ABSTRACT The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated.

Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of the heritability of this

disease. Here, to test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole-genome sequencing in 2,657 European

individuals with and without diabetes, and exome sequencing in 12,940 individuals from five ancestry groups. To increase statistical power, we expanded the sample size via genotyping and

large-scale sequencing does not support the idea that lower-frequency variants have a major role in predisposition to type 2 diabetes. Access through your institution Buy or subscribe This

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GENETIC STUDY OF TYPE 2 DIABETES HIGHLIGHTS THE POWER OF DIVERSE POPULATIONS FOR DISCOVERY AND TRANSLATION Article 12 May 2022 GENOME-WIDE ASSOCIATION ANALYSES HIGHLIGHT ETIOLOGICAL

DIFFERENCES UNDERLYING NEWLY DEFINED SUBTYPES OF DIABETES Article 04 November 2021 RARE VARIANT ANALYSES IN 51,256 TYPE 2 DIABETES CASES AND 370,487 CONTROLS REVEAL THE PATHOGENICITY

SPECTRUM OF MONOGENIC DIABETES GENES Article Open access 08 October 2024 ACCESSION CODES DATA DEPOSITS Whole-genome sequence data from the GoT2D project are available by application to the

European Genome-Phenome Archive (https://www.ebi.ac.uk/ega/home) under accession number EGAS00001001459 and from dbGAP (http://www.ncbi.nlm.nih.gov/gap) under accession number

phs000840.v1.p1. Whole-exome sequence data from the T2D-GENES project are available from the European Genome-Phenome Archive (https://www.ebi.ac.uk/ega/home) under accession number

EGAS00001001460 and from dbGAP (http://www.ncbi.nlm.nih.gov/gap) under accession numbers phs000847.v1.p1, phs001093.v1.p1, phs001095.v1.p1, phs001096.v1.p1, phs001097.v1.p1, phs001098.v1.p1,

phs001099.v1.p1, phs001100.v1.p1 and phs001102.v1.p1. Summary-level data from the exome array component of this project (and from the exome and genome sequences) can be freely accessed at

the Accelerating Medicines Partnership T2D portal (http://www.type2diabetesgenetics.org), and similar data from the GoT2D-imputed data at http://www.diagram-consortium.org. REFERENCES *

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references ACKNOWLEDGEMENTS Grant support and acknowledgments are listed in the Supplementary Information. AUTHOR INFORMATION Author notes * Clement Ma, Pierre Fontanillas, Loukas

Moutsianas, Xueling Sim, Adam E. Locke, Heather M. Highland, Cecilia M. Lindgren, Jeroen R. Huyghe, Eric R. Gamazon, Jinyan Huang, Aaron G. Day-Williams, Taylor J. Maxwell, Rector Arya, 

Marie Loh, Farook Thameem, Claes Ladenvall, Lu Qi, Kathleen Stirrups, Mark DePristo, Jaakko Tuomilehto, Dwaipayan Bharadwaj, Giriraj R. Chandak, Erik Ingelsson, Jong-Young Lee, Nancy J. Cox 

& David Altshuler Present address: † Present addresses are provided in the Supplementary Information., * Christian Fuchsberger, Jason Flannick, Tanya M. Teslovich, Anubha Mahajan,

Vineeta Agarwala and Kyle J. Gaulton: These authors contributed equally to this work. * Michael Boehnke, David Altshuler and Mark I. McCarthy: These authors jointly supervised this work. *

Hanna E. Abboud: Deceased. AUTHORS AND AFFILIATIONS * Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, USA Christian Fuchsberger,

 Tanya M. Teslovich, Clement Ma, Xueling Sim, Thomas W. Blackwell, Adam E. Locke, Anne U. Jackson, Jeroen R. Huyghe, Heather M. Stringham, Keng-Han Lin, Ryan P. Welch, Phoenix Kwan, Goo Jun,

 Goncalo Abecasis, Laura J. Scott, Hyun Min Kang & Michael Boehnke * Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical

University of Innsbruck, Innsbruck, Austria Christian Fuchsberger * Center for Biomedicine, European Academy of Bolzano/Bozen (EURAC), affiliated with the University of Lübeck, Bolzano,

Italy Christian Fuchsberger * Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA Jason Flannick, Vineeta Agarwala, Pierre Fontanillas, Cecilia M.

