Abstract

Multi-nucleotide variants (MNVs), defined as two or more nearby variants existing on the same haplotype in an individual, are a clinically and biologically important class of genetic variation. However, existing tools typically do not accurately classify MNVs, and understanding of their mutational origins remains limited. Here, we systematically survey MNVs in 125,748 whole exomes and 15,708 whole genomes from the Genome Aggregation Database (gnomAD). We identify 1,792,248 MNVs across the genome with constituent variants falling within 2 bp distance of one another, including 18,756 variants with a novel combined effect on protein sequence. Finally, we estimate the relative impact of known mutational mechanisms - CpG deamination, replication error by polymerase zeta, and polymerase slippage at repeat junctions - on the generation of MNVs. Our results demonstrate the value of haplotype-aware variant annotation, and refine our understanding of genome-wide mutational mechanisms of MNVs.

Multi-nucleotide variants (MNV) are genetic variants in close proximity of each other on the same haplotype whose functional impact is difficult to predict if they reside in the same codon. Here, Wang et al. use the gnomAD dataset to assemble a catalogue of MNVs and estimate their global mutation rate.

Details

Title
Landscape of multi-nucleotide variants in 125,748 human exomes and 15,708 genomes
Author
Wang, Qingbo 1   VIAFID ORCID Logo  ; Pierce-Hoffman, Emma 2 ; Cummings, Beryl B 3 ; Alföldi Jessica 4   VIAFID ORCID Logo  ; Francioli Laurent C 4   VIAFID ORCID Logo  ; Gauthier, Laura D 5 ; Hill, Andrew J 6 ; O’Donnell-Luria Anne H 4   VIAFID ORCID Logo  ; Armean, Irina M 7 ; Banks, Eric 8 ; Bergelson, Louis 8 ; Cibulskis Kristian 8 ; Collins, Ryan L 9 ; Connolly, Kristen M 10 ; Covarrubias, Miguel 8 ; Daly, Mark J 11 ; Donnelly, Stacey 2 ; Farjoun Yossi 8 ; Ferriera, Steven 12 ; Gabriel, Stacey 12 ; Gentry, Jeff 8 ; Gupta, Namrata 13 ; Thibault, Jeandet 8 ; Kaplan, Diane 8 ; Laricchia, Kristen M 4 ; Llanwarne Christopher 8 ; Minikel, Eric V 2 ; Munshi Ruchi 8 ; Neale, Benjamin M 4 ; Novod Sam 8 ; Petrillo Nikelle 8 ; Poterba, Timothy 11 ; Roazen, David 8 ; Ruano-Rubio, Valentin 8 ; Saltzman, Andrea 2 ; Samocha, Kaitlin E 14 ; Schleicher, Molly 2 ; Seed Cotton 15 ; Solomonson, Matthew 4 ; Soto, Jose 8 ; Tiao Grace 4 ; Tibbetts, Kathleen 8 ; Tolonen, Charlotte 8 ; Vittal, Christopher 15 ; Wade, Gordon 8 ; Wang Arcturus 11 ; Ware, James S 16 ; Watts, Nicholas A 4 ; Weisburd, Ben 8 ; Whiffin Nicola 16 ; Aguilar Salinas Carlos A 17 ; Ahmad, Tariq 18 ; Albert, Christine M 19 ; Ardissino Diego 20 ; Atzmon Gil 21 ; Barnard, John 22 ; Beaugerie Laurent 23 ; Benjamin, Emelia J 24 ; Boehnke, Michael 25 ; Bonnycastle, Lori L 26 ; Bottinger, Erwin P 27 ; Bowden, Donald W 28 ; Bown, Matthew J 29 ; Chambers, John C 30 ; Chan, Juliana C 31 ; Chasman, Daniel 32 ; Cho, Judy 27 ; Chung, Mina K 33 ; Cohen, Bruce 34 ; Correa, Adolfo 35 ; Dabelea Dana 36 ; Darbar Dawood 37 ; Duggirala Ravindranath 38 ; Dupuis Josée 39 ; Ellinor, Patrick T 40 ; Elosua Roberto 41 ; Erdmann, Jeanette 42 ; Tõnu, Esko 43 ; Färkkilä Martti 44 ; Florez, Jose 45 ; Franke, Andre 46 ; Getz Gad 47 ; Glaser, Benjamin 48 ; Glatt, Stephen J 49 ; Goldstein, David 50 ; Gonzalez Clicerio 51 ; Groop Leif 52 ; Haiman, Christopher 53 ; Hanis Craig 54 ; Harms, Matthew 55 ; Hiltunen Mikko 56 ; Holi, Matti M 57 ; Hultman, Christina M 58 ; Kallela Mikko 59 ; Kaprio Jaakko 60 ; Sekar, Kathiresan 45 ; Bong-Jo, Kim 61 ; Kim Young Jin 61 ; Kirov, George 62 ; Kooner Jaspal 63 ; Koskinen