Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2018-04-09

AUTHORS

Anubha Mahajan, Jennifer Wessel, Sara M Willems, Wei Zhao, Neil R Robertson, Audrey Y Chu, Wei Gan, Hidetoshi Kitajima, Daniel Taliun, N William Rayner, Xiuqing Guo, Yingchang Lu, Man Li, Richard A Jensen, Yao Hu, Shaofeng Huo, Kurt K Lohman, Weihua Zhang, James P Cook, Bram Peter Prins, Jason Flannick, Niels Grarup, Vassily Vladimirovich Trubetskoy, Jasmina Kravic, Young Jin Kim, Denis V Rybin, Hanieh Yaghootkar, Martina Müller-Nurasyid, Karina Meidtner, Ruifang Li-Gao, Tibor V Varga, Jonathan Marten, Jin Li, Albert Vernon Smith, Ping An, Symen Ligthart, Stefan Gustafsson, Giovanni Malerba, Ayse Demirkan, Juan Fernandez Tajes, Valgerdur Steinthorsdottir, Matthias Wuttke, Cécile Lecoeur, Michael Preuss, Lawrence F Bielak, Marielisa Graff, Heather M Highland, Anne E Justice, Dajiang J Liu, Eirini Marouli, Gina Marie Peloso, Helen R Warren, , , , Saima Afaq, Shoaib Afzal, Emma Ahlqvist, Peter Almgren, Najaf Amin, Lia B Bang, Alain G Bertoni, Cristina Bombieri, Jette Bork-Jensen, Ivan Brandslund, Jennifer A Brody, Noël P Burtt, Mickaël Canouil, Yii-Der I da Chen, Yoon Shin Cho, Cramer Christensen, Sophie V Eastwood, Kai-Uwe Eckardt, Krista Fischer, Giovanni Gambaro, Vilmantas Giedraitis, Megan L Grove, Hugoline G de Haan, Sophie Hackinger, Yang Hai, Sohee Han, Anne Tybjærg-Hansen, Marie-France Hivert, Bo Isomaa, Susanne Jäger, Marit E Jørgensen, Torben Jørgensen, Annemari Käräjämäki, Bong-Jo Kim, Sung Soo Kim, Heikki A Koistinen, Peter Kovacs, Jennifer Kriebel, Florian Kronenberg, Kristi Läll, Leslie A Lange, Jung-Jin Lee, Benjamin Lehne, Huaixing Li, Keng-Hung Lin, Allan Linneberg, Ching-Ti Liu, Jun Liu, Marie Loh, Reedik Mägi, Vasiliki Mamakou, Roberta McKean-Cowdin, Girish Nadkarni, Matt Neville, Sune F Nielsen, Ioanna Ntalla, Patricia A Peyser, Wolfgang Rathmann, Kenneth Rice, Stephen S Rich, Line Rode, Olov Rolandsson, Sebastian Schönherr, Elizabeth Selvin, Kerrin S Small, Alena Stančáková, Praveen Surendran, Kent D Taylor, Tanya M Teslovich, Barbara Thorand, Gudmar Thorleifsson, Adrienne Tin, Anke Tönjes, Anette Varbo, Daniel R Witte, Andrew R Wood, Pranav Yajnik, Jie Yao, Loïc Yengo, Robin Young, Philippe Amouyel, Heiner Boeing, Eric Boerwinkle, Erwin P Bottinger, Rajiv Chowdhury, Francis S Collins, George Dedoussis, Abbas Dehghan, Panos Deloukas, Marco M Ferrario, Jean Ferrières, Jose C Florez, Philippe Frossard, Vilmundur Gudnason, Tamara B Harris, Susan R Heckbert, Joanna M M Howson, Martin Ingelsson, Sekar Kathiresan, Frank Kee, Johanna Kuusisto, Claudia Langenberg, Lenore J Launer, Cecilia M Lindgren, Satu Männistö, Thomas Meitinger, Olle Melander, Karen L Mohlke, Marie Moitry, Andrew D Morris, Alison D Murray, Renée de Mutsert, Marju Orho-Melander, Katharine R Owen, Markus Perola, Annette Peters, Michael A Province, Asif Rasheed, Paul M Ridker, Fernando Rivadineira, Frits R Rosendaal, Anders H Rosengren, Veikko Salomaa, Wayne H -H Sheu, Rob Sladek, Blair H Smith, Konstantin Strauch, André G Uitterlinden, Rohit Varma, Cristen J Willer, Matthias Blüher, Adam S Butterworth, John Campbell Chambers, Daniel I Chasman, John Danesh, Cornelia van Duijn, Josée Dupuis, Oscar H Franco, Paul W Franks, Philippe Froguel, Harald Grallert, Leif Groop, Bok-Ghee Han, Torben Hansen, Andrew T Hattersley, Caroline Hayward, Erik Ingelsson, Sharon LR Kardia, Fredrik Karpe, Jaspal Singh Kooner, Anna Köttgen, Kari Kuulasmaa, Markku Laakso, Xu Lin, Lars Lind, Yongmei Liu, Ruth J F Loos, Jonathan Marchini, Andres Metspalu, Dennis Mook-Kanamori, Børge G Nordestgaard, Colin N A Palmer, James S Pankow, Oluf Pedersen, Bruce M Psaty, Rainer Rauramaa, Naveed Sattar, Matthias B Schulze, Nicole Soranzo, Timothy D Spector, Kari Stefansson, Michael Stumvoll, Unnur Thorsteinsdottir, Tiinamaija Tuomi, Jaakko Tuomilehto, Nicholas J Wareham, James G Wilson, Eleftheria Zeggini, Robert A Scott, Inês Barroso, Timothy M Frayling, Mark O Goodarzi, James B Meigs, Michael Boehnke, Danish Saleheen, Andrew P Morris, Jerome I Rotter, Mark I McCarthy