Lindgren, Christopher Hartl, Todd Green, Alisa Manning, Jason Carey, George Grant, Benjamin M. Neale, Shaun Purcell, Tõnu Esko, Mauricio O. Carneiro, Jared Maguire, Ryan Poplin, Khalid

Shakir, Timothy Fennell, Mark DePristo, Jacquelyn Murphy, Robert Onofrio, Eric Banks, Stacey Gabriel, Noël P. Burtt, Jose C. Florez & David Altshuler * Department of Molecular Biology,

Massachusetts General Hospital, Boston, Massachusetts, USA Jason Flannick & David Altshuler * Nuffield Department of Medicine, Wellcome Trust Centre for Human Genetics, University of

Oxford, Oxford, UK Anubha Mahajan, Kyle J. Gaulton, Loukas Moutsianas, Davis J. McCarthy, Manuel A. Rivas, John R. B. Perry, Neil R. Robertson, N. William Rayner, Juan Fernandez Tajes, 

Cecilia M. Lindgren, Martijn van de Bunt, Richard D. Pearson, Ashish Kumar, Yuhui Chen, Teresa Ferreira, Momoko Horikoshi, Erik Ingelsson, Inga Prokopenko, Anna L. Gloyn, Peter Donnelly, 

Gilean McVean, Andrew P. Morris & Mark I. McCarthy * Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA Vineeta

Agarwala * Department of Statistics, University of Oxford, Oxford, UK Davis J. McCarthy & Peter Donnelly * Genetics of Complex Traits, University of Exeter Medical School, University of

Exeter, Exeter, UK John R. B. Perry, Dorota Pasko, Andrew R. Wood & Timothy M. Frayling * MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK

John R. B. Perry, Robert A. Scott, Claudia Langenberg & Nicholas J. Wareham * Department of Twin Research and Genetic Epidemiology, King’s College London, London, UK John R. B. Perry, 

Massimo Mangino, Gabriela L. Surdulescu, Dylan Hodgkiss, Kerrin S. Small & Timothy D. Spector * Radcliffe Department of Medicine, Oxford Centre for Diabetes, Endocrinology and

Metabolism, University of Oxford, Oxford, UK Neil R. Robertson, N. William Rayner, Martijn van de Bunt, Nicola L. Beer, Momoko Horikoshi, Jonathan C. Levy, Christopher J. Groves, Matt

Neville, Fredrik Karpe, Inga Prokopenko, Katharine R. Owen, Anna L. Gloyn & Mark I. McCarthy * Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire, UK

N. William Rayner, Aaron G. Day-Williams, John Danesh, Kathleen Stirrups, Manjinder Sandhu, Inês Barroso & Eleftheria Zeggini * School of Computer Science, McGill University, Montreal,

Quebec, Canada Pablo Cingolani * McGill University and Génome Québec Innovation Centre, Montreal, Quebec, Canada Pablo Cingolani, Yoshihiko Nagai & Rob Sladek * 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, USA Heather M. Highland * Department of

Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA Josee Dupuis, Han Chen & Denis Rybin * National Heart, Lung, and Blood Institute's Framingham

Heart Study, Framingham, Massachusetts, USA Josee Dupuis * Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda,

Maryland, USA Peter S. Chines, Lori L. Bonnycastle, Narisu Narisu, Amy Swift & Francis S. Collins * Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts,

USA Han Chen & Liming Liang * Chronic Disease Epidemiology, Swiss Tropical and Public Health Institute, University of Basel, Basel, Switzerland Ashish Kumar * Institute of Genetic

Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany Martina Müller-Nurasyid, Janina S. Ried, Christian Gieger & Konstantin

Strauch * Department of Medicine I, University Hospital Grosshadern, Ludwig-Maximilians-Universität, Munich, Germany Martina Müller-Nurasyid * Institute of Medical Informatics, Biometry and

Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany Martina Müller-Nurasyid & Konstantin Strauch * DZHK (German Centre for Cardiovascular

Research), partner site Munich Heart Alliance, Munich, Germany Martina Müller-Nurasyid & Annette Peters * The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of

Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark Niels Grarup, Jette Bork-Jensen, Mette Hollensted, Johanne Marie Justesen, Anette P. Gjesing, Torben Hansen & 

Oluf Pedersen * Department of Medicine, Section of Genetic Medicine, The University of Chicago, Chicago, Illinois, USA Eric R. Gamazon, Hae Kyung Im & Nancy J. Cox * Department of

Statistics, Seoul National University, Seoul, South Korea Jaehoon Lee, Iksoo Huh, Yongkang Kim, Selyeong Lee & Taesung Park * Human Genetics Center, School of Public Health, The

University of Texas Health Science Center at Houston, Houston, Texas, USA Jennifer E. Below, Taylor J. Maxwell, Goo Jun & Craig L. Hanis * Saw Swee Hock School of Public Health, National

University of Singapore, National University Health System, Singapore Peng Chen, Xu Wang, Ching-Yu Cheng, Chiea-Chuen Khor, Wei Yen Lim, Jianjun Liu, Kee Seng Chia, Yik Ying Teo & E.

Shyong Tai * Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA Jinyan Huang, Frank B. Hu & Liming Liang * Center for Genome Science, Korea National

Institute of Health, Chungcheongbuk-do, South Korea Min Jin Go, Bong-Jo Kim, Young Jin Kim, Juyoung Lee, Bok-Ghee Han & Jong-Young Lee * The Jackson Laboratory for Genomic Medicine,

Farmington, Connecticut, USA Michael L. Stitzel * Departments of Computational Medicine & Bioinformatics and Human Genetics, University of Michigan, Ann Arbor, Michigan, USA Stephen C.