Seppo 64 ; Krumholz, Harlan M 65 ; Kugathasan Subra 66 ; Kwak, Soo Heon 67 ; Laakso Markku 68 ; Lehtimäki Terho 69 ; Loos Ruth J F 70 ; Lubitz, Steven A 71 ; Ma Ronald C W 72 ; Marrugat Jaume 73 ; Mattila, Kari M 69 ; McCarroll, Steven 74 ; McCarthy, Mark I 75 ; McGovern, Dermot 76 ; McPherson, Ruth 77 ; Meigs, James B 78 ; Melander Olle 79 ; Metspalu Andres 80 ; Nilsson, Peter M 81 ; O’Donovan Michael C 62 ; Dost, Ongur 34 ; Orozco, Lorena 82 ; Owen, Michael J 62 ; Palmer Colin N A 83 ; Palotie Aarno 84 ; Park, Kyong Soo 85 ; Pato, Carlos 86 ; Pulver, Ann E 87 ; Rahman, Nazneen 88 ; Remes, Anne M 89 ; Rioux, John D 90 ; Ripatti Samuli 91 ; Roden, Dan M 92 ; Saleheen Danish 93 ; Salomaa Veikko 94 ; Samani, Nilesh J 29 ; Scharf, Jeremiah 95 ; Schunkert Heribert 96 ; Shoemaker, Moore B 97 ; Sklar, Pamela 98 ; Soininen Hilkka 99 ; Sokol, Harry 23 ; Spector, Tim 100 ; Sullivan, Patrick F 101 ; Suvisaari Jaana 94 ; Shyong, Tai E 102 ; Teo, Yik Ying 103 ; Tuomi, Tiinamaija 104 ; Tsuang Ming 105 ; Turner, Dan 106 ; Tusie-Luna Teresa 107 ; Vartiainen Erkki 108 ; Watkins, Hugh 109 ; Weersma, Rinse K 110 ; Wessman Maija 111 ; Wilson, James G 112 ; Xavier, Ramnik J 113 ; Vawter, Marquis P 114 ; Karczewski, Konrad J 4   VIAFID ORCID Logo  ; MacArthur, Daniel G 115   VIAFID ORCID Logo 

1  The Broad Institute of MIT and Harvard, Program in Medical and Population Genetics, Cambridge, USA (GRID:grid.66859.34); Massachusetts General Hospital, Analytic and Translational Genetics Unit, Boston, USA (GRID:grid.32224.35) (ISNI:0000 0004 0386 9924); Harvard Medical School, Program in Bioinformatics and Integrative Genomics, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X) 
2  The Broad Institute of MIT and Harvard, Program in Medical and Population Genetics, Cambridge, USA (GRID:grid.66859.34) 
3  The Broad Institute of MIT and Harvard, Program in Medical and Population Genetics, Cambridge, USA (GRID:grid.66859.34); Massachusetts General Hospital, Analytic and Translational Genetics Unit, Boston, USA (GRID:grid.32224.35) (ISNI:0000 0004 0386 9924); Harvard Medical School, Program in Biomedical and Biological Sciences, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X) 
4  The Broad Institute of MIT and Harvard, Program in Medical and Population Genetics, Cambridge, USA (GRID:grid.66859.34); Massachusetts General Hospital, Analytic and Translational Genetics Unit, Boston, USA (GRID:grid.32224.35) (ISNI:0000 0004 0386 9924) 
5  The Broad Institute of MIT and Harvard, Program in Medical and Population Genetics, Cambridge, USA (GRID:grid.66859.34); Broad Institute of MIT and Harvard, Data Sciences Platform, Cambridge, USA (GRID:grid.66859.34) 
6  The Broad Institute of MIT and Harvard, Program in Medical and Population Genetics, Cambridge, USA (GRID:grid.66859.34); University of Washington, Department of Genome Sciences, Seattle, USA (GRID:grid.34477.33) (ISNI:0000000122986657) 
7  The Broad Institute of MIT and Harvard, Program in Medical and Population Genetics, Cambridge, USA (GRID:grid.66859.34); Massachusetts General Hospital, Analytic and Translational Genetics Unit, Boston, USA (GRID:grid.32224.35) (ISNI:0000 0004 0386 9924); Wellcome Genome Campus, Hinxton, European Molecular Biology Laboratory, European Bioinformatics Institute, Cambridge, UK (GRID:grid.225360.0) (ISNI:0000 0000 9709 7726) 
8  Broad Institute of MIT and Harvard, Data Sciences Platform, Cambridge, USA (GRID:grid.66859.34) 
9  The Broad Institute of MIT and Harvard, Program in Medical and Population Genetics, Cambridge, USA (GRID:grid.66859.34); Harvard Medical School, Program in Bioinformatics and Integrative Genomics, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X); Massachusetts General Hospital, Center for Genomic Medicine, Boston, USA (GRID:grid.32224.35) (ISNI:0000 0004 0386 9924) 
10  Broad Institute of MIT and Harvard, Genomics Platform, Cambridge, USA (GRID:grid.66859.34) 
11  The Broad Institute of MIT and Harvard, Program in Medical and Population Genetics, Cambridge, USA (GRID:grid.66859.34); Massachusetts General Hospital, Analytic and Translational Genetics Unit, Boston, USA (GRID:grid.32224.35) (ISNI:0000 0004 0386 9924); Broad Institute of MIT and Harvard, Stanley Center for Psychiatric Research, Cambridge, USA (GRID:grid.66859.34) 
12  Broad Institute of MIT and Harvard, Broad Genomics, Cambridge, USA (GRID:grid.66859.34) 
13  The Broad Institute of MIT and Harvard, Program in Medical and Population Genetics, Cambridge, USA (GRID:grid.66859.34); Broad Institute of MIT and Harvard, Broad Genomics, Cambridge, USA (GRID:grid.66859.34) 
14  Wellcome Genome Campus, Hinxton, Wellcome Sanger Institute, Cambridge, UK (GRID:grid.10306.34) (ISNI:0000 0004 0606 5382) 
15  Massachusetts General Hospital, Analytic and Translational Genetics Unit, Boston, USA (GRID:grid.32224.35) (ISNI:0000 0004 0386 9924); Broad Institute of MIT and Harvard, Stanley Center for Psychiatric Research, Cambridge, USA (GRID:grid.66859.34) 
16  The Broad Institute of MIT and Harvard, Program in Medical and Population Genetics, Cambridge, USA (GRID:grid.66859.34); Imperial College London, National Heart & Lung Institute and MRC London Institute of Medical Sciences, London, UK (GRID:grid.7445.2) (ISNI:0000 0001 2113 8111); Royal Brompton & Harefield Hospitals NHS Trust, Cardiovascular Research Centre, London, UK (GRID:grid.451052.7) (ISNI:0000 0004 0581 2008) 
17  Unidad de Investigacion de Enfermedades Metabolicas. Instituto Nacional de Ciencias Medicas y Nutricion, Mexico City, Mexico (GRID:grid.416850.e) (ISNI:0000 0001 0698 4037) 
18  Peninsula College of Medicine and Dentistry, Exeter, UK (GRID:grid.467855.d) (ISNI:0000 0004 0367 1942) 
19  Brigham and Women’s Hospital, Division of Preventive Medicine, Boston, USA (GRID:grid.62560.37) (ISNI:0000 0004 0378 8294); Brigham and Women’s Hospital and Harvard Medical School, Division of Cardiovascular Medicine, Boston, USA (GRID:grid.62560.37) (ISNI:0000 0004 0378 8294) 
20  University Hospital, Department of Cardiology, Parma, Italy (GRID:grid.411482.a) 
21  University of Haifa, Department of Biology, Faculty of Natural Sciences, Haifa, Israel (GRID:grid.18098.38) (ISNI:0000 0004 1937 0562); Albert Einstein College of Medicine, Departments of Medicine and Genetics, Bronx, USA (GRID:grid.251993.5) (ISNI:0000000121791997) 
22  Lerner Research Institute, Cleveland Clinic, Department of Quantitative Health Sciences, Cleveland, USA (GRID:grid.239578.2) (ISNI:0000 0001 0675 4725) 
23  Saint Antoine Hospital, Sorbonne Université, APHP, Gastroenterology Department, Paris, France (GRID:grid.412370.3) (ISNI:0000 0004 1937 1100) 
24  NHLBI and Boston University’s Framingham Heart Study, Framingham, USA (GRID:grid.189504.1) (ISNI:0000 0004 1936 7558); Boston University School of Medicine, Department of Medicine, Boston, USA (GRID:grid.189504.1) (ISNI:0000 0004 1936 7558); Boston University School of Public Health, Department of Epidemiology, Boston, USA (GRID:grid.189504.1) (ISNI:0000 0004 1936 7558) 
25  University of Michigan, Department of Biostatistics and Center for Statistical Genetics, Ann Arbor, USA (GRID:grid.214458.e) (ISNI:0000000086837370) 
26  National Institutes of Health, National Human Genome Research Institute, Bethesda, USA (GRID:grid.94365.3d) (ISNI:0000 0001 2297 5165) 
27  Icahn School of Medicine at Mount Sinai, The Charles Bronfman Institute for Personalized Medicine, New York, USA (GRID:grid.59734.3c) (ISNI:0000 0001 0670 2351) 
28  Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, USA (GRID:grid.241167.7) (ISNI:0000 0001 2185 3318); Wake Forest School of Medicine, Center for Genomics and Personalized Medicine Research, Winston-Salem, USA (GRID:grid.241167.7) (ISNI:0000 0001 2185 3318); Wake Forest School of Medicine, Center for Diabetes Research, Winston-Salem, USA (GRID:grid.241167.7) (ISNI:0000 0001 2185 3318) 
29  University of Leicester, Department of Cardiovascular Sciences, Leicester, UK (GRID:grid.9918.9) (ISNI:0000 0004 1936 8411); Glenfield Hospital, NIHR Leicester Biomedical Research Centre, Leicester, UK (GRID:grid.412925.9) (ISNI:0000 0004 0400 6581) 
30  Imperial College London, Department of Epidemiology and Biostatistics, London, UK (GRID:grid.7445.2) (ISNI:0000 0001 2113 8111); Ealing Hospital NHS Trust, Department of Cardiology, Southall, UK (GRID:grid.412922.e); Imperial College London, Imperial College Healthcare NHS Trust, London, UK (GRID:grid.7445.2) (ISNI:0000 0001 2113 8111) 
31  The Chinese University of Hong Kong, Department of Medicine and Therapeutics, Hong Kong, China (GRID:grid.10784.3a) (ISNI:0000 0004 1937 0482) 
32  Brigham and Women’s Hospital, Division of Preventive Medicine, Boston, USA (GRID:grid.62560.37) (ISNI:0000 0004 0378 8294); Harvard Medical School, Department of Medicine, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X) 
33  Cleveland Clinic, Departments of Cardiovascular Medicine, Cellular and Molecular Medicine, Molecular Cardiology and Quantitative Health Sciences, Cleveland, USA (GRID:grid.239578.2) (ISNI:0000 0001 0675 4725) 
34  Harvard Medical School, Department of Medicine, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X); McLean Hospital, Belmont, USA (GRID:grid.240206.2) (ISNI:0000 0000 8795 072X) 
35  University of Mississippi Medical Center, Department of Medicine, Jackson, USA (GRID:grid.410721.1) (ISNI:0000 0004 1937 0407) 
36  Colorado School of Public Health, Department of Epidemiology, Aurora, USA (GRID:grid.414594.9) (ISNI:0000 0004 0401 9614) 
37  University of Illinois at Chicago, Department of Medicine and Pharmacology, Chicago, USA (GRID:grid.185648.6) (ISNI:0000 0001 2175 0319) 
38  Texas Biomedical Research Institute, Department of Genetics, San Antonio, USA (GRID:grid.250889.e) (ISNI:0000 0001 2215 0219) 
39  NHLBI and Boston University’s Framingham Heart Study, Framingham, USA (GRID:grid.189504.1) (ISNI:0000 0004 1936 7558); Boston University School of Public Health, Department of Biostatistics, Boston, USA (GRID:grid.189504.1) (ISNI:0000 0004 1936 7558) 
40  The Broad Institute of MIT and Harvard, Program in Medical and Population Genetics, Cambridge, USA (GRID:grid.66859.34); Massachusetts General Hospital, Cardiac Arrhythmia Service and Cardiovascular Research Center, Boston, USA (GRID:grid.32224.35) (ISNI:0000 0004 0386 9924) 
41  Hospital del Mar Medical Research Institute (IMIM), Cardiovascular Epidemiology and Genetics, Barcelona, Spain (GRID:grid.20522.37) (ISNI:0000 0004 1767 9005); CIBER CV, Barcelona, Spain (GRID:grid.20522.37); University of Vic-Central University of Catalonia, Department of Medicine, Medical School, Barcelona, Spain (GRID:grid.20522.37) 
42  Institute for Cardiogenetics, University of Lübeck, Lübeck, Germany (GRID:grid.4562.5) (ISNI:0000 0001 0057 2672); Partner Site Hamburg/Lübeck/Kiel, DZHK (German Research Centre for Cardiovascular Research), Lübeck, Germany (GRID:grid.452396.f) (ISNI:0000 0004 5937 5237); University Heart Center Lübeck, Lübeck, Germany (GRID:grid.452396.f) 
43  The Broad Institute of MIT and Harvard, Program in Medical and Population Genetics, Cambridge, USA (GRID:grid.66859.34); University of Tartu, Estonian Genome Center, Institute of Genomics, Tartu, Estonia (GRID:grid.10939.32) (ISNI:0000 0001 0943 7661) 
44  Clinic of Gastroenterology, Helsinki University and Helsinki University Hospital, Helsinki, Finland (GRID:grid.7737.4) (ISNI:0000 0004 0410 2071) 
45  The Broad Institute of MIT and Harvard, Program in Medical and Population Genetics, Cambridge, USA (GRID:grid.66859.34); Massachusetts General Hospital, Center for Genomic Medicine, Boston, USA (GRID:grid.32224.35) (ISNI:0000 0004 0386 9924); Harvard Medical School, Department of Medicine, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X) 
46  Christian-Albrechts-University of Kiel, Institute of Clinical Molecular Biology (IKMB), Kiel, Germany (GRID:grid.9764.c) (ISNI:0000 0001 2153 9986) 
47  Harvard Medical School, Department of Medicine, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X); Bioinformatics Program, MGH Cancer Center and Department of Pathology, Boston, USA (GRID:grid.32224.35) (ISNI:0000 0004 0386 9924); Cancer Genome Computational Analysis, Broad Institute, Cambridge, USA (GRID:grid.66859.34) 
48  Hadassah-Hebrew University Medical Center, Endocrinology and Metabolism Department, Jerusalem, Israel (GRID:grid.17788.31) (ISNI:0000 0001 2221 2926) 
49  SUNY Upstate Medical University, Department of Psychiatry and Behavioral Sciences, Oneida, USA (GRID:grid.411023.5) (ISNI:0000 0000 9159 4457) 
50  Hammer Health Sciences, Institute for Genomic Medicine, Columbia University Medical Center, New York, USA (GRID:grid.239585.0) (ISNI:0000 0001 2285 2675); Hammer Health Sciences, Department of Genetics & Development, Columbia University Medical Center, New York, USA (GRID:grid.239585.0) (ISNI:0000 0001 2285 2675) 
51  Centro de Investigacion en Salud Poblacional. Instituto Nacional de Salud Publica MEXICO, Mexico, Mexico (GRID:grid.239585.0) 
52  Lund University, Lund, Sweden (GRID:grid.4514.4) (ISNI:0000 0001 0930 2361); University of Helsinki, Institute for Molecular Medicine Finland (FIMM), HiLIFE, Helsinki, Finland (GRID:grid.7737.4) (ISNI:0000 0004 0410 2071) 
53  Lund University Diabetes Centre, Lund, Sweden (GRID:grid.4514.4) (ISNI:0000 0001 0930 2361) 
54  University of Texas Health Science Center at Houston, Human Genetics Center, Houston, USA (GRID:grid.267308.8) (ISNI:0000 0000 9206 2401) 
55  Hammer Health Sciences, Department of Genetics & Development, Columbia University Medical Center, New York, USA (GRID:grid.239585.0) (ISNI:0000 0001 2285 2675); Columbia University, Department of Neurology, New York, USA (GRID:grid.21729.3f) (ISNI:0000000419368729) 
56  University of Eastern Finland, Institute of Biomedicine, Kuopio, Finland (GRID:grid.9668.1) (ISNI:0000 0001 0726 2490) 
57  Helsinki University Central Hospital, Lapinlahdentie, Department of Psychiatry, PL 320, Helsinki, Finland (GRID:grid.15485.3d) (ISNI:0000 0000 9950 5666) 
58  Karolinska Institutet, Department of Medical Epidemiology and Biostatistics, Stockholm, Sweden (GRID:grid.4714.6) (ISNI:0000 0004 1937 0626); Icahn School of Medicine at Mount Sinai, New York, USA (GRID:grid.59734.3c) (ISNI:0000 0001 0670 2351) 
59  Helsinki University Central Hospital, Department of Neurology, Helsinki, Finland (GRID:grid.15485.3d) (ISNI:0000 0000 9950 5666) 
60  Lund University Diabetes Centre, Lund, Sweden (GRID:grid.4514.4) (ISNI:0000 0001 0930 2361); University of Helsinki, Department of Public Health, Faculty of Medicine, Helsinki, Finland (GRID:grid.7737.4) (ISNI:0000 0004 0410 2071) 
61  Korea National Institute of Health, Center for Genome Science, Chungcheongbuk-do, Republic of Korea (GRID:grid.415482.e) (ISNI:0000 0004 0647 4899) 
62  Cardiff University School of Medicine, MRC Centre for Neuropsychiatric Genetics & Genomics, Cardiff, UK (GRID:grid.5600.3) (ISNI:0000 0001 0807 5670) 
63  Ealing Hospital NHS Trust, Department of Cardiology, Southall, UK (GRID:grid.412922.e); Imperial College London, Imperial College Healthcare NHS Trust, London, UK (GRID:grid.7445.2) (ISNI:0000 0001 2113 8111); Imperial College London, National Heart and Lung Institute, Cardiovascular Sciences, Hammersmith Campus, London, UK (GRID:grid.7445.2) (ISNI:0000 0001 2113 8111) 
64  THL-National Institute for Health and Welfare, Department of Health, Helsinki, Finland (GRID:grid.14758.3f) (ISNI:0000 0001 1013 0499) 
65  Yale School of Medicine, Section of Cardiovascular Medicine, Department of Internal Medicine, New Haven, USA (GRID:grid.47100.32) (ISNI:0000000419368710); Yale-New Haven Hospital, Center for Outcomes Research and Evaluation, New Haven, USA (GRID:grid.417307.6) 
66  Emory University School of Medicine, Division of Pediatric Gastroenterology, Atlanta, USA (GRID:grid.189967.8) (ISNI:0000 0001 0941 6502) 
67  Seoul National University Hospital, Department of Internal Medicine, Seoul, Republic of Korea (GRID:grid.412484.f) (ISNI:0000 0001 0302 820X) 
68  The University of Eastern Finland, Institute of Clinical Medicine, Kuopio, Finland (GRID:grid.9668.1) (ISNI:0000 0001 0726 2490); Kuopio University Hospital, Kuopio, Finland (GRID:grid.410705.7) (ISNI:0000 0004 0628 207X) 
69  Faculty of Medicine and Health Technology, Tampere University, Department of Clinical Chemistry, Fimlab Laboratories and Finnish Cardiovascular Research Center-Tampere, Tampere, Finland (GRID:grid.502801.e) (ISNI:0000 0001 2314 6254) 
70  Icahn School of Medicine at Mount Sinai, The Charles Bronfman Institute for Personalized Medicine, New York, USA (GRID:grid.59734.3c) (ISNI:0000 0001 0670 2351); Icahn School of Medicine at Mount Sinai, The Mindich Child Health and Development Institute, New York, USA (GRID:grid.59734.3c) (ISNI:0000 0001 0670 2351) 
71  The Broad Institute of MIT and Harvard, Program in Medical and Population Genetics, Cambridge, USA (GRID:grid.66859.34); Hospital del Mar Medical Research Institute (IMIM), Cardiovascular Epidemiology and Genetics, Barcelona, Spain (GRID:grid.20522.37) (ISNI:0000 0004 1767 9005) 
72  The Chinese University of Hong Kong, Department of Medicine and Therapeutics, Hong Kong, China (GRID:grid.10784.3a) (ISNI:0000 0004 1937 0482); The Chinese University of Hong Kong, Li Ka Shing Institute of Health Sciences, Hong Kong, China (GRID:grid.10784.3a) (ISNI:0000 0004 1937 0482); The Chinese University of Hong Kong, Hong Kong Institute of Diabetes and Obesity, Hong Kong, China (GRID:grid.10784.3a) (ISNI:0000 0004 1937 0482) 
73  University of Vic-Central University of Catalonia, Department of Medicine, Medical School, Barcelona, Spain (GRID:grid.10784.3a); Hospital del Mar Medical Research Institute (IMIM), Cardiovascular Research REGICOR Group, Barcelona, Spain (GRID:grid.20522.37) (ISNI:0000 0004 1767 9005) 
74  Massachusetts General Hospital, Center for Genomic Medicine, