Zaman, * Abdus Samad, * Mohammad Ishaq, * Ali R Gardezi, * Fazal-ur-Rehman Memon & * Philippe M Frossard * Replication cohorts * Tim Spector, * Leena Peltonen, * Markku S Nieminen, * Juha Sinisalo, * Veikko Salomaa, * Samuli Ripatti, * Derrick Bennett, * Karin Leander, * Bruna Gigante, * Ulf de Faire, * Silvia Pietri, * Francesca Gori, * Roberto Marchioli, * Suthesh Sivapalaratnam, * John J P Kastelein, * Mieke D Trip, * Eirini V Theodoraki, * George V Dedoussis, * Jamie C Engert, * Salim Yusuf & * Sonia S Anand Contributions J.F.P., J.C.H., D.S., J.C.C., J.H., N. Soranzo, R. Collins, J.D., P. Elliott, M.F., K.S., W.Z., A. Hamsten, S. Parish, M.L., H.W. (Chair), R. Clarke, P. Deloukas, J.S.K. H.W., D.S., R. Collins, J.S.K. J.C.H., W.Z., N. Soranzo, J.F.P., D.S., J.C.C., S. Parish, M.F. (Chair). HPS: J.C.H., S. Parish; LOLIPOP: W.Z.; PROCARDIS: A. Goel, H.O., R.J.S., S.H., A.M., A. Helgadottir, J.O., M.F., J.F.P.; PROMIS: D.S., K.S., M.M., S. Potter, S.E.H., P. Deloukas. CNG: J.H., M.D., M.L.; Karolinska: R.J.S.; Oxford: S.J., H.O.; Uppsala: T.A., A.C.S.; WTSI: R.G., S. Bumpsted, E.G., S.E., P.D. L.F., T.K., A.F.C., A. Gabrielsen, U.S., the MuTHER consortium, P. Eriksson. HPS: J.C.H., S. Parish, A.O., R. Clarke, L.B., P.S., J.A., R.P., R. Collins; LOLIPOP: J.C.C., G. Abecasis, N.A., M.C., P. Donnelly, P. Elliott, P.F., A.S.K., M.I.C., N.J.S., J. Scott, J. Sehmi, W.Z., J.S.K.; PROCARDIS: Sweden: A. Silveira, M.L.H., F.M.v.H., G.O., A. Hamsten; Germany: S. Rust, G. Assmann, U.S.; Italy: S. Barlera, G.T., M.G.F.; UK: R. Clarke, P.L., J.C.H., R. Collins, J.F.P., F.R.G., M.F., H.W.; PROMIS: D.S., A.R., M.Z., N. Shah, M.S., N.H.M., M.A., K.S.Z., A. Samad, M. Ishaq, A.R.G., F.M., N.J.S., P.M.F., P.D., J.D. UK Twins: N. Soranzo, T.S.; COROGENE-FINRISK: L.P., M.S.N., J. Sinisalo, V.S., S. Ripatti; ISIS: J.C.H., D.B., S. Parish; SHEEP/SCARF: K.L., B.G., U.d.F.; GISSI-P: S. Pietri, F.G., R.M.; AMC-PAS: S.S., J.J.P.K., M.D.T.; THISEAS: E.V.T., G.V.D.; INTERHEART: J.C.E., S.Y., S.S.A. For further details on author contributions, see the Supplementary Note. John F Peden1,2,54, Jemma C Hopewell3,54, Danish Saleheen4,5,54, John C Chambers6,7,54, Jorg Hager8,54, Nicole Soranzo9,54, Rory Collins3,54, John Danesh5,54, Paul Elliott6,10,54, Martin Farrall1,2,54, Kathy Stirrups9,54, Weihua Zhang6,7,54, Anders Hamsten11,12,54, Sarah Parish3,54, Mark Lathrop8,54, Hugh Watkins (Chair) 1,2,54, Robert Clarke3,54, Panos Deloukas9,54 & Jaspal S Kooner7,13,54, Anuj Goel1,2, Halit Ongen1,2, Rona J Strawbridge11,12, Simon Heath8, Anders Mälarstig11,12, Anna Helgadottir1,2, John Öhrvik11,12, Muhammed Murtaza9, Simon Potter14 & Sarah E Hunt14 Marc Delepine8, Shapour Jalilzadeh1,2, Tomas Axelsson15, Ann-Christine Syvanen15, Rhian Gwilliam14, Suzannah Bumpstead14, Emma Gray14 & Sarah Edkins14 Lasse Folkersen11,12, Theodosios Kyriakou1,2, Anders Franco-Cereceda16, Anders Gabrielsen17, Udo Seedorf18, the MuTHER consortium & Per Eriksson11,12 Alison Offer3, Louise Bowman3, Peter Sleight2, Jane Armitage3, Richard Peto3, Goncalo Abecasis19, Nabeel Ahmed20, Mark Caulfield21, Peter Donnelly22,23, Philippe Froguel24, Angad S Kooner20, Mark I McCarthy22,25,26, Nilesh J Samani27,28, James Scott13, Joban Sehmi13, Angela Silveira11,12, Mai-Lis Hellénius29, Ferdinand M van 't Hooft11,12, Gunnar Olsson30,31, Stephan Rust18, Gerd Assmann18, Simona Barlera32, Gianni Tognoni32,33, Maria Grazia Franzosi32, Pamela Linksted3, Fiona R Green34, Asif Rasheed4, Moazzam Zaidi4, Nabi Shah4, Maria Samuel4, Nadeem H Mallick35, Muhammad Azhar35, Khan S Zaman36, Abdus Samad37, Mohammad Ishaq37, Ali R Gardezi38, Fazal-ur-Rehman Memon39 & Philippe M Frossard4 Tim Spector40, Leena Peltonen9,41,45, Markku S Nieminen42, Juha Sinisalo43, Veikko Salomaa44, Samuli Ripatti44,45, Derrick Bennett3, Karin Leander46, Bruna Gigante46, Ulf de Faire46, Silvia Pietri32, Francesca Gori32, Roberto Marchioli47, Suthesh Sivapalaratnam48, John J P Kastelein48, Mieke D Trip48, Eirini V Theodoraki49, George V Dedoussis49, Jamie C Engert50,51, Salim Yusuf52 & Sonia S Anand52,53 Competing financial interests The authors declare no competing financial interests. Corresponding authors Correspondence to: * Hugh Watkins or * Danish Saleheen or * Rory Collins or * Jaspal S Kooner Author Details Supplementary information * Author information * Supplementary information PDF files * Supplementary Text and Figures (2M) Supplementary Figures 1–3, Supplementary Tables 1–4 and Supplementary Note. Additional data
• Genome-wide association identifies a susceptibility locus for coronary artery disease in the Chinese Han population
  - Nat Genet 43(4):345-349 (2011)
  Nature Genetics | Letter Genome-wide association identifies a susceptibility locus for coronary artery disease in the Chinese Han population * Fan Wang1, 12 * Cheng-Qi Xu1, 12 * Qing He2, 12 * Jian-Ping Cai2, 12 * Xiu-Chun Li1, 12 * Dan Wang1, 12 * Xin Xiong1, 12 * Yu-Hua Liao3, 12 * Qiu-Tang Zeng3, 12 * Yan-Zong Yang4, 12 * Xiang Cheng3, 12 * Cong Li1 * Rong Yang1 * Chu-Chu Wang1 * Gang Wu5 * Qiu-Lun Lu1 * Ying Bai1 * Yu-Feng Huang1 * Dan Yin1 * Qing Yang1 * Xiao-Jing Wang1 * Da-Peng Dai2 * Rong-Feng Zhang4 * Jing Wan6 * Jiang-Hua Ren6 * Si-Si Li1 * Yuan-Yuan Zhao1 * Fen-Fen Fu1 * Yuan Huang1 * Qing-Xian Li7 * Sheng-Wei Shi7 * Nan Lin7 * Zhen-Wei Pan8 * Yue Li9 * Bo Yu10 * Yan-Xia Wu11 * Yu-He Ke11 * Jian Lei11 * Nan Wang1 * Chun-Yan Luo1 * Li-Ying Ji1 * Lian-Jun Gao4 * Lei Li1 * Hui Liu1 * Er-Wen Huang1 * Jin Cui1 * Na Jia2 * Xiang Ren1 * Hui Li1 * Tie Ke1 * Xian-Qin Zhang1 * Jing-Yu Liu1 * Mu-Gen Liu1 * Hao Xia5 * Bo Yang5 * Li-Song Shi1 * Yun-Long Xia4 * Xin Tu1 * Qing K Wang1 * Affiliations * Contributions * Corresponding authorsJournal name:Nature GeneticsVolume: 43,Pages:345–349Year published:(2011)DOI:doi:10.1038/ng.783Received07 October 2010Accepted10 February 2011Published online06 March 2011 Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Coronary artery disease (CAD) causes more than 700,000 deaths each year in China. Previous genome-wide association studies (GWAS) in populations of European ancestry identified several genetic loci for CAD, but no such study has yet been reported in the Chinese population. Here we report a three-stage GWAS in the Chinese Han population. We identified a new association between rs6903956 in a putative gene denoted as C6orf105 on chromosome 6p24.1 and CAD (P = 5.00 × 10−3, stage 2 validation; P = 3.00 × 10−3, P = 1.19 × 10−8 and P = 4.00 × 10−3 in three independent stage 3 replication populations; P = 4.87 × 10−12, odds ratio = 1.51 in the combined population). The minor risk allele A of rs6903956 is associated with decreased C6orf105 mRNA expression. We report the first GWAS for CAD in the Chinese Han population and identify a SNP, rs6903956, in C6orf105 associated with susceptibility to CAD in this population. View full text Author information * Author information * Supplementary information Primary authors * These authors contributed equally to this work. * Fan Wang, * Cheng-Qi Xu, * Qing He, * Jian-Ping Cai, * Xiu-Chun Li, * Dan Wang, * Xin Xiong, * Yu-Hua Liao, * Qiu-Tang Zeng, * Yan-Zong Yang & * Xiang Cheng Affiliations * Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Institute, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China. * Fan Wang, * Cheng-Qi Xu, * Xiu-Chun Li, * Dan Wang, * Xin Xiong, * Cong Li, * Rong Yang, * Chu-Chu Wang, * Qiu-Lun Lu, * Ying Bai, * Yu-Feng Huang, * Dan Yin, * Qing Yang, * Xiao-Jing Wang, * Si-Si Li, * Yuan-Yuan Zhao, * Fen-Fen Fu, * Yuan Huang, * Nan Wang, * Chun-Yan Luo, * Li-Ying Ji, * Lei Li, * Hui Liu, * Er-Wen Huang, * Jin Cui, * Xiang Ren, * Hui Li, * Tie Ke, * Xian-Qin Zhang, * Jing-Yu Liu, * Mu-Gen Liu, * Li-Song Shi, * Xin Tu & * Qing K Wang * Beijing Hospital, Ministry of Health, Beijing, China. * Qing He, * Jian-Ping Cai, * Da-Peng Dai & * Na Jia * Institute of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. * Yu-Hua Liao, * Qiu-Tang Zeng & * Xiang Cheng * First Affiliated Hospital of Dalian Medical University, Dalian, China. * Yan-Zong Yang, * Rong-Feng Zhang, * Lian-Jun Gao & * Yun-Long Xia * Renmin Hospital of Wuhan University, Wuhan, China. * Gang Wu, * Hao Xia & * Bo Yang * Zhongnan Hospital of Wuhan University, Wuhan, China. * Jing Wan & * Jiang-Hua Ren * Affiliated Hospital of Jining Medical Collage, Shandong, China. * Qing-Xian Li, * Sheng-Wei Shi & * Nan Lin * Department of Pharmacology, Harbin Medical University, Harbin, China. * Zhen-Wei Pan * The First Affiliated Hospital, Harbin Medical University, Harbin, China. * Yue Li * The Second Affiliated Hospital, Harbin Medical University, Harbin, China. * Bo Yu * The First Hospital of Wuhan City, Wuhan, China. * Yan-Xia Wu, * Yu-He Ke & * Jian Lei Contributions Q.K.W., J.-P.C., X.T., Q.H. and M.-G.L. C.-Q.X., Q.H., J.-P.C., X.-C.L., D.W., X.X., Y.-H.L., Q.-T.Z., X.C., Y.-Z.Y., C.L., R.Y., C.-C.W., G.W., Q.-L.L., Y.B., Y.-F.H., D.Y., Q.Y., X.-J.W., D.-P.D., R.-F.Z., J.W., J.-H.R., S.-S.L., Y.-Y.Z., F.-F.F., Y.H., Q.-X.L., S.-W.S., N.L., Z.-W.P., Y.L., B.Y., Y.-X.W., Y.-H.K., J.L., N.W., C.-Y.L., L.-Y.J., L.-J.G., L.L., H. Liu, E.-W.H., J.C., N.J., X.R., H. Li, T.K., X.-Q.Z., J.-Y.L., H.X., B.Y., L.-S.S. and Y.-L.X. C.-Q.X., F.W., D.-P.D., J.-P.C., L.-S.S., X.-C.L., D.W., X.X., Q.H., X.T. and Q.K.W. C.-Q.X., F.W. and X.T. Q.K.W., F.W. and C.-Q.X. F.W. and C.-Q.X. Q.K.W., Q.H., J.-P.C., X.T., Y.-H.L. and Y.-Z.Y. Competing financial interests The authors declare no competing financial interests. Corresponding authors Correspondence to: * Qing K Wang or * Xin Tu Author Details * Fan Wang Search for this author in: * NPG journals * PubMed * Google Scholar * Cheng-Qi Xu Search for this author in: * NPG journals * PubMed * Google Scholar * Qing He Search for this author in: * NPG journals * PubMed * Google Scholar * Jian-Ping Cai Search for this author in: * NPG journals * PubMed * Google Scholar * Xiu-Chun Li Search for this author in: * NPG journals * PubMed * Google Scholar * Dan Wang Search for this author in: * NPG journals * PubMed * Google Scholar * Xin Xiong Search for this author in: * NPG journals * PubMed * Google Scholar * Yu-Hua Liao Search for this author in: * NPG journals * PubMed * Google Scholar * Qiu-Tang Zeng Search for this author in: * NPG journals * PubMed * Google Scholar * Yan-Zong Yang Search for this author in: * NPG journals * PubMed * Google Scholar * Xiang Cheng Search for this author in: * NPG journals * PubMed * Google Scholar * Cong Li Search for 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* NPG journals * PubMed * Google Scholar * Tie Ke Search for this author in: * NPG journals * PubMed * Google Scholar * Xian-Qin Zhang Search for this author in: * NPG journals * PubMed * Google Scholar * Jing-Yu Liu Search for this author in: * NPG journals * PubMed * Google Scholar * Mu-Gen Liu Search for this author in: * NPG journals * PubMed * Google Scholar * Hao Xia Search for this author in: * NPG journals * PubMed * Google Scholar * Bo Yang Search for this author in: * NPG journals * PubMed * Google Scholar * Li-Song Shi Search for this author in: * NPG journals * PubMed * Google Scholar * Yun-Long Xia Search for this author in: * NPG journals * PubMed * Google Scholar * Xin Tu Contact Xin Tu Search for this author in: * NPG journals * PubMed * Google Scholar * Qing K Wang Contact Qing K Wang Search for this author in: * NPG journals * PubMed * Google Scholar Supplementary information * Author information * Supplementary information PDF files * Supplementary Text and Figures 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Additional data
• Mutations in ORC1, encoding the largest subunit of the origin recognition complex, cause microcephalic primordial dwarfism resembling Meier-Gorlin syndrome
  - Nat Genet 43(4):350-355 (2011)
  Nature Genetics | Letter Mutations in ORC1, encoding the largest subunit of the origin recognition complex, cause microcephalic primordial dwarfism resembling Meier-Gorlin syndrome * Louise S Bicknell1, 8 * Sarah Walker2, 8 * Anna Klingseisen1 * Tom Stiff2 * Andrea Leitch1 * Claudia Kerzendorfer3 * Carol-Anne Martin1 * Patricia Yeyati1 * Nouriya Al Sanna4 * Michael Bober5 * Diana Johnson6 * Carol Wise7 * Andrew P Jackson1 * Mark O'Driscoll3 * Penny A Jeggo2 * Affiliations * Contributions * Corresponding authorsJournal name:Nature GeneticsVolume: 43,Pages:350–355Year published:(2011)DOI:doi:10.1038/ng.776Received02 August 2010Accepted25 January 2011Published online27 February 2011 Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Studies into disorders of extreme growth failure (for example, Seckel syndrome and Majewski osteodysplastic primordial dwarfism type II) have implicated fundamental cellular processes of DNA damage response signaling and centrosome function in the regulation of human growth. Here we report that mutations in ORC1, encoding a subunit of the origin recognition complex, cause microcephalic primordial dwarfism resembling Meier-Gorlin syndrome. We establish that these mutations disrupt known ORC1 functions including pre-replicative complex formation and origin activation. ORC1 deficiency perturbs S-phase entry and S-phase progression. Additionally, we show that Orc1 depletion in zebrafish is sufficient to markedly reduce body size during rapid embryonic growth. Our data suggest a model in which ORC1 mutations impair replication licensing, slowing cell cycle progression and consequently impeding growth during development, particularly at times of rapid proliferation. These findings! establish a novel mechanism for the pathogenesis of microcephalic dwarfism and show a surprising but important developmental impact of impaired origin licensing. View full text Figures at a glance * Figure 1: ORC1 expression and pre-RC complex assembly in ORC1-deficient cell lines from affected individuals. (,) ORC1 protein levels are markedly reduced in the ORC1-P1 cell line and less severely reduced in heterozygous parental cell lines. LBL cell extracts from control (WT), subject ORC1-P1 (p.Glu127Gly) (P1), and the subject's mother (M) and father (F) were separated into a soluble (sol.) or insoluble fraction that contained chromatin-bound proteins (insol.) and examined by protein blotting using the indicated antibodies. ORC1-N and ORC1-C detect epitopes at the ORC1 N or C terminus, respectively. KAP1 is a chromatin-bound protein used as a loading control. ORC2 served as a loading control for the soluble fraction. ORC1-N antibody was used subsequently. () We subjected extracts from control (WT) and ORC1-P1 cells (P1) to a two-step micrococcal nuclease (MNase) extraction procedure to derive chromatin enriched fractions, C1 and C2, of increasing MNase resistance and we examined these fractions by immunoblotting using the indicated antibodies. HP1 and histone H3 are chromatin-bou! nd proteins. Histone H3 is strongly enriched in the C2 fraction, showing the enrichment of chromatin binding proteins. () We examined cell extracts from ORC1-P4 (p.Arg105Gln) fibroblasts as in . * Figure 2: ORC1-deficient cells fail to efficiently activate replication origins. (–) ORC1-P4 cells showed impaired licensing of an Epstein-Barr virus (EBV) oriP origin. EBV uses virally encoded EBNA-1 and oriP and the host cell origin licensing complex. Consequently, EBNA-1-dependent EBV replication utilizes cellular ORC15, 19. ORC1 activity was monitored as the replication capacity of plasmid-294 (p294(OriP)), which encodes OriP and EBNA-1, in control (WT; 1BR3 hTERT) and ORC1-P4 hTERT fibroblasts. Following transfection with plasmid-294 and incubation to allow one population doubling (1 day for WT and 4 days for ORC1-P4), we extracted plasmid DNA examined it using DNA blotting following BamHI or BamHI+DpnI digestion using plasmid-294 as the probe. DpnI degrades unreplicated plasmids that retain bacterial Dam-dependent methylation. () Southern blot of plasmid-294 (p294(OriP)) and plasmid extracted from WT and ORC1-P4 cells. Non-transfected cells gave no signal (data not shown). () Quantification expressed as percent replicated DNA (BamHI+DpnI/BamHI) (! values are mean ± s.d. of three experiments). () Percent transfection frequency of WT hTERT and ORC1-P4 hTERT cells following transfection with GFP-expressing plasmid (values are mean ± s.d. of three experiments), showing a similar transfection frequency. The greater impact on EBV replication compared to cellular replication is likely because the plasmid contains a single origin, whereas human DNA has redundant origins. (,) Control (WT) and ORC1-P1 LBLs were treated with cytochalasin B (0.75 μg/ml) for 24 h to accumulate binucleate cells that failed to undergo cytokinesis. We added BrdU (20 μM) for 1 h, and BrdU incorporation into >4n cells (P3 compartment) was taken to represent re-replication in binucleate cells; () quantification of () mean ± s.d. of three experiments. * Figure 3: ORC1-deficient cells show slow S-phase progression. () Control (WT) or ORC1-P1 LBLs were BrdU labeled for 30 min and incubated for varying times before fluorescence-activated cell sorting. Early S-phase cells (above the 2N compartment) progress to late S phase (above the 4N compartment) over time. The rate of loss of BrdU+ early S-phase cells represents S-phase progression. () Quantification of early S-phase cells (highlighted as R3) (values are mean ± s.d. of three experiments). () WT or ORC1-P1 LBLs were labeled with [3H]TdR for 15 min (left) or 1 h (right) and subjected to sucrose-gradient sedimentation following fragmentation and concurrent lysis. Newly fired origins sediment within fractions 25–30, precluding an estimation of new origin firing. DNA from WT LBLs increases in size more rapidly compared to ORC1-P1 DNA. Plots show a representative profile from three experiments. () A diagram showing how smaller replication intermediates arise when origin firing is limited. Slow fork progression will also generate smaller ! replication intermediates. () Control or ORC1-P4 hTERT fibroblasts were BrdU-labeled for 15 min and analyzed by immunofluorescence. We enumerated pan-nuclear γH2AX+ (S-phase cells at time of analysis) and/or BrdU+ cells (S-phase at time of labeling). γH2AX+ cells lose γH2AX staining in the G2 phase; BrdU+ cells remain BrdU+ in the G2 phase. Results show BrdU+γH2AX+/total BrdU+ cells, indicating the percentage of BrdU+ cells still in S phase when sampled (values are mean ± s.d. of three experiments). The slope of the graph represents the rate of S-phase progression. Note that pan-nuclear γH2AX+ cells represent S-phase cells; we did not score defined γH2AX foci, a marker of DSBs. * Figure 4: ORC1-deficient cells show delayed G1 to S progression. All values represent mean ± s.d. of three experiments. () ORC1-P4 cells showed delayed G1/S phase entry following serum starvation. We serum starved control (WT) or ORC1-P4 primary fibroblasts for 3 days. We added serum and BrdU (20 μM) at time 0 to monitor S-phase entry by immunofluorescence. We estimated the percent of BrdU+ cells, representing cells that have entered S phase, at the indicated time points by immunofluorescence. The solid lines represent the time of entry from G1 into S phase. We also monitored entry into G2 by measuring CENPF+ cells (dotted lines). ORC1-P4 cells showed delayed entry into S phase following re-entry into G1 phase. () We treated 1BR3-hTERT cells (a control WT hTERT immortalized fibroblast) with control or ORC1 siRNA and analyzed them as in . () We transfected ORC1-P4 hTERT fibroblasts with empty vector or ORC1 complementary DNA plasmids and examined them as in (note that the actual timing of S-phase entry was faster in both hTERT cell lines! , but the delayed entry in ORC1-deficient cells remained). We also examined WT, ORC1-P1 and ATM−/− LBLs for chromosome aberrations in untreated cells and 24 h after exposure to 3 Gray (Gy) X-rays. ORC1-P1 LBLs showed a normal frequency of endogenous and radiation-induced chromosome aberrations; ATM−/− LBLs showed a tenfold increase in radiation-induced chromosome aberrations compared to control LBLs. * Figure 5: Depletion of Orc1 causes dwarfism in zebrafish. () Schematic of orc1 zebrafish protein and gene intron-exon structure. Red bars are the position of morpholino oligonucleotide (MO) target sites and the arrows are PCR primers. RT-PCR of orc1 MO from 3 days post fertilization (dpf) zebrafish embryos sorted according to phenotypic categories; WT, wild-type uninjected embryos. () Injection of splice-site targeted MOs to orc1 caused marked reduction in body size compared to standard control embryos or uninjected wild-type zebrafish. 'Dwarf' orc1 zebrafish were globally reduced in size and essentially otherwise normal aside from some subtle craniofacial features (hypoplasia of jaw cartilage, reduction in number or fusion of otoliths and smaller eye size). Severe embryos additionally had altered body curvature and decreased viability. () Quantification of phenotypes of MO-injected zebrafish. We defined categories with respect to zebrafish size: short, less than −1 s.d.; dwarf less than −2 s.d.; severe, less than −3 s.d. wit! h additional body curvature. We defined normal as −1 to 1 s.d. and long as >1 s.d. () Body surface area of zebrafish injected with orc1, mcm5 or control MOs expressed as s.d. relative to uninjected wild-type (AB) zebrafish embryos from the same matings. P < 0.001 for orc1-sp, orc1-atg or mcm5 MO versus control MO. Error bars, s.e.m. (n = 23 for control; n = 41 for orc1-sp; n = 66 for orc1-atg; and n = 65 for mcm5 MOs). orc1-sp, pooled splice-site targeted orc1 Mos; orc1-atg; translational blocking orc MO. () mcm5 MO zebrafish (5 dpf) also have reduced body size and are morphologically similar to orc1 MO zebrafish. Body surface area is significantly reduced (P < 0.001 mcm5 versus control MO). Quantification of mcm5 MO phenotype, see ,. Accession codes * Accession codes * Author information * Supplementary information Referenced accessions Entrez Nucleotide * NM_004153.3 * NM_199933.1 Author information * Accession codes * Author information * Supplementary information Primary authors * These authors contributed equally to this work. * Louise S Bicknell & * Sarah Walker Affiliations * Medical Research Council (MRC) Human Genetics Unit (HGU), Institute for Genetics and Molecular Medicine, Western General Hospital, Edinburgh, UK. * Louise S Bicknell, * Anna Klingseisen, * Andrea Leitch, * Carol-Anne Martin, * Patricia Yeyati & * Andrew P Jackson * DNA Double Strand Break Repair Laboratory, Genome Damage and Stability Centre, University of Sussex, Brighton, UK. * Sarah Walker, * Tom Stiff & * Penny A Jeggo * Human DNA Damage Response Disorders Group, Genome Damage and Stability Centre, University of Sussex, Brighton, UK. * Claudia Kerzendorfer & * Mark O'Driscoll * Pediatric Services Division, Dhahran Health Center, Dhahran, Saudi Arabia. * Nouriya Al Sanna * Division of Genetics, Department of Pediatrics, A.I. DuPont Hospital for Children, Wilmington, Delaware, USA. * Michael Bober * Sheffield Children's Hospital, Sheffield, UK. * Diana Johnson * Sarah M. and Charles E. Seay Center for Musculoskeletal Research, Texas Scottish Rite Hospital for Children, Dallas, Texas, USA. * Carol Wise Contributions L.S.B. and A.P.J. designed and performed the genetics experiments. A.K., A.L., C.-A.M., P.Y. and A.P.J. performed the zebrafish studies. S.W., T.S., C.K., M.O'D. and P.A.J. designed and performed the functional cell biology experiments. N.A.S., D.J., M.B. and C.W. provided clinical samples and data. P.A.J., A.P.J., L.S.B. and M.O'D. wrote the paper. Competing financial interests The authors declare no competing financial interests. Corresponding authors Correspondence to: * Mark O'Driscoll or * Andrew P Jackson Author Details * Louise S Bicknell Search for this author in: * NPG journals * PubMed * Google Scholar * Sarah Walker Search for this author in: * NPG journals * PubMed * Google Scholar * Anna Klingseisen Search for this author in: * NPG journals * PubMed * Google Scholar * Tom Stiff Search for this author in: * NPG journals * PubMed * Google Scholar * Andrea Leitch Search for this author in: * NPG journals * PubMed * Google Scholar * Claudia Kerzendorfer Search for this author in: * NPG journals * PubMed * Google Scholar * Carol-Anne Martin Search for this author in: * NPG journals * PubMed * Google Scholar * Patricia Yeyati Search for this author in: * NPG journals * PubMed * Google Scholar * Nouriya Al Sanna Search for this author in: * NPG journals * PubMed * Google Scholar * Michael Bober Search for this author in: * NPG journals * PubMed * Google Scholar * Diana Johnson Search for this author in: * NPG journals * PubMed * Google Scholar * Carol Wise Search for this author in: * NPG journals * PubMed * Google Scholar * Andrew P Jackson Contact Andrew P Jackson Search for this author in: * NPG journals * PubMed * Google Scholar * Mark O'Driscoll Contact Mark O'Driscoll Search for this author in: * NPG journals * PubMed * Google Scholar * Penny A Jeggo Search for this author in: * NPG journals * PubMed * Google Scholar Supplementary information * Accession codes * Author information * Supplementary information PDF files * Supplementary Text and Figures (2M) Supplementary Figures 1–5 and Supplementary Tables 1 and 2. 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• Mutations in the pre-replication complex cause Meier-Gorlin syndrome
  - Nat Genet 43(4):356-359 (2011)
  Nature Genetics | Letter Mutations in the pre-replication complex cause Meier-Gorlin syndrome * Louise S Bicknell1, 20 * Ernie M H F Bongers2, 20 * Andrea Leitch1 * Stephen Brown1 * Jeroen Schoots2 * Margaret E Harley1 * Salim Aftimos3 * Jumana Y Al-Aama4, 5 * Michael Bober6 * Paul A J Brown7 * Hans van Bokhoven8 * John Dean9 * Alaa Y Edrees5 * Murray Feingold10 * Alan Fryer11 * Lies H Hoefsloot2 * Nikolaus Kau12 * Nine V A M Knoers13 * James MacKenzie7 * John M Opitz14 * Pierre Sarda15 * Alison Ross9 * I Karen Temple16 * Annick Toutain17 * Carol A Wise18 * Michael Wright19 * Andrew P Jackson1 * Affiliations * Contributions * Corresponding authorsJournal name:Nature GeneticsVolume: 43,Pages:356–359Year published:(2011)DOI:doi:10.1038/ng.775Received30 July 2011Accepted26 January 2011Published online27 February 2011 Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Meier-Gorlin syndrome (ear, patella and short-stature syndrome) is an autosomal recessive primordial dwarfism syndrome characterized by absent or hypoplastic patellae and markedly small ears1, 2, 3. Both pre- and post-natal growth are impaired in this disorder, and although microcephaly is often evident, intellect is usually normal in this syndrome. We report here that individuals with this disorder show marked locus heterogeneity, and we identify mutations in five separate genes: ORC1, ORC4, ORC6, CDT1 and CDC6. All of these genes encode components of the pre-replication complex, implicating defects in replication licensing as the cause of a genetic syndrome with distinct developmental abnormalities. View full text Figures at a glance * Figure 1: The pre-replication complex and Meier-Gorlin syndrome. () Genome replication is licensed by the binding of a number of specialized proteins to origins of replication that then form the pre-replication complex9. The first step in complex formation is the loading of the heterohexameric origin recognition complex (comprising ORC1–6 proteins) onto chromatin in an ATP-dependent manner during the M and G1 phases of the cell