J. Parker * Department of Clinical Sciences, Lund University Diabetes Centre, Genetic and Molecular Epidemiology Unit, Lund University, Malmö, Sweden Tibor V. Varga & Paul W. Franks *

Department of Epidemiology, Colorado School of Public Health, University of Colorado, Aurora, Colorado, USA Tasha Fingerlin * Department of Endocrinology and Metabolism, Shanghai Diabetes

Institute, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China Cheng Hu & Weiping Jia * Singapore Eye Research Institute, Singapore National Eye

Centre, Singapore Mohammad Kamran Ikram, Tin Aung, Ching-Yu Cheng, Chiea-Chuen Khor & Tien Yin Wong * Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of

Singapore, National University Health System, Singapore Mohammad Kamran Ikram, Tin Aung, Ching-Yu Cheng, Chiea-Chuen Khor & Tien Yin Wong * The Eye Academic Clinical Programme, Duke-NUS

Graduate Medical School, Singapore Mohammad Kamran Ikram, Tin Aung, Ching-Yu Cheng & Tien Yin Wong * Interdisciplinary Program in Bioinformatics, Seoul National University, Seoul, South

Korea Min-Seok Kwon, Joon Yoon & Taesung Park * Department of Human Genetics, McGill University, Montreal, Quebec, Canada Yoshihiko Nagai & Rob Sladek * Research Institute of the

McGill University Health Centre, Montreal, Quebec, Canada Yoshihiko Nagai * Department of Epidemiology and Biostatistics, Imperial College London, London, UK Weihua Zhang, Uzma Afzal, 

Benjamin Lehne, Marie Loh, William R. Scott, Paul Elliott & John C. Chambers * Department of Cardiology, Ealing Hospital NHS Trust, Southall, Middlesex, UK Weihua Zhang, Sian-Tsung Tan, 

Jaspal Singh Kooner & John C. Chambers * Departments of Medicine and Genetics, Albert Einstein College of Medicine, New York, USA Nir Barzilai & Gil Atzmon * Department of Systems

Pharmacology and Translational Therapeutics, University of Pennsylvania - Perelman School of Medicine, Philadelphia, Pennsylvania, USA Benjamin F. Voight * Department of Genetics, University

of Pennsylvania - Perelman School of Medicine, Philadelphia, Pennsylvania, USA Benjamin F. Voight * Department of Medicine, University of Texas Health Science Center, San Antonio, Texas,

USA Christopher P. Jenkinson, Hanna E. Abboud, Sharon P. Fowler, Farook Thameem, Donna M. Lehman & Ralph A. DeFronzo * Research, South Texas Veterans Health Care System, San Antonio,

Texas, USA Christopher P. Jenkinson * Faculty of Health Sciences, Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, Kuopio, Finland Teemu Kuulasmaa, Johanna

Kuusisto, Alena Stančáková & Markku Laakso * Kuopio University Hospital, Kuopio, Finland Johanna Kuusisto & Markku Laakso * Center for Genomics and Personalized Medicine Research,

Wake Forest School of Medicine, Winston-Salem, North Carolina, USA Maggie C. Y. Ng, Nicholette D. Palmer, Pamela J. Hicks & Donald W. Bowden * Center for Diabetes Research, Wake Forest

School of Medicine, Winston-Salem, North Carolina, USA Maggie C. Y. Ng, Nicholette D. Palmer, Pamela J. Hicks & Donald W. Bowden * Department of Biochemistry, Wake Forest School of

Medicine, Winston-Salem, North Carolina, USA Nicholette D. Palmer, Pamela J. Hicks & Donald W. Bowden * Centre for Research in Epidemiology and Population Health, Inserm, U1018,

Villejuif, France Beverley Balkau * German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany Heiner Boeing * Department of Public Health and Caring Sciences, Geriatrics,

Uppsala University, Uppsala, Sweden Vilmantas Giedraitis & Lars Lannfelt * Centre for Chronic Disease Control, New Delhi, India Dorairaj Prabhakaran & Shah B. Ebrahim * The Charles

Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai, New York, USA Omri Gottesman, Yingchang Lu, Erwin P. Bottinger & Ruth J. F. Loos * National

Heart and Lung Institute, Cardiovascular Sciences, Hammersmith Campus, Imperial College London, London, UK James Scott, Sian-Tsung Tan & Jaspal Singh Kooner * Department of Genome

Sciences, University of Washington School of Medicine, Seattle, Washington, USA Joshua D. Smith * Department of Medicine, Analytic and Translational Genetics Unit, Massachusetts General

Hospital, Boston, Massachusetts, USA Benjamin M. Neale & Mark J. Daly * Department of Medicine, Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts,

USA Benjamin M. Neale, Shaun Purcell & Jose C. Florez * Department of Psychiatry, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York,

USA Shaun Purcell * Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK Adam S. Butterworth, Joanna M. M. Howson, John Danesh & Manjinder Sandhu *

Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China Heung Man Lee, Vincent K. L. Lam, Wing Yee So, Claudia H. T. Tam, Juliana C. N. Chan & 

Ronald C. W. Ma * Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea Soo-Heon Kwak & Kyong Soo Park * Department of Medicine, University

of Pennsylvania, Philadelphia, Pennsylvania, USA Wei Zhao * Department of Public Health and Primary Care, NIHR Blood and Transplant Research Unit in Donor Health and Genomics, University of

Cambridge, Cambridge, UK John Danesh * Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, and College of Medicine, Seoul

National University, Seoul, South Korea Kyong Soo Park * Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA Danish Saleheen * Center

for Non-Communicable Diseases, Karachi, Pakistan Danish Saleheen * Cardiovascular Division, Baylor College of Medicine, Houston, Texas, USA David Aguilar * Department of Pediatrics,

University of Texas Health Science Center, San Antonio, Texas, USA Rector Arya & Daniel Esten Hale * Department of Medicine, Yong Loo Lin School of Medicine, National University of

Singapore, National University Health System, Singapore Edmund Chan & E. Shyong Tai * Department of Epidemiology, Murcia Regional Health Council, IMIB-Arrixaca, Murcia, Spain Carmen

Navarro * CIBER Epidemiología y Salud Pública (CIBERESP), Universidad de Murcia, Murcia, Spain Carmen Navarro * Unit of Preventive Medicine and Public Health, School of Medicine, University

of Murcia, Spain Carmen Navarro * Cancer Research and Prevention Institute (ISPO), Florence, Italy Domenico Palli * Department of Medicine, University of Mississippi Medical Center, Jackson,

Mississippi, USA Adolfo Correa & Herman A. Taylor Jr. * South Texas Diabetes and Obesity Institute, Regional Academic Health Center, University of Texas Rio Grande Valley, Brownsville,

Texas, USA Joanne E. Curran, Satish Kumar & John Blangero * Department of Genetics, Texas Biomedical Research Institute, San Antonio, Texas, USA Vidya S. Farook, Sobha Puppala & 

Ravindranath Duggirala * Department of Internal Medicine, Section on Nephrology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA Barry I. Freedman * Center of

Biostatistics and Bioinformatics, University of Mississippi Medical Center, Jackson, Mississippi, USA Michael Griswold * Department of Paediatrics, Yong Loo Lin School of Medicine, National

University of Singapore, National University Health System, Singapore Chiea-Chuen Khor * Division of Human Genetics, Genome Institute of Singapore, A*STAR, Singapore Chiea-Chuen Khor & 

Jianjun Liu * CNRS-UMR8199, Lille University, Lille Pasteur Institute, Lille, France Dorothée Thuillier, Loïc Yengo & Philippe Froguel * Julius Center for Health Sciences and Primary

Care, University Medical Center Utrecht, Utrecht, Netherlands Yvonne T. van der Schouw * Institute of Health Sciences, University of Oulu, Oulu, Finland Marie Loh * Translational Laboratory

in Genetic Medicine (TLGM), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore Marie Loh * Jackson Heart Study, University of Mississippi Medical Center, Jackson,

Mississippi, USA Solomon K. Musani * College of Public Services, Jackson State University, Jackson, Mississippi, USA Gregory Wilson * Department of Clinical Science, KG Jebsen Center for

Diabetes Research, University of Bergen, Bergen, Norway Pål Rasmus Njølstad * Department of Pediatrics, Haukeland University Hospital, Bergen, Norway Pål Rasmus Njølstad * Institute of Human

Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany Thomas Schwarzmayr, Thomas Wieland, Tim M. Strom & Thomas Meitinger *

Department of Clinical Sciences, Diabetes and Endocrinology, Lund University Diabetes Centre, Malmö, Sweden João Fadista, Jasmina Kravic, Valeriya Lyssenko, Claes Ladenvall, Anders H.

Rosengren & Leif Groop * Institute of Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany Christian

Herder & Michael Roden * German Center for Diabetes Research (DZD), Neuherberg, Germany Christian Herder, Jennifer Kriebel, Michael Roden, Martin Hrabé de Angelis, Barbara Thorand, 

Christa Meisinger, Annette Peters, Cornelia Huth & Harald Grallert * Institute of Regional Health Research, University of Southern Denmark, Odense, Denmark Ivan Brandslund * Department

of Clinical Biochemistry, Vejle Hospital, Vejle, Denmark Ivan Brandslund * Department of Internal Medicine and Endocrinology, Vejle Hospital, Vejle, Denmark Cramer Christensen * Department

of Health, National Institute for Health and Welfare, Helsinki, Finland Heikki A. Koistinen, Leena Kinnunen & Jaakko Tuomilehto * Abdominal Center: Endocrinology, University of Helsinki

and Helsinki University Central Hospital, Helsinki, Finland Heikki A. Koistinen, Liisa Hakaste & Tiinamaija Tuomi * Minerva Foundation Institute for Medical Research, Helsinki, Finland

Heikki A. Koistinen * Department of Medicine, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland Heikki A. Koistinen * Division of Cardiovascular and Diabetes

Medicine, Medical Research Institute, Ninewells Hospital and Medical School, Dundee, UK Alex S. F. Doney * Estonian Genome Center, University of Tartu, Tartu, Estonia Tõnu Esko, Lili

Milani, Evelin Mihailov, Andres Metspalu, Reedik Mägi & Andrew P. Morris * Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA Tõnu Esko & David Altshuler *

Division of Endocrinology, Boston Children's Hospital, Boston, Massachusetts, USA Tõnu Esko * Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK

Andrew J. Farmer * Folkhälsan Research Centre, Helsinki, Finland Liisa Hakaste, Bo Isomaa & Tiinamaija Tuomi * Research Programs Unit, Diabetes and Obesity, University of Helsinki,

Helsinki, Finland Liisa Hakaste & Tiinamaija Tuomi * Steno Diabetes Center, Gentofte, Denmark Marit E. Jørgensen * Research Centre for Prevention and Health, Capital Region of Denmark,

Glostrup, Denmark Torben Jørgensen & Allan Linneberg * Department of Public Health, Institute of Health Sciences, University of Copenhagen, Copenhagen, Denmark Torben Jørgensen * Faculty

of Medicine, Aalborg University, Aalborg, Denmark Torben Jørgensen * Department of Primary Health Care, Vaasa Central Hospital, Vaasa, Finland Annemari Käräjämäki * Diabetes Center, Vaasa

Health Care Center, Vaasa, Finland Annemari Käräjämäki * Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany

Jennifer Kriebel, Barbara Thorand, Christa Meisinger, Annette Peters, Cornelia Huth, Harald Grallert & Christian Gieger * Research Unit of Molecular Epidemiology, Helmholtz Zentrum

München, German Research Center for Environmental Health, Neuherberg, Germany Jennifer Kriebel, Harald Grallert, Christian Gieger & Thomas Illig * Institute for Biometrics and

Epidemiology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany Wolfgang Rathmann * Department of Public Health, Section of

General Practice, Aarhus University, Aarhus, Denmark Torsten Lauritzen * Department of Clinical Experimental Research, Rigshospitalet, Glostrup, Denmark Allan Linneberg * Department of

Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark Allan Linneberg * Department of Clinical Sciences, Hypertension and Cardiovascular

Disease, Lund University, Malmö, Sweden Olle Melander * Oxford NIHR Biomedical Research Centre, Oxford University Hospitals Trust, Oxford, UK Matt Neville, Fredrik Karpe, Katharine R. Owen, 

Anna L. Gloyn & Mark I. McCarthy * Department of Clinical Sciences, Diabetes and Cardiovascular Disease, Genetic Epidemiology, Lund University, Malmö, Sweden Marju Orho-Melander *

Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA Lu Qi, Qibin Qi, Frank B. Hu & Paul W. Franks * Channing Division of Network Medicine, Department of

Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA Lu Qi * Department of Epidemiology and Population Health, Albert Einstein College of Medicine,

New York, USA Qibin Qi * Department of Endocrinology and Diabetology, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany Michael Roden * Department of Public Health and Clinical

Medicine, Umeå University, Umeå, Sweden Olov Rolandsson & Paul W. Franks * Nuffield Department of Medicine, High Throughput Genomics, Oxford Genomics Centre, Wellcome Trust Centre for

Human Genetics, University of Oxford, Oxford, UK Christine Blancher, Gemma Buck, Joseph Trakalo & David Buck * Institute of Experimental Genetics, Helmholtz Zentrum München, German

Research Center for Environmental Health, Neuherberg, Germany Martin Hrabé de Angelis * Center of Life and Food Sciences Weihenstephan, Technische Universität München,

Freising-Weihenstephan, Germany Martin Hrabé de Angelis * William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London,

UK Panos Deloukas * Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah, Saudi Arabia Panos Deloukas *

Department of Clinical Sciences, Medicine, Lund University, Malmö, Sweden Peter Nilsson * Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark Torben Hansen *

Department of Social Services and Health Care, Jakobstad, Finland Bo Isomaa * Metabolic Research Laboratories, Institute of Metabolic Science, University of Cambridge, Cambridge, UK Stephen

P. O’Rahilly & Inês Barroso * Pat Macpherson Centre for Pharmacogenetics and Pharmacogenomics, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK Colin N. A. Palmer

* Foundation for Research in Health, Exercise and Nutrition, Kuopio Research Institute of Exercise Medicine, Kuopio, Finland Rainer Rauramaa * Center for Vascular Prevention, Danube

University Krems, Krems, Austria Jaakko Tuomilehto * Diabetes Research Group, King Abdulaziz University, Jeddah, Saudi Arabia Jaakko Tuomilehto * Instituto de Investigacion Sanitaria del

Hospital Universario LaPaz (IdiPAZ), University Hospital LaPaz, Autonomous University of Madrid, Madrid, Spain Jaakko Tuomilehto * National Institute for Health and Welfare, Helsinki,

Finland Jaakko Tuomilehto & Veikko Salomaa * Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA Richard M.