ABSTRACT

We aggregated coding variant data for 81,412 type 2 diabetes cases and 370,832 controls of diverse ancestry, identifying 40 coding variant association signals (P < 2.2 × 10-7); of these, 16 map outside known risk-associated loci. We make two important observations. First, only five of these signals are driven by low-frequency variants: even for these, effect sizes are modest (odds ratio ≤1.29). Second, when we used large-scale genome-wide association data to fine-map the associated variants in their regional context, accounting for the global enrichment of complex trait associations in coding sequence, compelling evidence for coding variant causality was obtained for only 16 signals. At 13 others, the associated coding variants clearly represent 'false leads' with potential to generate erroneous mechanistic inference. Coding variant associations offer a direct route to biological insight for complex diseases and identification of validated therapeutic targets; however, appropriate mechanistic inference requires careful specification of their causal contribution to disease predisposition. More... »

PAGES

559-571

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  • Journal

    TITLE

    Nature Genetics

    ISSUE

    4

    VOLUME

    50

    Author Affiliations

  • Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7BN, UK
  • Departments of Epidemiology and Medicine, Diabetes Translational Research Center, Indiana University, Indianapolis, IN, 46202-2872, USA
  • MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, CB2 0QQ, UK
  • Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania, 19104, USA
  • Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 7LE, UK
  • Division of Preventive Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, 02215, USA
  • Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, 48109, USA
  • Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire, CB10 1SA, UK
  • Department of Pediatrics, The Institute for Translational Genomics and Population Sciences, LABioMed at Harbor-UCLA Medical Center, Torrance, California, 90502, US
  • The Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai, New York, 10029, USA
  • Division of Nephrology and Hypertension, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah, 84132, US
  • Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, 98101, USA
  • Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of the Chinese Academy of Sciences, Shanghai, People’s Republic of China
  • Department of Biostatistical Sciences, Division of Public Health Sciences, Wake Forest University Health Sciences, Winston Salem, North Carolina, 27157, USA
  • Department of Cardiology, Ealing Hospital, London North West Healthcare NHS Trust, Middlesex, UB1 3HW, UK
  • Department of Biostatistics, University of Liverpool, Liverpool, L69 3GA, UK
  • Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts, 02114, USA
  • The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, 2200, Denmark
  • Department of Clinical Sciences, Diabetes and Endocrinology, Lund University Diabetes Centre, Malmö, 20502, Sweden
  • Center for Genome Science, Korea National Institute of Health, Chungcheongbuk-do, Republic of Korea
  • Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, 02118, USA
  • Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, EX1 2LU, UK
  • DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, 81675, Germany
  • German Center for Diabetes Research (DZD), Neuherberg, 85764, Germany
  • Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, 2300 RC, The Netherlands
  • Department of Clinical Sciences, Lund University Diabetes Centre, Genetic and Molecular Epidemiology Unit, Lund University, Malmö, SE-214 28, Sweden
  • MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, EH4 2XU, UK
  • Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Palo Alto, CA, 94304, US
  • Faculty of Medicine, University of Iceland, Reykjavik, 101, Iceland
  • Department of Genetics Division of Statistical Genomics, Washington University School of Medicine, St. Louis, Missouri, 63110, USA
  • Department of Epidemiology, Erasmus University Medical Center, Rotterdam, 3015CN, The Netherlands
  • Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, 75185, Sweden