cycle. Further proteins, including CDC6 and CDT1, are then recruited to the pre-replicative complex that then permit reiterative loading of the multimeric MCM helicase. At the commencement of the S phase, replication is started by the MCM helicase unwinding the DNA and the recruitment of additional replication proteins. The five proteins implicated in Meier-Gorlin syndrome are highlighted in white text (ORC1, ORC4, ORC6, CDT1 and CDC6). () Individual P1 has a severe developmental malformation syndrome with marked microtia and extreme retroflexion and dislocation of the knees (top row, 'R', right; 'L' left). His m! alformations include lobar congenital emphysema (arrow head) and a severe cortical dysplasia of the brain. Parasagittal T2-weighted magnetic resonance imaging at age 1 month showing severe pachygyria, most severe frontally, along with ventricular enlargement. () Two individuals (P11 and P9) with classical Meier-Gorlin syndrome. (,) We obtained informed consent to publish the photographs from the subjects' parents. * Figure 2: Pre-replication complex proteins mutated in Meier-Gorlin syndrome. Schematics for each protein depicting known protein domains with positions of mutations shown by filled circles. Each filled circle represents one affected individual. ClustalW2 alignment of protein residues surrounding substituted amino acids (with the positions of substituted resides indicated by red boxes). WA, Walker A; WB Walker B, S1, Sensor 1; S2, Sensor 2 motifs. BAH, bromo-associated homology domain; AAA, ATPase associated with a wide range of cellular activites; WH, winged helix domain. Accession codes * Accession codes * Author information * Supplementary information Referenced accessions Entrez Nucleotide * NM_004153.2 * NM_181742.3 * NM_014321.3 * NM_030928.3 * NM_001254.3 Author information * Accession codes * Author information * Supplementary information Primary authors * These authors contributed equally to this work. * Louise S Bicknell & * Ernie M H F Bongers Affiliations * Medical Research Council (MRC) Human Genetics Unit (HGU), Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, UK. * Louise S Bicknell, * Andrea Leitch, * Stephen Brown, * Margaret E Harley & * Andrew P Jackson * Department of Human Genetics, Institute for Genetic and Metabolic Disease, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. * Ernie M H F Bongers, * Jeroen Schoots & * Lies H Hoefsloot * Northern Regional Genetics Service, Auckland Hospital, Auckland, New Zealand. * Salim Aftimos * Department of Genetic Medicine, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia. * Jumana Y Al-Aama * Princess Al Jawhara Center of Excellence in the Research of Hereditary Disorders, King Abdulaziz University, Jeddah, Saudi Arabia. * Jumana Y Al-Aama & * Alaa Y Edrees * Division of Genetics, Department of Pediatrics, A.I. DuPont Hospital for Children, Wilmington, Delaware, USA. * Michael Bober * Department of Pathology, Aberdeen Royal Infirmary, Aberdeen, UK. * Paul A J Brown & * James MacKenzie * Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences and Institute for Genetic and Metabolic Disease, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. * Hans van Bokhoven * Department of Clinical Genetics, Ashgrove House, Foresterhill, Aberdeen, UK. * John Dean & * Alison Ross * National Birth Defects Center, Waltham, Massachusetts, USA. * Murray Feingold * Department of Clinical Genetics, Royal Liverpool Children's Hospital, Alder Hey, Liverpool, UK. * Alan Fryer * Aberdeen Maternity Hospital, Foresterhill, Aberdeen, UK. * Nikolaus Kau * Department of Medical Genetics, University Medical Centre Utrecht, Utrecht, The Netherlands. * Nine V A M Knoers * Human Genetics and Obstetrics and Gynecology, University of Utah, Medical Genetics, Salt Lake City, Utah, USA. * John M Opitz * Service de Génétique Médicale, Centre de Référence Anomalies du Développement Centre Hospitalier Regional Universitaire de Montpellier, Hôpital Arnaud de Villeneuve, Montpellier, France. * Pierre Sarda * Division of Human Genetics, University of Southampton, Faculty of Medicine, Southampton General Hospital, Southampton, UK. * I Karen Temple * Service de Génétique, Hôpital Bretonneau, Tours, France. * Annick Toutain * Sarah M. and Charles E. Seay Center for Musculoskeletal Research, Texas Scottish Rite Hospital for Children, Dallas, Texas, USA. * Carol A Wise * Northern Genetics Service, Newcastle Upon Tyne Hospitals National Health Service Trust, Central Parkway, Newcastle Upon Tyne, UK. * Michael Wright Contributions L.S.B. performed microsatellite genotyping. L.S.B., S.B. and J.S. performed mutation screening of cases and controls with the help of A.L., E.M.H.F.B., L.H.H., H.v.B. and N.V.A.M.K. M.E.H. performed chromosome breakage analysis. E.M.H.F.B. and A.P.J. clinically characterized the Meier-Gorlin syndrome cases and performed review of phenotypes and sample collection. S.A., J.Y.A.-A., M.B., P.A.J.B., H.v.B., J.D., A.Y.E., M.F., A.F., N.K., N.V.A.M.K., J.M., J.M.O., P.S., A.R., I.K.T., A.T., C.A.W. and M.W. contributed clinical cases and clinical data for the study. A.P.J. and L.S.B. wrote the paper with E.M.H.F.B. Competing financial interests The authors declare no competing financial interests. Corresponding authors Correspondence to: * Andrew P Jackson or * Ernie M H F Bongers Author Details * Louise S Bicknell Search for this author in: * NPG journals * PubMed * Google Scholar * Ernie M H F Bongers Contact Ernie M H F Bongers Search for this author in: * NPG journals * PubMed * Google Scholar * Andrea Leitch Search for this author in: * NPG journals * PubMed * Google Scholar * Stephen Brown Search for this author in: * NPG journals * PubMed * Google Scholar * Jeroen Schoots Search for this author in: * NPG journals * PubMed * Google Scholar * Margaret E Harley Search for this author in: * NPG journals * PubMed * Google Scholar * Salim Aftimos Search for this author in: * NPG journals * PubMed * Google Scholar * Jumana Y Al-Aama Search for this author in: * NPG journals * PubMed * Google Scholar * Michael Bober Search for this author in: * NPG journals * PubMed * Google Scholar * Paul A J Brown Search for this author in: * NPG journals * PubMed * Google Scholar * Hans van Bokhoven Search for this author in: * NPG journals * PubMed * Google Scholar * John Dean Search for this author in: * NPG journals * PubMed * Google Scholar * Alaa Y Edrees Search for this author in: * NPG journals * PubMed * Google Scholar * Murray Feingold Search for this author in: * NPG journals * PubMed * Google Scholar * Alan Fryer Search for this author in: * NPG journals * PubMed * Google Scholar * Lies H Hoefsloot Search for this author in: * NPG journals * PubMed * Google Scholar * Nikolaus Kau Search for this author in: * NPG journals * PubMed * Google Scholar * Nine V A M Knoers Search for this author in: * NPG journals * PubMed * Google Scholar * James MacKenzie Search for this author in: * NPG journals * PubMed * Google Scholar * John M Opitz Search for this author in: * NPG journals * PubMed * Google Scholar * Pierre Sarda Search for this author in: * NPG journals * PubMed * Google Scholar * Alison Ross Search for this author in: * NPG journals * PubMed * Google Scholar * I Karen Temple Search for this author in: * NPG journals * PubMed * Google Scholar * Annick Toutain Search for this author in: * NPG journals * PubMed * Google Scholar * Carol A Wise Search for this author in: * NPG journals * PubMed * Google Scholar * Michael Wright Search for this author in: * NPG journals * PubMed * Google Scholar * Andrew P Jackson Contact Andrew P Jackson Search for this author in: * NPG journals * PubMed * Google Scholar Supplementary information * Accession codes * Author information * Supplementary information PDF files * Supplementary Text and Figures (2M) Supplementary Note, Supplementary Figure 1 and Supplementary Tables 1 and 2. Additional data
• Mutations in origin recognition complex gene ORC4 cause Meier-Gorlin syndrome
  - Nat Genet 43(4):360-364 (2011)
  Nature Genetics | Letter Mutations in origin recognition complex gene ORC4 cause Meier-Gorlin syndrome * Duane L Guernsey1 * Makoto Matsuoka1 * Haiyan Jiang1 * Susan Evans1 * Christine Macgillivray2 * Mathew Nightingale1 * Scott Perry1 * Meghan Ferguson3 * Marissa LeBlanc4 * Jean Paquette5 * Lysanne Patry5 * Andrea L Rideout3 * Aidan Thomas3 * Andrew Orr2 * Chris R McMaster4 * Jacques L Michaud5 * Cheri Deal5 * Sylvie Langlois6 * Duane W Superneau7 * Sandhya Parkash3, 8 * Mark Ludman3, 8 * David L Skidmore3, 8 * Mark E Samuels1, 5 * Affiliations * Contributions * Corresponding authorJournal name:Nature GeneticsVolume: 43,Pages:360–364Year published:(2011)DOI:doi:10.1038/ng.777Received05 August 2010Accepted14 January 2011Published online27 February 2011 Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Meier-Gorlin syndrome is a rare autosomal recessive genetic condition whose primary clinical hallmarks include small stature, small external ears and small or absent patellae. Using marker-assisted mapping in multiple families from a founder population and traditional coding exon sequencing of positional candidate genes, we identified three different mutations in the gene encoding ORC4, a component of the eukaryotic origin recognition complex, in five individuals with Meier-Gorlin syndrome. In two such individuals that were negative for mutations in ORC4, we found potential mutations in ORC1 and CDT1, two other genes involved in origin recognition. ORC4 is well conserved in eukaryotes, and the yeast equivalent of the human ORC4 missense mutation was shown to be pathogenic in functional assays of cell growth. This is the first report, to our knowledge, of a germline mutation in any gene of the origin recognition complex in a vertebrate organism. View full text Figures at a glance * Figure 1: Families with Meier-Gorlin syndrome and phenotype. () Maritime-Acadian family 137, individual 1652. () Louisiana-Acadian family 152 with affected identical twins, individuals 1768 and 1769. () Quebec family 153, individual 1882. () Quebec family 155, individual 1899. () Maritime-Acadian family 158, individual 1939. () Individual 1882's face (at 8.3 years old). () Individual 1652 (at 4 years old). () Individual 1652 (at 4 years old). () Individual 1882's right knee X-ray (at 7.9 years old). () Individual 1882's left knee X-ray (7.9 years old). () Individual 1939's lateral left knee X- ray (at age 18 years). () Individual 1939's anterior posterior image of the right knee (at age 18 years). In , and , G 17, R LDM and L LDM are radiological markers placed on the films to provide orientation and could not be removed for publication. In pedigrees, filled symbols indicate affected individuals and black dots within symbols indicate obligate carriers (all unaffected). Nucleotide mutation status is shown for each sequenced individual ! for ORC4 at equivalent position 174. A, wild type; G causes the mutation resulting in p.Tyr174Cys; ins refers to the 4-bp insertion c.874_875insAACA in exon 11; del refers to the large multi-exon deletion mapped by real-time PCR. Consent was obtained from subjects or a family member for the publication of photographs. * Figure 2: Yeast analysis of the ORC4 missense mutation. The mutation resulting in the orc4Y232C allele results in a growth defect in yeast. A diploid yeast strain with one of its two ORC4 alleles inactivated (ORC4/orc4ΔkanMX4) was transformed with a low-copy (1–2 copies per cell) plasmid containing the wild-type ORC4 gene, the orc4Y232c allele or empty vector. Strains were sporulated and the four products of the meiotic division were isolated by tetrad dissection. We confirmed that all four haploid progeny contained the transformed plasmids based on leucine prototrophy. Those that also contained an inactivated ORC4 gene were identified by kanamycin resistance. () The wild-type ORC4 gene was required for viability as evidenced by the absence of growth for two of the four progeny in cells that were transformed with empty vector. The colonies arising from the two spores from the meiotic division that contained an inactivated ORC4 gene but transformed with a plasmid expressing the orc4Y232c allele were viable but grew more slowly ! than those that contained the wild-type ORC4 gene. () We determined the growth of haploid yeast with an inactivated ORC4 gene transformed with plasmids expressing wild-type ORC4 or the orc4Y232C allele in liquid culture at 25 °C in synthetic complete medium lacking leucine to ensure plasmid maintenance. () We imaged live cells in haploid yeast with an inactivated ORC4 gene transformed with plasmids expressing the wild-type ORC4 gene or the orc4Y233C allele. We determined the percentage of cells containing no buds, a small bud or a large bud from three random fields of at least 100 cells. () The narrow chitin band revealed by calcofluor white staining of cultures expressing the orc4Y232C allele indicate cultures are accumulating cells with large buds. Two examples are shown. Accession codes * Accession codes * Author information * Supplementary information Referenced accessions Entrez Nucleotide * NM_002552 * NM_004153.3 * NM_030928.3 Author information * Accession codes * Author information * Supplementary information Affiliations * Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada. * Duane L Guernsey, * Makoto Matsuoka, * Haiyan Jiang, * Susan Evans, * Mathew Nightingale, * Scott Perry & * Mark E Samuels * Department of Ophthalmology and Visual Sciences, Dalhousie University, Halifax, Nova Scotia, Canada. * Christine Macgillivray & * Andrew Orr * Maritime Medical Genetics Service, Izaak Walton Killam (IWK) Health Centre, Halifax, Nova Scotia, Canada. * Meghan Ferguson, * Andrea L Rideout, * Aidan Thomas, * Sandhya Parkash, * Mark Ludman & * David L Skidmore * Department of Biochemistry and Molecular Biology, Dalhousie University, Halifax, Nova Scotia, Canada. * Marissa LeBlanc & * Chris R McMaster * Centre de Recherche du Centre Hospitalier Universitaire (CHU) Ste-Justine, Université de Montréal, Montréal, Quebec, Canada. * Jean Paquette, * Lysanne Patry, * Jacques L Michaud, * Cheri Deal & * Mark E Samuels * Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada. * Sylvie Langlois * Our Lady of the Lakes Genetics Services, Baton Rouge, Lousiana, USA. * Duane W Superneau * Division of Medical Genetics, Department of Pediatrics, Dalhousie University, Halifax, Nova Scotia, Canada. * Sandhya Parkash, * Mark Ludman & * David L Skidmore Contributions D.L.G. supervised molecular studies and participated in manuscript preparation. M.M. performed molecular studies. H.J. performed statistical genetic and bioinformatic analyses. S.E. performed molecular studies. C.M. participated in clinical ascertainment and sample collection. M.N. performed molecular studies. S. Perry performed statistical genetic and bioinformatic analyses. M.F. participated in clinical ascertainment and sample collection. M. LeBlanc performed functional studies in yeast. J.P. performed molecular studies. L.P. performed molecular studies. A.L.R. and A.T. participated in clinical ascertainment and sample collection. A.O. participated in clinical ascertainment. C.R.M. supervised functional studies in yeast and participated in manuscript preparation. J.L.M., C.D., S.L., D.W.S. and S. Parkash performed clinical ascertainment and phenotyping studies and participated in manuscript preparation. M. Ludman helped supervise clinical ascertainment. D.L.S. supervised ! and performed clinical ascertainment and phenotyping studies and participated in manuscript preparation. M.E.S. supervised all aspects of the project and participated in manuscript preparation. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Mark E Samuels Author Details * Duane L Guernsey Search for this author in: * NPG journals * PubMed * Google Scholar * Makoto Matsuoka Search for this author in: * NPG journals * PubMed * Google Scholar * Haiyan Jiang Search for this author in: * NPG journals * PubMed * Google Scholar * Susan Evans Search for this author in: * NPG journals * PubMed * Google Scholar * Christine Macgillivray Search for this author in: * NPG journals * PubMed * Google Scholar * Mathew Nightingale Search for this author in: * NPG journals * PubMed * Google Scholar * Scott Perry Search for this author in: * NPG journals * PubMed * Google Scholar * Meghan Ferguson Search for this author in: * NPG journals * PubMed * Google Scholar * Marissa LeBlanc Search for this author in: * NPG journals * PubMed * Google Scholar * Jean Paquette Search for this author in: * NPG journals * PubMed * Google Scholar * Lysanne Patry Search for this author in: * NPG journals * PubMed * Google Scholar * Andrea L Rideout Search for this author in: * NPG journals * PubMed * Google Scholar * Aidan Thomas Search for this author in: * NPG journals * PubMed * Google Scholar * Andrew Orr Search for this author in: * NPG journals * PubMed * Google Scholar * Chris R McMaster Search for this author in: * NPG journals * PubMed * Google Scholar * Jacques L Michaud Search for this author in: * NPG journals * PubMed * Google Scholar * Cheri Deal Search for this author in: * NPG journals * PubMed * Google Scholar * Sylvie Langlois Search for this author in: * NPG journals * PubMed * Google Scholar * Duane W Superneau Search for this author in: * NPG journals * PubMed * Google Scholar * Sandhya Parkash Search for this author in: * NPG journals * PubMed * Google Scholar * Mark Ludman Search for this author in: * NPG journals * PubMed * Google Scholar * David L Skidmore Search for this author in: * NPG journals * PubMed * Google Scholar * Mark E Samuels Contact Mark E Samuels Search for this author in: * NPG journals * PubMed * Google Scholar Supplementary information * Accession codes * Author information * Supplementary information PDF files * Supplementary Text and Figures (6M) Supplementary Note, Supplementary Figures 1–7 and Supplementary Tables 1 and 2. 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• Multiple self-healing squamous epithelioma is caused by a disease-specific spectrum of mutations in TGFBR1
  - Nat Genet 43(4):365-369 (2011)
  Nature Genetics | Letter Multiple self-healing squamous epithelioma is caused by a disease-specific spectrum of mutations in TGFBR1 * David R Goudie1, 16 * Mariella D'Alessandro2, 16 * Barry Merriman3 * Hane Lee3 * Ildikó Szeverényi4 * Stuart Avery4 * Brian D O'Connor3 * Stanley F Nelson3 * Stephanie E Coats1 * Arlene Stewart1 * Lesley Christie5 * Gabriella Pichert6 * Jean Friedel7 * Ian Hayes8 * Nigel Burrows9 * Sean Whittaker10 * Anne-Marie Gerdes11, 12 * Sigurd Broesby-Olsen13 * Malcolm A Ferguson-Smith14 * Chandra Verma15 * Declan P Lunny4 * Bruno Reversade4 * E Birgitte Lane2, 4 * Affiliations * Contributions * Corresponding authorJournal name:Nature GeneticsVolume: 43,Pages:365–369Year published:(2011)DOI:doi:10.1038/ng.780Received08 July 2010Accepted04 February 2011Published online27 February 2011 Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Multiple self-healing squamous epithelioma (MSSE), also known as Ferguson-Smith disease (FSD), is an autosomal-dominant skin cancer condition characterized by multiple squamous-carcinoma–like locally invasive skin tumors that grow rapidly for a few weeks before spontaneously regressing, leaving scars1, 2. High-throughput genomic sequencing of a conservative estimate (24.2 Mb) of the disease locus on chromosome 9 using exon array capture identified independent mutations in TGFBR1 in three unrelated families. Subsequent dideoxy sequencing of TGFBR1 identified 11 distinct monoallelic mutations in 18 affected families, firmly establishing TGFBR1 as the causative gene. The nature of the sequence variants, which include mutations in the extracellular ligand-binding domain and a series of truncating mutations in the kinase domain, indicates a clear genotype-phenotype correlation between loss-of-function TGFBR1 mutations and MSSE. This distinguishes MSSE from the Marfan syndrome�! �related disorders in which missense mutations in TGFBR1 lead to developmental defects with vascular involvement but no reported predisposition to cancer. View full text Figures at a glance * Figure 1: Mutations in TGFBR1 in individuals with MSSE. () TGFBR1, with identified mutation positions shown over the exons as open (missense mutations) or filled (truncations) arrowheads. () Domain structure of the TGFβRI protein showing the MSSE mutations identified in this study (above protein) and other mutations from Marfan syndrome-related disorders (below protein: these published mutations22, 24, 26, 29, 30, 31, 32, 33, 34, 35, 36, 37 are annotated and listed in Supplementary Table 2). Exon derivation of the protein is indicated in by numbers matching the exons in . Functional domains are color-coded: extracellular ligand-binding domain (yellow), transmembrane domain (green), glycine-serine-rich domain (purple), cytoplasmic kinase domain (blue). SP, signal peptide; TM, transmembrane domain. The MSSE mutations are clustered in the extracellular domain (mostly missense mutations) or in the kinase domain (truncations). * Figure 2: Expression of TGFβRI protein in MSSE tumors. () Clinical appearance of an MSSE tumor, shown here in a Danish individual with a mutation in TGFBR1 resulting in p.Pro83Leu (family 12). Image shows a large squamous epithelioma with typical clinical features which grows in 3–4 weeks from a small papule into this dome-shaped keratoacanthoma-like tumor with rolled edges and central hyperkeratotic plug. These tumors then typically regress spontaneously within a few weeks, leaving pitted scars. (–) Immunohistochemical visualization of TGFβRI with goat polyclonal antibody to the extracellular domain, shown in normal epidermis (), in a tumor from an individual with a mutation in TGFBR1 causing p.Gly52Arg (), in a tumor with a TGFBR1 c.806-2A>C mutation (), in an epidermal squamous cell carcinoma sample () and in a negative control with no primary antibody (). Staining is localized predominantly to the plasma membrane of epidermal keratinocytes in all cases. Scale bars, 20 μm. * Figure 3: Loss of heterozygosity in a TGFBR1 c.806-2A>C tumor with retention of the mutant allele. We microdissected formalin-fixed tumor sections from the tumor shown in Figure 2d, analyzed the DNA by pyrosequencing and compared the sequence with that obtained from the subject's leukocytes. () The heterozygous state of this c.806-2A>C mutation is confirmed by the presence of 'A' and 'C' peaks in leucocyte DNA (gray bar). () The 'A' peak corresponding to the wild-type allele has been lost in the tumor. () Leucocyte DNA from an unaffected control shows homozygosity for the wild-type 'A' allele. * Figure 4: In silico modeling of the extracellular domain of the TGF-β signaling complex to illustrate the impact of the MSSE mutations in exon 2. The signaling complex assembles as two dimers of TGFβRI and TGFβRII interacting with a dimer of TGF-β, viewed as from outside the cell (the plasma membrane would lie behind, in the plane of the page). () Space-filling surface model. () Ribbon model. The residues at which mutations are found in individuals with MSSE are indicated in red (,) and labeled individually in ; these residues lie along the interface at which TGFβRI interacts with the previously assembled TGFβRII and TGF-β or at the interaction between TGFβRI and TGF-β directly. Yellow, TGFβRI receptor; brown, TGFβRII receptor; aquamarine, TGF-β ligand; asterisks, N-terminal ends of the proteins. * Figure 5: Effect of alterations to the extracellular domain of TGFβRI on TGF-β signaling through SMAD2/3. () HEK293T cells, co-transfected with SMAD3 activation reporter construct and TGFBR1 missense variants in the extracellular domain, or GFP (control), or the most common mutation in TGFBR1 seen in Loeys-Dietz syndrome cases for comparison (LD), were cultured with or without recombinant TGF-β1 (100 pM) for 24 h and harvested for luciferase assay (Online Methods). Except for the cells transfected with constitutively active TGFBR1 (CA), TGF-β was required to stimulate strong luciferase activity, and the response was repressed by the TGFβRI receptor inhibitor compound SB 431542. Response to TGF-β1 was unaffected by transfection with wild-type TGFBR1 when compared to control GFP-only transfectants but was suppressed by most of the mutant TGFBR1 constructs irrespective of the mutation site. All the MSSE mutants showed partial reduction of the wild-type signal transduction level in this assay; in the absence of TGF-β1 stimulation, the LD mutant showed some constitutive activati! on. The error bars show s.e.m. from three experiments run in triplicate. () Immunoblotting analyses of phosphorylated SMAD2 and TGFβRI expression in cell lines shown in as red bars. In the absence of TGF-β1 stimulation, phosphorylated SMAD2 expression was lower in the MSSE mutants than in the wild-type construct, whereas in the classic Loeys-Dietz syndrome mutant (p.Arg487Gln) the signal was still active. () SMAD2-mediated TGF-β signaling in subject-derived lymphoblastoid cells was unaffected compared to that of wild-type cells. Expression of mutant TGFβRI was determined by the reactivity of hemagglutinin antibody with the HA tag cloned onto each construct; actin served as a loading control. WT, wild-type; CA, constitutively active TGFβRI; SB, SB431542 (TGFβRI receptor inhibitor); LD, Loeys-Dietz syndrome mutant construct; HA, hemagglutinin. Accession codes * Accession codes * Author information * Supplementary information Referenced accessions Entrez Nucleotide * NT_008470.19 * NM_004612.2 * NT_022517.18 * NM_001024847.2 GenBank * NP_004603.1 * CAJ18600.1 * NP_036907.2 * NP_989577.1 * NP_001015961.1 Author information * Accession codes * Author information * Supplementary information Primary authors * These authors contributed equally to this work. * David R Goudie & * Mariella D'Alessandro Affiliations * Human Genetics Unit, University of Dundee College of Medicine, Dentistry and Nursing, Dundee, UK. * David R Goudie, * Stephanie E Coats & * Arlene Stewart * Cancer Research UK Cell Structure Research Group, Division of Molecular Medicine, University of Dundee College of Life Sciences, University of Dundee, Dundee, UK. * Mariella D'Alessandro & * E Birgitte Lane * Department of Human Genetics, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, California, USA. * Barry Merriman, * Hane Lee, * Brian D O'Connor & * Stanley F Nelson * Institute of Medical Biology, A*STAR, Singapore. * Ildikó Szeverényi, * Stuart Avery, * Declan P Lunny, * Bruno Reversade & * E Birgitte Lane * Division of Medical Sciences, College of Medicine, Dentistry and Nursing, University of Dundee, Dundee, UK. * Lesley Christie * Clinical Genetics, Guy's and St. Thomas's National Health Service (NHS) Trust, London, UK. * Gabriella Pichert * Unité de Dermatologie, Centre Hospitalier William-Morey, Chalon-sur-Saône, France. * Jean Friedel * Northern Regional Genetics Service, Auckland City Hospital, Auckland, New Zealand. * Ian Hayes * Department of Dermatology, Addenbrookes Hospital, Cambridge, UK. * Nigel Burrows * St. John's Institute of Dermatology, Guy's and St. Thomas's NHS Foundation Trust, King's College, London, UK. * Sean Whittaker * Department of Clinical Genetics, Rigshospitalet, Copenhagen, Denmark. * Anne-Marie Gerdes * Department of Clinical Genetics, Odense University Hospital, Odense, Denmark. * Anne-Marie Gerdes * Department of Dermatology, Odense University Hospital, Odense, Denmark. * Sigurd Broesby-Olsen * Resource Centre for Comparative Genomics, Department of Veterinary Medicine, Cambridge University, Cambridge, UK. * Malcolm A Ferguson-Smith * Bioinformatics Institute, A*STAR, Singapore. * Chandra Verma Contributions D.R.G. and E.B.L. initiated the project. D.R.G., M.A.F.