Watanabe * Department of Physiology & Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California, USA Richard M. Watanabe * Diabetes and Obesity

Research Institute, Keck School of Medicine, University of Southern California, Los Angeles, California, USA Richard M. Watanabe * Department of Medical Sciences, Molecular Medicine and

Science for Life Laboratory, Uppsala University, Uppsala, Sweden Ann-Christine Syvänen * Cedars-Sinai Diabetes and Obesity Research Institute, Los Angeles, California, USA Richard N. Bergman

* Functional Genomics Unit, CSIR-Institute of Genomics & Integrative Biology (CSIR-IGIB), New Delhi, India Dwaipayan Bharadwaj * Department of Biomedical Science, Hallym University,

Chuncheon, South Korea Yoon Shin Cho * CSIR-Centre for Cellular and Molecular Biology, Hyderabad, Telangana, India Giriraj R. Chandak * Li Ka Shing Institute of Health Sciences, The Chinese

University of Hong Kong, Hong Kong, China Juliana C. N. Chan & Ronald C. W. Ma * Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Hong Kong, China

Juliana C. N. Chan & Ronald C. W. Ma * MRC-PHE Centre for Environment and Health, Imperial College London, London, UK Paul Elliott * The Biostatistics Center, The George Washington

University, Rockville, Maryland, USA Kathleen A. Jablonski * Department of Medicine, Division of Endocrinology, Diabetes and Nutrition, and Program in Personalized and Genomic Medicine,

University of Maryland School of Medicine, Baltimore, Maryland, USA Toni I. Pollin * Department of Endocrinology and Metabolism, All India Institute of Medical Sciences, New Delhi, India

Nikhil Tandon * Department of Genomics of Common Disease, School of Public Health, Imperial College London, London, UK Philippe Froguel & Inga Prokopenko * Life Sciences Institute,

National University of Singapore, Singapore Yik Ying Teo * Department of Statistics and Applied Probability, National University of Singapore, Singapore Yik Ying Teo * Endocrinology and

Metabolism Service, Hadassah-Hebrew University Medical Center, Jerusalem, Israel Benjamin Glaser * The Medical School, Institute of Cellular Medicine, Newcastle University, Newcastle, UK

Mark Walker * Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden Erik Ingelsson * Hannover Unified Biobank, Hannover

Medical School, Hanover, Germany Thomas Illig * Institute for Human Genetics, Hannover Medical School, Hanover, Germany Thomas Illig * Department of Medical Sciences, Uppsala University,

Uppsala, Sweden Lars Lind * Data Sciences and Data Engineering, Broad Institute, Cambridge, Massachusetts, USA Yossi Farjoun * Institute for Molecular Medicine Finland (FIMM), University of

Helsinki, Helsinki, Finland Tiinamaija Tuomi & Leif Groop * Imperial College Healthcare NHS Trust, Imperial College London, London, UK Jaspal Singh Kooner & John C. Chambers *

Clinical Research Centre, Centre for Molecular Medicine, Ninewells Hospital and Medical School, Dundee, UK Andrew D. Morris * The Usher Institute to the Population Health Sciences and

Informatics, University of Edinburgh, Edinburgh, UK Andrew D. Morris * University of Exeter Medical School, University of Exeter, Exeter, UK Andrew T. Hattersley * Department of Natural

Science, University of Haifa, Haifa, Israel Gil Atzmon * Institute of Human Genetics, Technische Universität München, Munich, Germany Tim M. Strom & Thomas Meitinger * Departments of

Medicine and Human Genetics, The University of Chicago, Chicago, Illinois, USA Graeme I. Bell * Cardiovascular & Metabolic Disorders Program, Duke-NUS Medical School Singapore, Singapore

E. Shyong Tai * Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, UK Gilean McVean * Department of Physiology and Biophysics, University of Mississippi

Medical Center, Jackson, Mississippi, USA James G. Wilson * Department of Laboratory Medicine & Institute for Human Genetics, University of California, San Francisco, San Francisco,

California, USA Mark Seielstad * Blood Systems Research Institute, San Francisco, California, USA Mark Seielstad * General Medicine Division, Massachusetts General Hospital and Department of

Medicine, Harvard Medical School, Boston, Massachusetts, USA James B. Meigs * Division of Endocrinology and Metabolism, Department of Medicine, McGill University, Montreal, Quebec, Canada

Rob Sladek * Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA Eric S. Lander * Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA Karen

L. Mohlke * Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA Jose C. Florez & David Altshuler * Department of Medicine, Diabetes Research Center (Diabetes