  • Section of Biology and Genetics, Department of Neurosciences, Biomedicine and Movement sciences, University of Verona, Verona, 37134, Italy
  • Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands
  • deCODE Genetics, Amgen inc., Reykjavik, 101, Iceland
  • Institute of Genetic Epidemiology, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, 79106, Germany
  • CNRS-UMR8199, Lille University, Lille Pasteur Institute, Lille, 59000, France
  • Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, Michigan, 48109, USA
  • Department of Epidemiology, University of North Carolina, Chapel Hill, NC, 27514, USA
  • Human Genetics Center, The University of Texas Graduate School of Biomedical Sciences at Houston, The University of Texas Health Science Center at Houston, Houston, Texas, 77030, USA
  • Department of Public Health Sciences, Institute of Personalized Medicine, Penn State College of Medicine, Hershey, PA, USA
  • William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
  • National Institute for Health Research, Barts Cardiovascular Biomedical Research Unit, Queen Mary University of London, London, London, EC1M 6BQ, UK
  • Department of Epidemiology and Biostatistics, Imperial College London, London, W2 1PG, UK
  • Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
  • Department of Clinical Sciences, Hypertension and Cardiovascular Disease, Lund University, Malmö, 20502, Sweden
  • Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, 2100, Denmark
  • Department of Epidemiology & Prevention, Public Health Sciences, Wake Forest University Health Sciences, Winston-Salem, NC, 27157-1063, USA
  • Department of Clinical Biochemistry, Vejle Hospital, Vejle, 7100, Denmark
  • Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, 02142, USA
  • Department of Biomedical Science, Hallym University, Chuncheon, Republic of Korea
  • Medical Department, Lillebælt Hospital Vejle, Vejle, Denmark
  • Institute of Cardiovascular Science, University College London, London, WC1E 6BT
  • Department of Nephrology and Medical Intensive Care Charité, University Medicine Berlin, Berlin, 10117, Germany
  • Estonian Genome Center, University of Tartu, Tartu, 51010, Estonia
  • Università Cattolica del Sacro Cuore, Roma, 00168, Italy
  • Department of Public Health and Caring Sciences, Geriatrics, Uppsala University, Uppsala, SE-751 85, Sweden
  • Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, Texas, USA
  • Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Copenhagen, 2100, Denmark
  • Department of Medicine, Universite de Sherbrooke, Sherbrooke, QC, J1K 2R1, Canada
  • Folkhälsan Research Centre, Helsinki, 00014, Finland
  • National Institute of Public Health, Southern Denmark University, Copenhagen, 1353, Denmark
  • Faculty of Medicine, Aalborg University, Aalborg, Denmark
  • Diabetes Center, Vaasa Health Care Center, Vaasa, Finland
  • Department of Medicine, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland
  • Integrated Research and Treatment (IFB) Center Adiposity Diseases, University of Leipzig, Leipzig, 04103, Germany
  • Research Unit of Molecular Epidemiology, Institute of Epidemiology II, Helmholtz Zentrum München Research Center for Environmental Health, Neuherberg, 85764, Germany
  • Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, 6020, Austria
  • Institute of Mathematical Statistics, University of Tartu, Tartu, Estonia
  • Department of Medicine, Division of Bioinformatics and Personalized Medicine, University of Colorado Denver, Aurora, CO, USA, 80045
  • Department of Ophthalmology, Taichung Veterans General Hospital, Taichung, 40705, Taiwan
  • Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
  • Translational Laboratory in Genetic Medicine (TLGM), Agency for Science, Technology and Research (A, *, STAR), Singapore, 138648, Singapore
  • Dromokaiteio Psychiatric Hospital, National and Kapodistrian University of Athens, Athens, Greece
  • Department of Preventive Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, California, 90007, US
  • Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, 10069, USA
  • Oxford NIHR Biomedical Research Centre, Oxford University Hospitals Trust, Oxford, OX3 7LE, UK
  • Institute for Biometrics and Epidemiology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany
  • Department of Biostatistics, University of Washington, Seattle, WA, 98195-7232, USA
  • Center for Public Health Genomics, Department Public Health Sciences, University of Virginia School of Medicine, Charlottesville, Virginia, 22908, US
  • The Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, DK-2730, Denmark
  • Department of Public Health and Clinical Medicine, Umeå University, Umeå, 90187, Sweden
  • Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, 21205, US
  • Department of Twin Research and Genetic Epidemiology, King’s College London, London, SE1 7EH, UK
  • Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, 70210, Finland
  • MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, CB1 8RN, UK
  • Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, 85764, Germany
  • Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
  • Department of Medicine, University of Leipzig, Leipzig, 04103, Germany
  • Danish Diabetes Academy, Odense, Denmark
  • Robertson Centre for Biostatistics, University of Glasgow, Glasgow, UK
  • Institut Pasteur de Lille, INSERM U1167, Université Lille Nord de France, Lille, F-59000, France
  • Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), Nuthetal, 14558, Germany
  • Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, 77030, US
  • Department of Public Health and Primary Care, University of Cambridge, Cambridge, CB1 8RN, UK
  • Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, 20892, USA
  • Department of Nutrition and Dietetics, Harokopio University of Athens, Athens, 17671, Greece
  • MRC-PHE Centre for Environment and Health, Imperial College London, London, W2 1PG, UK
  • Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah, 21589, Saudi Arabia
  • Research Centre on Epidemiology and Preventive Medicine (EPIMED), Department of Medicine and Surgery, University of Insubria, Varese, 2100, Italy
  • Department of Cardiology, Toulouse University School of Medicine, Rangueil Hospital, Toulouse, 31059, France
  • Department of Medicine, Harvard Medical School, Boston, Massachusetts, 02115, USA
  • Center for Non-Communicable Diseases, Karachi, Pakistan
  • Laboratory of Epidemiology and Population Sciences, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA
  • Department of Epidemiology, Cardiovascular Health Research Unit, University of Washington, Seattle, WA, 98195, USA
  • Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA
  • UKCRC Centre of Excellence for Public Health (NI), Queens University of Belfast, Northern Ireland, BT7 1NN, UK
  • Big Data Institute, Li Ka Shing Centre For Health Information and Discovery, University of Oxford, Oxford, OX37BN, UK
  • National Institute for Health and Welfare, Helsinki, 00271, Finland
  • Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, 85764, Germany
  • Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, 27599, USA
  • Department of Public Health, University Hospital of Strasbourg, Strasbourg, F-67081, France
  • The Usher Institute to the Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, EH16 4UX, UK
  • Aberdeen Biomedical Imaging Centre, School of Medicine Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, AB25 2ZD, UK
  • Department of Clinical Sciences, Diabetes and Cardiovascular Disease, Genetic Epidemiology, Lund University, Malmö, 20502, Sweden
  • Finnish Institute for Molecular Medicine (FIMM), University of Helsinki, Helsinki, Finland
  • Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, 3015CN, The Netherlands
  • Department of Internal Medicine, Taichung Veterans General Hospital, Taichung Taiwan, National Yang-Ming University, School of Medicine, Taipei, Taiwan, National Defense Medical Center, School of Medicine, Taipei, Taiwan, Taichung, 40705, Taiwan
  • Division of Endocrinology and Metabolism, Department of Medicine, McGill University, Montreal, Quebec, H3A 1A1, Canada
  • Division of Population Health Sciences, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, UK
  • Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität, Munich, 80802, Germany
  • USC Roski Eye Institute, Department of Ophthalmology, Keck School of Medicine of the University of Southern California, Los Angeles, California, 90033, US
  • Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, 48109, USA
  • NIHR Blood and Transplant Research Unit in Donor Health and Genomics, Department of Public Health and Primary Care, University of Cambridge, Cambridge, CB1 8RN, UK
  • Imperial College Healthcare NHS Trust, Imperial College London, London, W12 0HS, UK
  • British Heart Foundation, Cambridge Centre of Excellence, Department of Medicine, University of Cambridge, Cambridge, CB2 0QQ, UK
  • Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, 02115, USA
  • Department of Genomics of Common Disease, School of Public Health, Imperial College London, London, W12 0NN, UK
  • Clinical Cooparation Group Nutrigenomics and Type 2 Diabetes, Helmholtz Zentrum München, Technical University Munich, Germany
  • Faculty of Health Sciences, University of Southern Denmark, Odense, 5000, Denmark
  • University of Exeter Medical School, University of Exeter, Exeter, EX2 5DW, UK
  • Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, 94305, US
  • National Heart and Lung Institute, Cardiovascular Sciences, Hammersmith Campus, Imperial College London, London, W12 0NN, UK
  • Department of Medical Sciences, Uppsala University, Uppsala, SE-751 85, Sweden
  • Mindich Child Health and Development Institute, The Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
  • Department of Statistics, University of Oxford, Oxford, OX1 3TG, UK
  • Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, 2300 RC, The Netherlands
  • Pat Macpherson Centre for Pharmacogenetics and Pharmacogenomics, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, UK
  • Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN, 55454, US
  • Kaiser Permanent Washington Health Research Institute, Seattle, WA, 98101, USA
  • Foundation for Research in Health, Exercise and Nutrition, Kuopio Research Institute of Exercise Medicine, Kuopio, Finland
  • Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, G12 8TA, UK
  • Department of Hematology, School of Clinical Medicine, University of Cambridge, Cambridge, CB2 0AH
  • Divisions of Endocrinology and Nephrology, University Hospital Leipzig, Liebigstgr. 18, Leipzig, 04103, Germany
  • Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland
  • Diabetes Research Group, King Abdulaziz University, Jeddah, 21589, Saudi Arabia
  • Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi, 39216, USA
  • Metabolic Research Laboratories, Wellcome Trust – MRC Institute of Metabolic Science, University of Cambridge, Cambridge, CB22 0QQ, UK
  • Division of Endocrinology, Diabetes and Metabolism, Cedars-Sinai Medical Center, Los Angeles, CA, 90048
  • General Medicine Division, Massachusetts General Hospital and Department of Medicine, Harvard Medical School, Boston, Massachusetts, 02114, USA
  • Departments of Pediatrics and Medicine, The Institute for Translational Genomics and Population Sciences, LABioMed at Harbor-UCLA Medical Center, Torrance, California, 90502, US
  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/s41588-018-0084-1

    DOI

    http://dx.doi.org/10.1038/s41588-018-0084-1

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1103192964

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/29632382


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    51 schema:description We aggregated coding variant data for 81,412 type 2 diabetes cases and 370,832 controls of diverse ancestry, identifying 40 coding variant association signals (P &lt; 2.2 × 10<sup>-7</sup>); of these, 16 map outside known risk-associated loci. We make two important observations. First, only five of these signals are driven by low-frequency variants: even for these, effect sizes are modest (odds ratio ≤1.29). Second, when we used large-scale genome-wide association data to fine-map the associated variants in their regional context, accounting for the global enrichment of complex trait associations in coding sequence, compelling evidence for coding variant causality was obtained for only 16 signals. At 13 others, the associated coding variants clearly represent 'false leads' with potential to generate erroneous mechanistic inference. Coding variant associations offer a direct route to biological insight for complex diseases and identification of validated therapeutic targets; however, appropriate mechanistic inference requires careful specification of their causal contribution to disease predisposition.
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    61 association
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