-S., G.P., A.-M.G., S.B.-O., J.F., I.H., N.B. and S.W. identified, ascertained and took samples from subjects' families. E.B.L., M.D., D.R.G. and B.R. designed strategies, supervised and implemented the project. B.M., H.L., B.D.O. and S.F.N. designed and performed re-analysis of linkage data, array capture reagents, high-throughput sequencing and data analysis and interpretation. M.D. and S.E.C. performed the dideoxy sequencing. D.R.G., L.C. and A.S. performed the loss of heterozygosity (LOH) studies. D.R.G. performed the linkage and haplotype analysis of the discovered variants. I.S., B.R. and S.A. performed the functional assays. D.P.L. performed the immunohistochemistry. C.V. carried out the structural modeling. E.B.L., D.R.G., M.D. and I.S. wrote the paper with contributions from the other authors. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * E Birgitte Lane Author Details * David R Goudie Search for this author in: * NPG journals * PubMed * Google Scholar * Mariella D'Alessandro Search for this author in: * NPG journals * PubMed * Google Scholar * Barry Merriman Search for this author in: * NPG journals * PubMed * Google Scholar * Hane Lee Search for this author in: * NPG journals * PubMed * Google Scholar * Ildikó Szeverényi Search for this author in: * NPG journals * PubMed * Google Scholar * Stuart Avery Search for this author in: * NPG journals * PubMed * Google Scholar * Brian D O'Connor Search for this author in: * NPG journals * PubMed * Google Scholar * Stanley F Nelson Search for this author in: * NPG journals * PubMed * Google Scholar * Stephanie E Coats Search for this author in: * NPG journals * PubMed * Google Scholar * Arlene Stewart Search for this author in: * NPG journals * PubMed * Google Scholar * Lesley Christie Search for this author in: * NPG journals * PubMed * Google Scholar * Gabriella Pichert Search for this author in: * NPG journals * PubMed * Google Scholar * Jean Friedel Search for this author in: * NPG journals * PubMed * Google Scholar * Ian Hayes Search for this author in: * NPG journals * PubMed * Google Scholar * Nigel Burrows Search for this author in: * NPG journals * PubMed * Google Scholar * Sean Whittaker Search for this author in: * NPG journals * PubMed * Google Scholar * Anne-Marie Gerdes Search for this author in: * NPG journals * PubMed * Google Scholar * Sigurd Broesby-Olsen Search for this author in: * NPG journals * PubMed * Google Scholar * Malcolm A Ferguson-Smith Search for this author in: * NPG journals * PubMed * Google Scholar * Chandra Verma Search for this author in: * NPG journals * PubMed * Google Scholar * Declan P Lunny Search for this author in: * NPG journals * PubMed * Google Scholar * Bruno Reversade Search for this author in: * NPG journals * PubMed * Google Scholar * E Birgitte Lane Contact E Birgitte Lane Search for this author in: * NPG journals * PubMed * Google Scholar Supplementary information * Accession codes * Author information * Supplementary information PDF files * Supplementary Text and Figures (2M) Supplementary Tables 1–3 and Supplementary Figures 1–4. Additional data
• Silencing of microRNA families by seed-targeting tiny LNAs
  - Nat Genet 43(4):371-378 (2011)
  Nature Genetics | Technical Report Silencing of microRNA families by seed-targeting tiny LNAs * Susanna Obad1 * Camila O dos Santos2 * Andreas Petri1 * Markus Heidenblad1 * Oliver Broom1 * Cristian Ruse2 * Cexiong Fu2 * Morten Lindow1 * Jan Stenvang1 * Ellen Marie Straarup1 * Henrik Frydenlund Hansen1 * Troels Koch1 * Darryl Pappin2 * Gregory J Hannon2 * Sakari Kauppinen1, 3 * Affiliations * Contributions * Corresponding authorJournal name:Nature GeneticsVolume: 43,Pages:371–378Year published:(2011)DOI:doi:10.1038/ng.786Received30 November 2010Accepted15 February 2011Published online20 March 2011 Abstract * Abstract * Accession codes * Author information * Supplementary information Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg The challenge of understanding the widespread biological roles of animal microRNAs (miRNAs) has prompted the development of genetic and functional genomics technologies for miRNA loss-of-function studies. However, tools for exploring the functions of entire miRNA families are still limited. We developed a method that enables antagonism of miRNA function using seed-targeting 8-mer locked nucleic acid (LNA) oligonucleotides, termed tiny LNAs. Transfection of tiny LNAs into cells resulted in simultaneous inhibition of miRNAs within families sharing the same seed with concomitant upregulation of direct targets. In addition, systemically delivered, unconjugated tiny LNAs showed uptake in many normal tissues and in breast tumors in mice, coinciding with long-term miRNA silencing. Transcriptional and proteomic profiling suggested that tiny LNAs have negligible off-target effects, not significantly altering the output from mRNAs with perfect tiny LNA complementary sites. Considered ! together, these data support the utility of tiny LNAs in elucidating the functions of miRNA families in vivo. View full text Figures at a glance * Figure 1: Schematic overview of the miRNA silencing approach using seed-targeting tiny LNAs. () miRNAs bind to partially complementary target sites in the 3′ UTRs of target mRNAs and thereby mediate translational repression or mRNA degradation. () Tiny LNAs are designed as fully LNA-modified phosphorothioate oligonucleotides complementary to the seed region. () The high binding affinity of tiny LNAs enables functional inhibition of co-expressed members of miRNA seed families, which leads to de-repression of target mRNAs. * Figure 2: Inhibition of miR-21 function by tiny antimiR-21. () Relative luciferase activity of the miR-21 reporter co-transfected into HeLa cells with tiny antimiR-21, 2′-O-Me antimiR-21, LNA scramble (scr) or mismatch (mm) controls. Error bars, s.e.m. () We determined the concentration of antimiR-21 required for half-maximal inhibition (IC50) of miR-21 in HeLa cells using the miR-21 reporter. Error bars, s.e.m. () RNA blot analysis of miR-21 in HeLa cells transfected with 5 nM antimiR-21 or LNA scramble control. U6 is shown as a control. () De-repression of HeLa mRNAs with canonical miR-21 seed sites after transfection with 5 nM antimiR-21. Cumulative distributions of mRNA changes between antimiR-21–treated and mock-treated cells are shown for each seed site (one-sided Kolmogorov-Smirnov test). () Protein blot analysis of Pdcd4 expression in HeLa cells (same cells as in ). Tubulin is shown as a control. () Colony formation of PC3 cells transfected with antimiR-21 or LNA scramble control. *P < 0.05; n = 3; error bars, s.e.m. () R! elative luciferase activity of the miR-21 reporter in HeLa cells co-transfected with tiny LNAs targeting the mature miR-21 sequence. Error bars, s.e.m. () Protein blot analysis of Ago2 immunoprecipitates from antimiR-21–transfected HeLa cells. IgG was used as a control. () RNA blot analysis of RNAs from immunoprecipitated Ago2 samples probed for antimiR-21. The antimiR-21 oligonucleotide (14 pg and 140 pg per sample) was used as a control. () Subcellular localization of antimiR-21 in HEK293 cells using immunofluorescence microscopy (red, FLAG-tagged Ago2; green, FAM-labeled antimiR-21; blue, nuclei co-stained with DAPI; scale bar, 10 μm). * Figure 3: Silencing of miRNA families by seed-targeting tiny LNAs in cultured cells. () Relative luciferase activity of the AldoA 3′ UTR reporter co-transfected into HeLa cells with pre–miR-122 and tiny antimiR-122 or LNA scramble control. Error bars, s.e.m. Protein blot analysis of AldoA expression in HeLa cells transfected with 5 nM antimiR-122 or LNA scramble control. Tubulin is shown as a loading control. () Relative luciferase activity of the miR-155 reporter co-transfected into LPS-treated RAW264.7 cells with tiny antimiR-155 or LNA scramble control. Error bars, s.e.m. Protein blot analysis of PU.1 expression in RAW264.7 cells co-transfected with pre-miR-155 and 5 nM tiny antimiR-155 or LNA scramble control. Tubulin is shown as a loading control. () Relative luciferase activity of the miR-221 and miR-222 reporters co-transfected into PC3 cells with tiny antimiR or LNA scramble control. Error bars, s.e.m. () Protein blot analysis of p27 expression in PC3 cells transfected with tiny antimiR or LNA scramble control. Tubulin is shown as a loading contr! ol. () Relative luciferase activity of the HMGA2 3′ UTR reporter co-transfected into Huh-7 cells with 10 nM pre–let-7a, -7b, -7c, -7d, -7e, -7f, -7g, -7i or miR-98 and tiny antilet-7 or LNA scramble control. Error bars, s.e.m. () Relative luciferase activity of the HMGA2 3′ UTR reporter co-transfected into HeLa cells with tiny antilet-7. Error bars, s.e.m. () Protein blot analysis of HMGA2 and RAS expression in HeLa cells transfected with tiny antilet-7 or LNA scramble control. Tubulin is shown as a loading control. * Figure 4: Silencing of miR-21 in vivo by tiny antimiR-21. () Uptake of 35S-labeled antimiR-21 in mice over time after treatment with single intravenous doses of 10 mg/kg. Individual mice were killed at different time points and sectioned sagittally for whole-body autoradiography. Uptake of 35S-labeled antimiR-21 is shown for selected tissues. () RNA blot analysis of liver, kidney and lung RNA from mice treated with three intravenous doses of 10 mg/kg tiny antimiR-21 or LNA control or with saline. The RNA blot was probed for miR-21 and U6. () Protein blot analysis of BTG2 expression in kidney, liver and lung of mice treated with three intravenous doses of 10 mg/kg tiny antimiR-21 or LNA scramble control or with saline. () RNA blot analysis of liver and kidney RNA from mice killed at different time points after treatment with single intravenous doses of 25 mg/kg antimiR-21 or LNA scramble control. The RNA blot was probed for miR-21 and U6. () Representative images of miR-21 luciferase reporter de-repression in breast tumor (right sid! e tumors) after treatment with antimiR-21 (upper panel) or LNA control (lower panel). Left side tumors express luciferase alone. We carried out imaging before first injection (D0) and at 3, 7 and 9 days (D3, D7 and D9) after the last injection. () In vivo image analysis quantification of two independent experiments. Luciferase activity was normalized to tumor size. *P < 0.05, n = 7 for antimiR-treated group and n = 5 for LNA control; **P < 0.01, n = 5 for both groups. Error bars, s.e.m. * Figure 5: Silencing of miR-122 in the mouse liver by seed-targeting tiny LNA. () RNA blot analysis of liver RNAs from mice after treatment with three intravenous doses of 20 mg/kg tiny antimiR-122, 15-mer antimiR-122 or LNA scramble control or with saline. The RNA blot was probed for miR-122 and U6. () Total plasma cholesterol levels in mice treated with three intravenous injections of tiny antimiR-122, 15-mer antimiR-122, LNA scramble control or with saline (error bars, s.e.m.; n = 5; ***P < 0.001, one-way ANOVA). () Quantification of the AldoA and Bckdk mRNAs (same samples as in , normalized to GAPDH; error bars, s.e.m.; n = 5; ***P < 0.001, one-way ANOVA). () Hierarchical clustering of samples using filtered microarray expression data from mice treated with tiny antimiR-122, 15-mer antimiR-122, LNA scramble control or with saline (same samples as in ; n = 5, except for 15-mer antimiR and LNA scramble control, where n = 4). () Hierarchical clustering of genes showing differential expression at a false discovery rate of 1% when comparing antimiR-122 ! profiles to controls or when comparing the two antimiR-122 profiles directly. Predicted miR-122 targets (7-mer and 8-mer seed match sites) are indicated with black lines between the heatmap and the dendrogram. () De-repression of liver mRNAs with canonical miR-122 seed match sites (same samples as in ). We determined the significance of the differences from mRNAs with no sites using one-sided Kolmogorov-Smirnov tests. () Venn diagrams showing the number of liver mRNAs upregulated by antimiRs both with 8-mer or 7-mer seed matches in the 3′ UTRs. * Figure 6: Off-target analysis. () Schematic representation of the different seed match sites in miR-122 target mRNAs and the putative perfect-match binding sites of the tiny antimiR-122 and the LNA scramble control, respectively. () De-repression of proteins encoded by mRNAs with canonical miR-122 seed match sites after treatment with 3 × 20 mg/kg tiny antimiR-122. The cumulative fraction plots show the distribution of log2 fold changes between the antimiR-122– and LNA-control–treated mice for each seed match type. Proteins encoded by mRNAs with perfect-match binding sites to antimiR-122 or LNA scramble control did not show a significant shift relative to saline control. () Relative luciferase activity of a Renilla luciferase reporter co-transfected into HeLa cells with three siRNAs, three LNA gapmers targeting the Renilla ORF (red and orange), three tiny LNAs with binding sites within the siRNA or LNA gapmer target sequences (gray), tiny LNAs binding to the 5′ UTR (black), ORF (blue) or 3′ UTR (! green) of Renilla luciferase, respectively. Error bars, s.e.m. () Schematic representation of the mechanism of action of siRNAs and LNA gapmers and binding of tiny LNAs to a perfect-match mRNA site. Accession codes * Abstract * Accession codes * Author information * Supplementary information Referenced accessions ArrayExpress * E-MEXP-2801 * E-MEXP-2802 * E-MEXP-2803 * E-MEXP-2804 Author information * Abstract * Accession codes * Author information * Supplementary information Affiliations * Santaris Pharma, Hørsholm, Denmark. * Susanna Obad, * Andreas Petri, * Markus Heidenblad, * Oliver Broom, * Morten Lindow, * Jan Stenvang, * Ellen Marie Straarup, * Henrik Frydenlund Hansen, * Troels Koch & * Sakari Kauppinen * Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA. * Camila O dos Santos, * Cristian Ruse, * Cexiong Fu, * Darryl Pappin & * Gregory J Hannon * Copenhagen Institute of Technology, Aalborg University, Ballerup, Denmark. * Sakari Kauppinen Contributions S.O., C.O.d.S., A.P., M.H., O.B., C.R., C.F. and E.M.S. performed experiments and contributed data. H.F.H. performed synthesis of oligonucleotides. S.O., C.O.d.S., A.P., M.H., M.L., J.S., T.K., D.P., G.J.H. and S.K. designed experiments and discussed the data. S.K. supervised the study and wrote the manuscript together with S.O. and with input from other authors. Competing financial interests S.O., O.B., A.P., M.H., M.L., J.S., E.M.S., H.F.H., T.K. and S.K. are employees of Santaris Pharma, a clinical stage biopharmaceutical company that develops RNA-based therapeutics. Corresponding author Correspondence to: * Sakari Kauppinen Author Details * Susanna Obad Search for this author in: * NPG journals * PubMed * Google Scholar * Camila O dos Santos Search for this author in: * NPG journals * PubMed * Google Scholar * Andreas Petri Search for this author in: * NPG journals * PubMed * Google Scholar * Markus Heidenblad Search for this author in: * NPG journals * PubMed * Google Scholar * Oliver Broom Search for this author in: * NPG journals * PubMed * Google Scholar * Cristian Ruse Search for this author in: * NPG journals * PubMed * Google Scholar * Cexiong Fu Search for this author in: * NPG journals * PubMed * Google Scholar * Morten Lindow Search for this author in: * NPG journals * PubMed * Google Scholar * Jan Stenvang Search for this author in: * NPG journals * PubMed * Google Scholar * Ellen Marie Straarup Search for this author in: * NPG journals * PubMed * Google Scholar * Henrik Frydenlund Hansen Search for this author in: * NPG journals * PubMed * Google Scholar * Troels Koch Search for this author in: * NPG journals * PubMed * Google Scholar * Darryl Pappin Search for this author in: * NPG journals * PubMed * Google Scholar * Gregory J Hannon Search for this author in: * NPG journals * PubMed * Google Scholar * Sakari Kauppinen Contact Sakari Kauppinen Search for this author in: * NPG journals * PubMed * Google Scholar Supplementary information * Abstract * Accession codes * Author information * Supplementary information PDF files * Supplementary Text and Figures (3M) Supplementary Note, Supplementary Figures 1–14 and Supplementary Tables 1–5. 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• Large-scale analysis of the regulatory architecture of the mouse genome with a transposon-associated sensor
  - Nat Genet 43(4):379-386 (2011)
  Nature Genetics | Technical Report Large-scale analysis of the regulatory architecture of the mouse genome with a transposon-associated sensor * Sandra Ruf1 * Orsolya Symmons1 * Veli Vural Uslu1 * Dirk Dolle2 * Chloé Hot1 * Laurence Ettwiller2 * François Spitz1 * Affiliations * Contributions * Corresponding authorJournal name:Nature GeneticsVolume: 43,Pages:379–386Year published:(2011)DOI:doi:10.1038/ng.790Received17 November 2010Accepted16 February 2011Published online20 March 2011 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 We present here a Sleeping Beauty–based transposition system that offers a simple and efficient way to investigate the regulatory architecture of mammalian chromosomes in vivo. With this system, we generated several hundred mice and embryos, each with a regulatory sensor inserted at a random genomic position. This large sampling of the genome revealed the widespread presence of long-range regulatory activities along chromosomes, forming overlapping blocks with distinct tissue-specific expression potentials. The presence of tissue-restricted regulatory activities around genes with widespread expression patterns challenges the gene-centric view of genome regulation and suggests that most genes are modulated in a tissue-specific manner. The local hopping property of Sleeping Beauty provides a dynamic approach to map these regulatory domains at high resolution and, combined with Cre-mediated recombination, allows for the determination of their functions by engineering mice wit! h specific chromosomal rearrangements. View full text Figures at a glance * Figure 1: The GROMIT strategy. () Schematic representation of the transposase-expressing transgene and the regulatory sensor. The coding sequence of the improved HSB16 Sleeping Beauty transposase35 is under the control of the mouse Prm1 promoter region, which is specifically active in the male germline36. The SBlac transposon contains a LacZ reporter gene under the control of the minimal promoter of the human β-globin gene (β)31 and a loxP site (red triangle), cloned within the inverted or direct repeats of the Sleeping Beauty transposon (white arrowheads)35. () The breeding scheme. We mated males transgenic for both the transposase and transposon transgenes (seed males) to wild-type females to produce F0 animals with new insertions. We performed additional breeding to segregate the different insertions and establish lines with single integrants. () Distribution of 550 mapped SBlac insertions (blue triangles) on the mouse genome. * Figure 2: Genomic distribution and transcriptional activity of the different insertions. () Fraction of insertions within exons, introns or intergenic intervals (based on RefSeq genes). () Proportion of insertions at different distances from TSS. The observed dataset contains all insertions mapped to single loci, excluding the ones corresponding to the local hotspots associated with the starting concatemers A and C or subsequent local remobilizations. We analyzed 165 of these insertions for reporter activity, forming the 'expression tested' dataset. We obtained random distributions by analyzing independent randomizations with the same sample size as in the observed dataset. () Expression status of the insertions for all expression-tested insertions or for different subsets according to their distance relative to the nearest TSS. Insertions within 50 kb of a TSS in E11.5 embryos showed expression less frequently than insertions farther away from a TSS (P = 0.00739, significance level 0.025), but the complexity of the corresponding patterns was similar with mostly! tissue-restricted expression (data not shown). () Examples of LacZ expression from different insertions in E11.5 embryos. * Figure 3: Examples of patterns of activities associated with different insertions. (−) We performed LacZ staining on E11.5 embryos heterozygous for the different insertions of the regulatory sensor. For each insertion, a schematic representation of the locus is shown. Genes are represented by black arrowheads, pointing in the direction of their transcription except for in , where black bars correspond to the different exons and the gray block corresponds to the gene body. () A transposon 80 kb from Sox9 showed strong LacZ staining in known Sox9 expression domains47 in the limb condensing mesenchyme (lb), the sclerotome (sc) and the developing ear (ot). However, we detected no expression in the neural tissues, where this gene is also strongly expressed47. () LacZ expression in the third pharyngal pouch (black arrow, th) of a transposon inserted into the gene body of Foxn1 mimics endogenous gene expression in the developing thymus primordium48. (,) LacZ staining of insertions that are not in the vicinity of developmental regulators. Insets in are sectioned! embryos showing expression in the floor plate of the neural tube (arrowhead, fp) and in the maxillary (arrow, mx). Scale bars are indicated in mm. () Comparison of the transposon (left) and endogenous gene (right) expression in E11.5 embryos revealed shared domains (ey, anterior-most part of the eye; ba, second branchial arch; fa, face; lb, proximal limb; st, stomach) between Efnb2 and the SB-177321e insertion about 500 kb away. However, strong expression of Efnb2 in the brain and developing vascular system was not recapitulated by the transposon. * Figure 4: Short- and long-range activities detected by transposons inserted into the same loci. () We obtained two insertions (SB-183036-emb4 and SB-176069-emb50) in the 2-Mb gene desert between Arrdc4 and Nr2f2. These insertions shared expression domains (white arrows) in the face and midbrain and showed insertion-specific expression (red arrows), illustrating the existence of overlapping but distinct regulatory landscapes with their own tissue specificity. () Insertions in the Col1a1-Dlx4 interval showed different activities. The insertion 70 kb upstream of Dlx4 (SB-177611d) showed LacZ activity in the visceral arches (arrow), partially mirroring Dlx3 and Dlx4 expression, but showed only weak staining in the limb apical ectodermal ridge and no staining in the mandibular arch, compared to the Dlx3, and Dlx4 endogenous genes49. An insertion in an intron of Pdk2 (SB-178137a) showed no expression. Upon remobilization of this one insertion, we discovered two new insertions in the same neighborhood. A very local insertion (remob1, 0.6 kb away) showed also no expression, wh! ereas another (remob2, 17 kb away) was expressed more broadly, notably in the neural tube and brain, matching the flanking genes' activities. * Figure 5: Comparison between the genomic regulatory potential and intrinsic activities of nearby enhancers. (–) An insertion 300 kb upstream of Sall1 is localized between two evolutionarily conserved enhancer elements as schematized in . The reporter gene () recapitulates most expression domains of the endogenous gene detected by in situ hybridization (). Expression in the limbs (white arrowhead) and forebrain (black arrowhead) overlaps with activity determined for the two flanking Vista enhancers mapped in the region (LBL-72 () and LBL-71 ()). However, although LBL-72 can drive expression of a reporter gene throughout the whole autopod in a transgenic assay (), in the endogenous context, this activity is silenced both in the most distal mesenchyme and in a proximal anterior region of the autopod (,, red arrows). For simplicity, additional enhancers with activities corresponding to other Sall1 and SB-182529a expression domains, which had been previously identified2 but which are localized further away from SB-182529a, are not shown. Photos of the transgenic embryos for Vista enh! ancers (,) were taken from the Vista Enhancer Browser2. * Figure 6: Mapping genomic regulatory domains with sequential tranposition and/or recombination. () Schematic representation of the Myc-Gsdmc interval, including the non-coding Pvt1 gene and the initial insertion from the SB-179039 line. Upon local transposition from SB-179039, we obtained SB-184347, located ~890 kb away from SB-179039. Cre-mediated recombination in trans between the loxP sites produced chromosomes with the deletion or the duplication of the intervening region. The breeding strategy is detailed in Supplementary Figure 9. (−) In situ hybridization of the endogenous Myc gene showed enrichment of expression notably in the face (fa) and somites (so) coinciding with LacZ expression domains observed both with SB-184347 () and SB-179039 () in E11.5 embryos. In SB-179039, LacZ expression was stronger than in SB-184347 and included a specific rhombic lip domain (rl) not observed for Myc or SB-184347. Both domains were lost when the 890-kb region was deleted (), whereas the duplication led only to quantitative differences when compared to SB-179039 (data not sh! own). Author information * Abstract * Author information * Supplementary information Affiliations * Developmental Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany. * Sandra Ruf, * Orsolya Symmons, * Veli Vural Uslu, * Chloé Hot & * François Spitz * Centre for Organismal Studies, Heidelberg University, Heidelberg, Germany. * Dirk Dolle & * Laurence Ettwiller Contributions F.S. conceived and designed the GROMIT strategy. S.R., O.S., V.V.U., C.H. and F.S. performed the experiments. O.S., D.D. and L.E. performed the statistical analyses. All authors discussed the results and contributed to the writing of the manuscript. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * François Spitz Author Details * Sandra Ruf Search for this author in: * NPG journals * PubMed * Google Scholar * Orsolya Symmons Search for this author in: * NPG journals * PubMed * Google Scholar * Veli Vural Uslu Search for this author in: * NPG journals * PubMed * Google Scholar * Dirk Dolle Search for this author in: * NPG journals * PubMed * Google Scholar * Chloé Hot Search for this author in: * NPG journals * PubMed * Google Scholar * Laurence Ettwiller Search for this author in: * NPG journals * PubMed * Google Scholar * François Spitz Contact François Spitz Search for this author in: * NPG journals * PubMed * Google Scholar Supplementary information * Abstract * Author information * Supplementary information PDF files * Supplementary Text and Figures (8M) Supplementary Note, Supplementary Figures 1–9 and Supplementary Tables 1–3. Additional data
• Addendum: Resequencing of 31 wild and cultivated soybean genomes identifies patterns of genetic diversity and selection
  - Nat Genet 43(4):387 (2011)
  Nature Genetics | Addendum Addendum: Resequencing of 31 wild and cultivated soybean genomes identifies patterns of genetic diversity and selection * Hon-Ming Lam * Xun Xu * Xin Liu * Wenbin Chen * Guohua Yang * Fuk-Ling Wong * Man-Wah Li * Weiming He * Nan Qin * Bo Wang * Jun Li * Min Jian * Jian Wang * Guihua Shao * Jun Wang * Samuel Sai-Ming Sun * Gengyun ZhangJournal name:Nature GeneticsVolume: 43,Page:387Year published:(2011)DOI:doi:10.1038/ng0411-387Published online29 March 2011 Article tools * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Nat. Genet.42, 1053–1059 (2010); published online 14 November 2010; addendum published after print 29 March 2011 Raw data of short reads for each soybean accession can be downloaded as individual files from the NCBI website. The corresponding file name and soybean accession are listed in the addendum. Further information on the soybean accessions can be found in the supplementary information online. The full dataset can also be downloaded from the following ftp site: ftp://public.genomics.org.cn/BGI/soybean_resequencing/. Additional data Author Details * Hon-Ming Lam Search for this author in: * NPG journals * PubMed * Google Scholar * Xun Xu Search for this author in: * NPG journals * PubMed * Google Scholar * Xin Liu Search for this author in: * NPG journals * PubMed * Google Scholar * Wenbin Chen Search for this author in: * NPG journals * PubMed * Google Scholar * Guohua Yang Search for this author in: * NPG journals * PubMed * Google Scholar * Fuk-Ling Wong Search for this author in: * NPG journals * PubMed * Google Scholar * Man-Wah Li Search for this author in: * NPG journals * PubMed * Google Scholar * Weiming He Search for this author in: * NPG journals * PubMed * Google Scholar * Nan Qin Search for this author in: * NPG journals * PubMed * Google Scholar * Bo Wang Search for this author in: * NPG journals * PubMed * Google Scholar * Jun Li Search for this author in: * NPG journals * PubMed * Google Scholar * Min Jian Search for this author in: * NPG journals * PubMed * Google Scholar * Jian Wang Search for this author in: * NPG journals * PubMed * Google Scholar * Guihua Shao Search for this author in: * NPG journals * PubMed * Google Scholar * Jun Wang Search for this author in: * NPG journals * PubMed * Google Scholar * Samuel Sai-Ming Sun Search for this author in: * NPG journals * PubMed * Google Scholar * Gengyun Zhang Search for this author in: * NPG journals * PubMed * Google Scholar
• Erratum: Genome-wide association identifies multiple ulcerative colitis susceptibility loci
  - Nat Genet 43(4):388 (2011)
  Nature Genetics | Erratum Erratum: Genome-wide association identifies multiple ulcerative colitis susceptibility loci * Dermot P B McGovern * Agnès Gardet * Leif Törkvist * Philippe Goyette * Jonah Essers * Kent D Taylor * Benjamin M Neale * Rick T H Ong * Caroline Lagacé * Chun Li * Todd Green * Christine R Stevens * Claudine Beauchamp * Phillip R Fleshner * Marie Carlson * Mauro D'Amato * Jonas Halfvarson * Martin L Hibberd * Mikael Lördal * Leonid Padyukov * Angelo Andriulli * Elisabetta Colombo * Anna Latiano * Orazio Palmieri * Edmond-Jean Bernard * Colette Deslandres * Daan W Hommes * Dirk J de Jong * Pieter C Stokkers * Rinse K Weersma * The NIDDK IBD Genetics Consortium * Yashoda Sharma * Mark S Silverberg * Judy H Cho * Jing Wu * Kathryn Roeder * Steven R Brant * L Phillip Schumm * Richard H Duerr * Marla C Dubinsky * Nicole L Glazer * Talin Haritunians * Andy Ippoliti * Gil Y Melmed * David S Siscovick * Eric A Vasiliauskas * Stephan R Targan * Vito Annese * Cisca Wijmenga * Sven Pettersson * Jerome I Rotter * Ramnik J Xavier * Mark J Daly * John D Rioux * Mark SeielstadJournal name:Nature GeneticsVolume: 43,Page:388Year published:(2011)DOI:doi:10.1038/ng0411-388cPublished online29 March 2011 Article tools * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Nat. Genet.42, 332–337 (2010); published online 14 March 2010; corrected after print 29 March 2011 In the version of this article initially published, Kathryn Roeder's affiliation was incorrect. Her correct affiliation is the Department of Statistics, Carnegie Mellon University, Pittsburgh, Pennsylvania, USA. The error has been corrected in the HTML and PDF versions of the article. Additional data Author Details * Dermot P B McGovern Search for this author in: * NPG journals * PubMed * Google Scholar * Agnès Gardet Search for this author in: * NPG journals * PubMed * Google Scholar * Leif Törkvist Search for this author in: * NPG journals * PubMed * Google Scholar * Philippe Goyette Search for this author in: * NPG journals * PubMed * Google Scholar * Jonah Essers Search for this author in: * NPG journals * PubMed * Google Scholar * Kent D Taylor Search for this author in: * NPG journals * PubMed * Google Scholar * Benjamin M Neale Search for this author in: * NPG journals * PubMed * Google Scholar * Rick T H Ong Search for this author in: * NPG journals * PubMed * Google Scholar * Caroline Lagacé Search for this author in: * NPG journals * PubMed * Google Scholar * Chun Li Search for this author in: * NPG journals * PubMed * Google Scholar * Todd Green Search for this author in: * NPG journals * PubMed * Google Scholar * Christine R Stevens Search for this author in: * NPG journals * PubMed * Google Scholar * Claudine Beauchamp Search for this author in: * NPG journals * PubMed * Google Scholar * Phillip R Fleshner Search for this author in: * NPG journals * PubMed * Google Scholar * Marie Carlson Search for this author in: * NPG journals * PubMed * Google Scholar * Mauro D'Amato Search for this author in: * NPG journals * PubMed * Google Scholar * Jonas Halfvarson Search for this author in: * NPG journals * PubMed * Google Scholar * Martin L Hibberd Search for this author in: * NPG journals * PubMed * Google Scholar * Mikael Lördal Search for this author in: * NPG journals * PubMed * Google Scholar * Leonid Padyukov Search for this author in: * NPG journals * PubMed * Google Scholar * Angelo Andriulli Search for this author in: * NPG journals * PubMed * Google Scholar * Elisabetta Colombo Search for this author in: * NPG journals * PubMed * Google Scholar * Anna Latiano Search for this author in: * NPG journals * PubMed * Google Scholar * Orazio Palmieri Search for this author in: * NPG journals * PubMed * Google Scholar * Edmond-Jean Bernard Search for this author in: * NPG journals * PubMed * Google Scholar * Colette Deslandres Search for this author in: * NPG journals * PubMed * Google Scholar * Daan W Hommes Search for this author in: * NPG journals * PubMed * Google Scholar * Dirk J de Jong Search for this author in: * NPG journals * PubMed * Google Scholar * Pieter C Stokkers Search for this author in: * NPG journals * PubMed * Google Scholar * Rinse K Weersma Search for this author in: * NPG journals * PubMed * Google Scholar * The NIDDK IBD Genetics Consortium * Yashoda Sharma Search for this author in: * NPG journals * PubMed * Google Scholar * Mark S Silverberg Search for this author in: * NPG journals * PubMed * Google Scholar * Judy H Cho Search for this author in: * NPG journals * PubMed * Google Scholar * Jing Wu Search for this author in: * NPG journals * PubMed * Google Scholar * Kathryn Roeder Search for this author in: * NPG journals * PubMed * Google Scholar * Steven R Brant Search for this author in: * NPG journals * PubMed * Google Scholar * L Phillip Schumm Search for this author in: * NPG journals * PubMed * Google Scholar * Richard H Duerr Search for this author in: * NPG journals * PubMed * Google Scholar * Marla C Dubinsky Search for this author in: * NPG journals * PubMed * Google Scholar * Nicole L Glazer Search for this author in: * NPG journals * PubMed * Google Scholar * Talin Haritunians Search for this author in: * NPG journals * PubMed * Google Scholar * Andy Ippoliti Search for this author in: * NPG journals * PubMed * Google Scholar * Gil Y Melmed Search for this author in: * NPG journals * PubMed * Google Scholar * David S Siscovick Search for this author in: * NPG journals * PubMed * Google Scholar * Eric A Vasiliauskas Search for this author in: * NPG journals * PubMed * Google Scholar * Stephan R Targan Search for this author in: * NPG journals * PubMed * Google Scholar * Vito Annese Search for this author in: * NPG journals * PubMed * Google Scholar * Cisca Wijmenga Search for this author in: * NPG journals * PubMed * Google Scholar * Sven Pettersson Search for this author in: * NPG journals * PubMed * Google Scholar * Jerome I Rotter Search for this author in: * NPG journals * PubMed * Google Scholar * Ramnik J Xavier Search for this author in: * NPG journals * PubMed * Google Scholar * Mark J Daly Search for this author in: * NPG journals * PubMed * Google Scholar * John D Rioux Search for this author in: * NPG journals * PubMed * Google Scholar * Mark Seielstad Search for this author in: * NPG journals * PubMed * Google Scholar
• Corrigendum: Genome-wide association study identifies new HLA class II haplotypes strongly protective against narcolepsy
  - Nat Genet 43(4):388 (2011)
  Nature Genetics | Corrigendum Corrigendum: Genome-wide association study identifies new HLA class II haplotypes strongly protective against narcolepsy * Hyun Hor * Zoltán Kutalik * Yves Dauvilliers * Armand Valsesia * Gert J Lammers * Claire E H M Donjacour * Alex Iranzo * Joan Santamaria * Rosa Peraita Adrados * José L Vicario * Sebastiaan Overeem * Isabelle Arnulf * Ioannis Theodorou * Poul Jennum * Stine Knudsen * Claudio Bassetti * Johannes Mathis * Michel Lecendreux * Geert Mayer * Peter Geisler * Antonio Benetó * Brice Petit * Corinne Pfister * Julie Vienne Bürki * Gérard Didelot * Michel Billiard * Guadalupe Ercilla * Willem Verduijn * Frans H J Claas * Peter Vollenwider * Gerard Waeber * Dawn M Waterworth * Vincent Mooser * Raphaël Heinzer * Jacques S Beckmann * Sven Bergmann * Mehdi TaftiJournal name:Nature GeneticsVolume: 43,Page:388Year published:(2011)DOI:doi:10.1038/ng0411-388aPublished online29 March 2011 Article tools * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Nat. Genet.42, 786–789 (2010); published online 15 August 2010; corrected after print 27 October 2010 In the version of this article initially published, the name of author Peter Vollenweider was incorrectly written as Peter Vollenwider. Also, Claudio Bassetti's affiliation was incorrectly listed as Neurocentro (Ente ospedaliero cantonale) della Svizzera Italiana, Ospedale Civico, Lugano, Switzerland. His correct affiliation is Department of Neurology, University Hospital Zurich, Zurich, Switzerland. These errors have been corrected in the HTML and PDF versions of the article. Additional data Author Details * Hyun Hor Search for this author in: * NPG journals * PubMed * Google Scholar * Zoltán Kutalik Search for this author in: * NPG journals * PubMed * Google Scholar * Yves Dauvilliers Search for this author in: * NPG journals * PubMed * Google Scholar * Armand Valsesia Search for this author in: * NPG journals * PubMed * Google Scholar * Gert J Lammers Search for this author in: * NPG journals * PubMed * Google Scholar * Claire E H M Donjacour Search for this author in: * NPG journals * PubMed * Google Scholar * Alex Iranzo Search for this author in: * NPG journals * PubMed * Google Scholar * Joan Santamaria Search for this author in: * NPG journals * PubMed * Google Scholar * Rosa Peraita Adrados Search for this author in: * NPG journals * PubMed * Google Scholar * José L Vicario Search for this author in: * NPG journals * PubMed * Google Scholar * Sebastiaan Overeem Search for this author in: * NPG journals * PubMed * Google Scholar * Isabelle Arnulf Search for this author in: * NPG journals * PubMed * Google Scholar * Ioannis Theodorou Search for this author in: * NPG journals * PubMed * Google Scholar * Poul Jennum Search for this author in: * NPG journals * PubMed * Google Scholar * Stine Knudsen Search for this author in: * NPG journals * PubMed * Google Scholar * Claudio Bassetti Search for this author in: * NPG journals * PubMed * Google Scholar * Johannes Mathis Search for this author in: * NPG journals * PubMed * Google Scholar * Michel Lecendreux Search for this author in: * NPG journals * PubMed * Google Scholar * Geert Mayer Search for this author in: * NPG journals * PubMed * Google Scholar * Peter Geisler Search for this author in: * NPG journals * PubMed * Google Scholar * Antonio Benetó Search for this author in: * NPG journals * PubMed * Google Scholar * Brice Petit Search for this author in: * NPG journals * PubMed * Google Scholar * Corinne Pfister Search for this author in: * NPG journals * PubMed * Google Scholar * Julie Vienne Bürki Search for this author in: * NPG journals * PubMed * Google Scholar * Gérard Didelot Search for this author in: * NPG journals * PubMed * Google Scholar * Michel Billiard Search for this author in: * NPG journals * PubMed * Google Scholar * Guadalupe Ercilla Search for this author in: * NPG journals * PubMed * Google Scholar * Willem Verduijn Search for this author in: * NPG journals * PubMed * Google Scholar * Frans H J Claas Search for this author in: * NPG journals * PubMed * Google Scholar * Peter Vollenwider Search for this author in: * NPG journals * PubMed * Google Scholar * Gerard Waeber Search for this author in: * NPG journals * PubMed * Google Scholar * Dawn M Waterworth Search for this author in: * NPG journals * PubMed * Google Scholar * Vincent Mooser Search for this author in: * NPG journals * PubMed * Google Scholar * Raphaël Heinzer Search for this author in: * NPG journals * PubMed * Google Scholar * Jacques S Beckmann Search for this author in: * NPG journals * PubMed * Google Scholar * Sven Bergmann Search for this author in: * NPG journals * PubMed * Google Scholar * Mehdi Tafti Search for this author in: * NPG journals * PubMed * Google Scholar
• Corrigendum: Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis
  - Nat Genet 43(4):388 (2011)
  Nature Genetics | Corrigendum Corrigendum: Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis * Benjamin F Voight * Laura J Scott * Valgerdur Steinthorsdottir * Andrew P Morris * Christian Dina * Ryan P Welch * Eleftheria Zeggini * Cornelia Huth * Yurii S Aulchenko * Gudmar Thorleifsson * Laura J McCulloch * Teresa Ferreira * Harald Grallert * Najaf Amin * Guanming Wu * Cristen J Willer * Soumya Raychaudhuri * Steve A McCarroll * Claudia Langenberg * Oliver M Hofmann * Josée Dupuis * Lu Qi * Ayellet V Segrè * Mandy van Hoek * Pau Navarro * Kristin Ardlie * Beverley Balkau * Rafn Benediktsson * Amanda J Bennett * Roza Blagieva * Eric Boerwinkle * Lori L Bonnycastle * Kristina Bengtsson Boström * Bert Bravenboer * Suzannah Bumpstead * Noisël P Burtt * Guillaume Charpentier * Peter S Chines * Marilyn Cornelis * David J Couper * Gabe Crawford * Alex S F Doney * Katherine S Elliott * Amanda L Elliott * Michael R Erdos * Caroline S Fox * Christopher S Franklin * Martha Ganser * Christian Gieger * Niels Grarup * Todd Green * Simon Griffin * Christopher J Groves * Candace Guiducci * Samy Hadjadj * Neelam Hassanali * Christian Herder * Bo Isomaa * Anne U Jackson * Paul R V Johnson * Torben Jørgensen * Wen H L Kao * Norman Klopp * Augustine Kong * Peter Kraft * Johanna Kuusisto * Torsten Lauritzen * Man Li * Aloysius Lieverse * Cecilia M Lindgren * Valeriya Lyssenko * Michel Marre * Thomas Meitinger * Kristian Midthjell * Mario A Morken * Narisu Narisu * Peter Nilsson * Katharine R Owen * Felicity Payne * John R B Perry * Ann-Kristin Petersen * Carl Platou * Christine Proença * Inga Prokopenko * Wolfgang Rathmann * N William Rayner * Neil R Robertson * Ghislain Rocheleau * Michael Roden * Michael J Sampson * Richa Saxena * Beverley M Shields * Peter Shrader * Gunnar Sigurdsson * Thomas Sparsø * Klaus Strassburger * Heather M Stringham * Qi Sun * Amy J Swift * Barbara Thorand * Jean Tichet * Tiinamaija Tuomi * Rob M van Dam * Timon W van Haeften * Thijs van Herpt * Jana V van Vliet-Ostaptchouk * G Bragi Walters * Michael N Weedon * Cisca Wijmenga * Jacqueline Witteman * The MAGIC investigators * The GIANT Consortium * Richard N Bergman * Stephane Cauchi * Francis S Collins * Anna L Gloyn * Ulf Gyllensten * Torben Hansen * Winston A Hide * Graham A Hitman * Albert Hofman * David J Hunter * Kristian Hveem * Markku Laakso * Karen L Mohlke * Andrew D Morris * Colin N A Palmer * Peter P Pramstaller * Igor Rudan * Eric Sijbrands * Lincoln D Stein * Jaakko Tuomilehto * Andre Uitterlinden * Mark Walker * Nicholas J Wareham * Richard M Watanabe * Gonçalo R Abecasis * Bernhard O Boehm * Harry Campbell * Mark J Daly * Andrew T Hattersley * Frank B Hu * James B Meigs * James S Pankow * Oluf Pedersen * H-Erich Wichmann * Inês Barroso * Jose C Florez * Timothy M Frayling * Leif Groop * Rob Sladek * Unnur Thorsteinsdottir * James F Wilson * Thomas Illig * Philippe Froguel * Cornelia M van Duijn * Kari Stefansson * David Altshuler * Michael Boehnke * Mark I McCarthyJournal name:Nature GeneticsVolume: 43,Page:388Year published:(2011)DOI:doi:10.1038/ng0411-388bPublished online29 March 2011 Article tools * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Nat. Genet.42, 579–589 (2010); published online 27 June 2010; corrected after print 27 August 2010 In the version of this article initially published, there was an error in Table 1. Specifically, for rs5945326, the risk and non-risk alleles were reversed. The correct risk allele at rs5945326 is A, the non-risk allele is G and the risk allele frequency in HapMap CEU is 0.79. These errors have been corrected in the HTML and PDF versions of the article. Additional data Author Details * Benjamin F Voight Search for this author in: * NPG journals * PubMed * Google Scholar * Laura J Scott Search for this author in: * NPG journals * PubMed * Google Scholar * Valgerdur Steinthorsdottir Search for this author in: * NPG journals * PubMed * Google Scholar * Andrew P Morris Search for this author in: * NPG journals * PubMed * Google Scholar * Christian Dina Search for this author in: * NPG journals * PubMed * Google Scholar * Ryan P Welch Search for this author in: * NPG journals * PubMed * Google Scholar * Eleftheria Zeggini Search for this author in: * NPG journals * PubMed * Google Scholar * Cornelia Huth Search for this author in: * NPG journals * PubMed * Google Scholar * Yurii S Aulchenko Search for this author in: * NPG journals * PubMed * Google Scholar * Gudmar Thorleifsson Search for this author in: * NPG journals * PubMed * Google Scholar * Laura J McCulloch Search for this author in: * NPG journals * PubMed * Google Scholar * Teresa Ferreira Search for this author in: * NPG journals * PubMed * Google Scholar * Harald Grallert Search for this author in: * NPG journals * PubMed * Google Scholar * Najaf Amin Search for this author in: * NPG journals * PubMed * Google Scholar * Guanming Wu Search for this author in: * NPG journals * PubMed * Google Scholar * Cristen J Willer Search for this author in: * NPG journals * PubMed * Google Scholar * Soumya Raychaudhuri Search for this author in: * NPG journals * PubMed * Google Scholar * Steve A McCarroll Search for this author in: * NPG journals * PubMed * Google Scholar * Claudia Langenberg Search for this author in: * NPG journals * PubMed * Google Scholar * Oliver M Hofmann Search for this author in: * NPG journals * PubMed * Google Scholar * Josée Dupuis Search for this author in: * NPG journals * PubMed * Google Scholar * Lu Qi Search for this author in: * NPG journals * PubMed * Google Scholar * Ayellet V Segrè Search for this author in: * NPG journals * PubMed * Google Scholar * Mandy van Hoek Search for this author in: * NPG journals * PubMed * Google Scholar * Pau Navarro Search for this author in: * NPG journals * PubMed * Google Scholar * Kristin Ardlie Search for this author in: * NPG journals * PubMed * Google Scholar * Beverley Balkau Search for this author in: * NPG journals * PubMed * Google Scholar * Rafn Benediktsson Search for this author in: * NPG journals * PubMed * Google Scholar * Amanda J Bennett Search for this author in: * NPG journals * PubMed * Google Scholar * Roza Blagieva Search for this author in: * NPG journals * PubMed * Google Scholar * Eric Boerwinkle Search for this author in: * NPG journals * PubMed * Google Scholar * Lori L Bonnycastle Search for this author in: * NPG journals * PubMed * Google Scholar * Kristina Bengtsson Boström Search for this author in: * NPG journals * PubMed * Google Scholar * Bert Bravenboer Search for this author in: * NPG journals * PubMed * Google Scholar * Suzannah Bumpstead Search for this author in: * NPG journals * PubMed * Google Scholar * Noisël P Burtt Search for this author in: * NPG journals * PubMed * Google Scholar * Guillaume Charpentier Search for this author in: * NPG journals * PubMed * Google Scholar * Peter S Chines Search for this author in: * NPG journals * PubMed * Google Scholar * Marilyn Cornelis Search for this author in: * NPG journals * PubMed * Google Scholar * David J Couper Search for this author in: * NPG journals * PubMed * Google Scholar * Gabe Crawford Search for this author in: * NPG journals * PubMed * Google Scholar * Alex S F Doney Search for this author in: * NPG journals * PubMed * Google Scholar * Katherine S Elliott Search for this author in: * NPG journals * PubMed * Google Scholar * Amanda L Elliott Search for this author in: * NPG journals * PubMed * Google Scholar * Michael R Erdos Search for this author in: * NPG journals * PubMed * Google Scholar * Caroline S Fox Search for this author in: * NPG journals * PubMed * Google Scholar * Christopher S Franklin Search for this author in: * NPG journals * PubMed * Google Scholar * Martha Ganser Search for this author in: * NPG journals * PubMed * Google Scholar * Christian Gieger Search for this author in: * NPG journals * PubMed * Google Scholar * Niels Grarup Search for this author in: * NPG journals * PubMed * Google Scholar * Todd Green Search for this author in: * NPG journals * PubMed * Google Scholar * Simon Griffin Search for this author in: * NPG journals * PubMed * Google Scholar * Christopher J Groves Search for this author in: * NPG journals * PubMed * Google Scholar * Candace Guiducci Search for this author in: * NPG journals * PubMed * Google Scholar * Samy Hadjadj Search for this author in: * NPG journals * PubMed * Google Scholar * Neelam Hassanali Search for this author in: * NPG journals * PubMed * Google Scholar * Christian Herder Search for this author in: * NPG journals * PubMed * Google Scholar * Bo Isomaa Search for this author in: * NPG journals * PubMed * Google Scholar * Anne U Jackson Search for this author in: * NPG journals * PubMed * Google Scholar * Paul R V Johnson Search for this author in: * NPG journals * PubMed * Google Scholar * Torben Jørgensen Search for this author in: * NPG journals * PubMed * Google Scholar * Wen H L Kao Search for this author in: * NPG journals * PubMed * Google Scholar * Norman Klopp Search for this author in: * NPG journals * PubMed * Google Scholar * Augustine Kong Search for this author in: * NPG journals * PubMed * Google Scholar * Peter Kraft Search for this author in: * NPG journals * PubMed * Google Scholar * Johanna Kuusisto Search for this author in: * NPG journals * PubMed * Google Scholar * Torsten Lauritzen Search for this author in: * NPG journals * PubMed * Google Scholar * Man Li Search for this author in: * NPG journals * PubMed * Google Scholar * Aloysius Lieverse Search for this author in: * NPG journals * PubMed * Google Scholar * Cecilia M Lindgren Search for this author in: * NPG journals * PubMed * Google Scholar * Valeriya Lyssenko Search for this author in: * NPG journals * PubMed * Google Scholar * Michel Marre Search for this author in: * NPG journals * PubMed * Google Scholar * Thomas Meitinger Search for this author in: * NPG journals * PubMed * Google Scholar * Kristian Midthjell Search for this author in: * NPG journals * PubMed * Google Scholar * Mario A Morken Search for this author in: * NPG journals * PubMed * Google Scholar * Narisu Narisu Search for this author in: * NPG journals * PubMed * Google Scholar * Peter Nilsson Search for this author in: * NPG journals * PubMed * Google Scholar * Katharine R Owen Search for this author in: * NPG journals * PubMed * Google Scholar * Felicity Payne Search for this author in: * NPG journals * PubMed * Google Scholar * John R B Perry Search for this author in: * NPG journals * PubMed * Google Scholar * Ann-Kristin Petersen Search for this author in: * NPG journals * PubMed * Google Scholar * Carl Platou Search for this author in: * NPG journals * PubMed * Google Scholar * Christine Proença Search for this author in: * NPG journals * PubMed * Google Scholar * Inga Prokopenko Search for this author in: * NPG journals * PubMed * Google Scholar * Wolfgang Rathmann Search for this author in: * NPG journals * PubMed * Google Scholar * N William Rayner Search for this author in: * NPG journals * PubMed * Google Scholar * Neil R Robertson Search for this author in: * NPG journals * PubMed * Google Scholar * Ghislain Rocheleau Search for this author in: * NPG journals * PubMed * Google Scholar * Michael Roden Search for this author in: * NPG journals * PubMed * Google Scholar * Michael J Sampson Search for this author in: * NPG journals * PubMed * Google Scholar * Richa Saxena Search for this author in: * NPG journals * PubMed * Google Scholar * Beverley M Shields Search for this author in: * NPG journals * PubMed * Google Scholar * Peter Shrader Search for this author in: * NPG journals * PubMed * Google Scholar * Gunnar Sigurdsson Search for this author in: * NPG journals * PubMed * Google Scholar * Thomas Sparsø Search for this author in: * NPG journals * PubMed * Google Scholar * Klaus Strassburger Search for this author in: * NPG journals * PubMed * Google Scholar * Heather M Stringham Search for this author in: * NPG journals * PubMed * Google Scholar * Qi Sun Search for this author in: * NPG journals * PubMed * Google Scholar * Amy J Swift Search for this author in: * NPG journals * PubMed * Google Scholar * Barbara Thorand Search for this author in: * NPG journals * PubMed * Google Scholar * Jean Tichet Search for this author in: * NPG journals * PubMed * Google Scholar * Tiinamaija Tuomi Search for this author in: * NPG journals * PubMed * Google Scholar * Rob M van Dam Search for this author in: * NPG journals * PubMed * Google Scholar * Timon W van Haeften Search for this author in: * NPG journals * PubMed * Google Scholar * Thijs van Herpt Search for this author in: * NPG journals * PubMed * Google Scholar * Jana V van Vliet-Ostaptchouk Search for this author in: * NPG journals * PubMed * Google Scholar * G Bragi Walters Search for this author in: * NPG journals * PubMed * Google Scholar * Michael N Weedon Search for this author in: * NPG journals * PubMed * Google Scholar * Cisca Wijmenga Search for this author in: * NPG journals * PubMed * Google Scholar * Jacqueline Witteman Search for this author in: * NPG journals * PubMed * Google Scholar * The MAGIC investigators Search for this author in: * NPG journals * PubMed * Google Scholar * The GIANT Consortium Search for this author in: * NPG journals * PubMed * Google Scholar * Richard N Bergman Search for this author in: * NPG journals * PubMed * Google Scholar * Stephane Cauchi Search for this author in: * NPG journals * PubMed * Google Scholar * Francis S Collins Search for this author in: * NPG journals * PubMed * Google Scholar * Anna L Gloyn 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