Unit), Massachusetts General Hospital, Boston, Massachusetts, USA Jose C. Florez & David Altshuler * Department of Biostatistics, University of Liverpool, Liverpool, UK Andrew P. Morris

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search for this author inPubMed Google Scholar CONTRIBUTIONS Author contributions are described in the Supplementary Information. CORRESPONDING AUTHORS Correspondence to Michael Boehnke or

Mark I. McCarthy. ETHICS DECLARATIONS COMPETING INTERESTS R.A.D. has been a member of advisory boards for Astra Zeneca, Novo Nordisk, Janssen, Lexicon and Boehringer-Ingelheim; received

research support from Bristol Myers Squibb, Boehringer- Ingelheim, Takeda and Astra Zeneca; and is a member of speakers’ bureaus for Novo-Nordisk and Astra Zeneca. J.C.F. has received

consulting honoraria from Pfizer and PanGenX. M.I.M. has received consulting and advisory board honoraria from Pfizer, Lilly, and NovoNordisk. G.M. and P.D. are co-founders of Genomics PLC,

which provides genome analytics. D.A. is an employee of and holds equity in Vertex Pharmaceuticals. EXTENDED DATA FIGURES AND TABLES EXTENDED DATA FIGURE 1 SUMMARY OF SAMPLES AND QUALITY

CONTROL PROCEDURES. This figure summarizes data generation for whole-genome sequencing (GoT2D), exome sequencing (GoT2D and T2D-GENES), exome array genotyping (DIAGRAM), and GWAS imputation

(DIAGRAM). EXTENDED DATA FIGURE 2 POWER FOR SINGLE AND AGGREGATE VARIANT ASSOCIATION. A–G, Power to detect single-variant association (_α_ = 5 × 10−8) at varying minor allele frequencies

(_x_-axis) and allelic ORs (_y_-axis) for seven effective sample size (_N_eff) scenarios relevant to the genomes (A–C) and exomes (D–G) components of this project. A, Variant observed in

2,657 samples (the effective size of the GoT2D integrated panel). B, Variant observed in 28,350 samples (the effective size of the imputed data set). C, Variant observed in the GoT2D

integrated panel and the imputed data set (effective sample size 31,007). D, Ancestry-specific variant in 2,000 samples (the size of each of the non-European exome sequence data sets). E,

European-specific variant in 5,000 samples (the combined size of the European exome sequence data sets). F, Variant observed with shared frequency across all ancestry groups in 12,940

samples (the size of the combined exome sequence data set). G, Variant observed in the combined exome array and sequencing data set (effective sample size 82,758). H, I, Power for gene-based

test of association (SKAT-O) according to liability variance explained. In H, 50% of the variants contribute to disease risk and the remaining 50% have no effect on disease risk; in I, 100%

of the variants contribute to disease risk. For each, sample sizes considered are 2,000 (ancestry-specific effects; green) and 12,940 (ancestry-shared effects; blue). Power is shown for two

levels of significance (_α_ = 2.5 × 10−6 and _α_ = 0.001). From these simulation studies, it is clear that under the optimistic model, where effects are shared across all ethnicities (blue

line) and all variants contribute, power is >60% for 1% variance explained and _α_ = 2.5 × 10−6. However, power declines rapidly if either criterion is relaxed. EXTENDED DATA FIGURE 3

SINGLE VARIANT ANALYSES. A–C, Manhattan plot of single-variant analyses generated from exome sequence data in 6,504 cases and 6,436 controls of African American, East Asian, European,

Hispanic, and South Asian ancestry (A); exome array genotypes in 28,305 cases and 51,549 controls of European ancestry (B); and combined meta-analysis of exome array and exome sequence

samples (C). Coding variants are categorized according to their relationships to the previously reported lead variant from GWAS region. Loci achieving genome-wide significance only in the

combined analysis are highlighted in bold. The _HNF1A_ variant reaching genome-wide significance in the combined analysis is a synonymous variant (Thr515Thr). The dashed horizontal line in

each panel designates the threshold for genome-wide significance (_P_ < 5 × 10−8). EXTENDED DATA FIGURE 4 CLASSIFICATION OF CODING VARIANTS ACCORDING TO THEIR RELATIONSHIP TO REPORTED

LEAD VARIANTS FOR EACH GWAS REGION. The ideogram shows the location of 25 coding variant associations at 16 loci described in the text. The number in each circle corresponds to the number of

associated variants at each locus. Variants are grouped into five categories based on inferred relationship with the GWAS lead variant. For some of these categories, the figure includes

representative regional association plots based on exome array meta-analysis data from 28,305 cases and 51,549 controls. The locus displayed for each category is designated in bold. The

first plot in each panel shows the unconditional association results; the middle plot the association results after conditioning on the non-coding GWAS SNP; and the last plot the results

after conditioning on the most significantly associated coding variant. Each point represents an SNP in the exome array meta-analysis, plotted with its _P_ value (on a –log10 scale) as a

function of the genomic position (hg19). In each panel, the lead coding variant is represented by the purple symbol. The colour-coding of all other SNPs indicates LD with the lead SNP

(estimated by European _r_2 from 1000G March 2012 reference panel: red _r_2 ≥ 0.8; gold 0.6 ≤ _r_2 < 0.8; green 0.4 ≤ _r_2 < 0.6; cyan 0.2 ≤ _r_2 < 0.4; blue _r_2 < 0.2; grey

_r_2 unknown). Gene annotations are taken from the University of California Santa Cruz genome browser. GWS: genome-wide significance. *Seven variants, three at _ASCC2,_ and one each at

_THADA_, _TSPAN8_, _FES_ and _HNF4A_ did not achieve genome-wide significance themselves, but are included because they fall into genes and/or regions with other significant association

signals (see text). EXTENDED DATA FIGURE 5 EXCLUSION OF SYNTHETIC ASSOCIATIONS AND CONSTRUCTION OF CREDIBLE CAUSAL VARIANT SETS AT T2D GWAS LOCI. Ten T2D GWAS loci were selected for

synthetic association testing (_P_ < 0.001; see Methods). A, The effect size observed at the GWAS index SNV (sequence data) before (navy blue) and after (light blue, grey) conditioning on

candidate rare and low-frequency (MAF <5%) variants which could produce synthetic association. B, Example of synthetic association exclusion at the _TCF7L2_ locus. Error bars represent

95% confidence intervals for the index SNP odds ratio as rare variants are greedily added to the model. C, The size of credible sets at T2D GWAS loci when constructed from the GoT2D data,

compared to the sizes when restricted to variants in the 1000G or HapMap data. EXTENDED DATA FIGURE 6 GENOME ENRICHMENT ANALYSIS IN GOT2D WHOLE GENOME SEQUENCE DATA. _n_ = 2,657. A,

Functional annotation categories were defined using transcription, chromatin state and transcription factor binding data from GENCODE, ENCODE and other studies. B, T2D association statistics

for variants at each T2D locus were jointly modelled with functional annotation using fgwas. In the resulting model we identified enrichment of coding exons (CDS), transcription factor

binding sites (TFBS), mature adipose active enhancers and promoters (hASC-t4 EnhA, TssA), pancreatic islet active and weak enhancers (HI EnhA, EnhWk), pre-adipose active and weak enhancers

(hASC-t1 EnhA, EnhWk), embryonic stem cell active promoters (H1-hESC TssA) and 5′UTRs. Dots represent enrichment estimates and horizontal lines the 95% confidence intervals. C, At the

_CCND2_ locus, three variants not present in HapMap2 have a combined 90% posterior probability of being causal (rs4238013, rs3217801, rs73040004). One of these variants, rs3217801, is a 2-bp

indel that overlaps an islet enhancer element. EXTENDED DATA FIGURE 7 LOW FREQUENCY VARIANTS IN EXOME ARRAY DATA. Results from meta-analysis of 43,045 low-frequency and common coding

variants on the exome array (assayed in 79,854 European subjects). A, Observed allelic ORs as a property of allele MAF. Variants missing in more than eight cohorts or polymorphic in only one

cohort were excluded. Coloured lines represent contours for liability variance explained. Regions shaded grey denote ranges of OR and MAF consistent with 80% power (in this case, at α = 5 ×

 10−7) to detect single-variant associations in this data set (given the observed range of missing data). Variants with a black collar are those highlighted by a bounding analysis as having

a probability >0.8 of having liability-scale variance (LVE) > 0.1%. B, Distribution of each variant in the MAF/OR space was computed by assuming T2D prevalence of 8% and a beta and

normal distribution for MAF and OR, respectively. Probability is obtained by integrating the joint MAF–OR distributions over ranges of LVE. C, Single variant association, liability and

bounding results for the known T2D GWAS variants on the exome array (see Methods). SUPPLEMENTARY INFORMATION SUPPLEMENTARY INFORMATION This file contains Supplementary Tables and Figures 1–

32 (see separate excel file for Supplementary Table 20) and Author contribution and acknowledgement lists. (PDF 23107 kb) SUPPLEMENTARY TABLE 20 This file contains an Overview of 634 genes

at 81 GWAS-identified T2D loci. (XLSX 77 kb) POWERPOINT SLIDES POWERPOINT SLIDE FOR FIG. 1 POWERPOINT SLIDE FOR FIG. 2 POWERPOINT SLIDE FOR FIG. 3 RIGHTS AND PERMISSIONS Reprints and

permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Fuchsberger, C., Flannick, J., Teslovich, T. _et al._ The genetic architecture of type 2 diabetes. _Nature_ 536, 41–47 (2016).

https://doi.org/10.1038/nature18642 Download citation * Received: 20 May 2015 * Accepted: 12 June 2016 * Published: 11 July 2016 * Issue Date: 04 August 2016 * DOI:

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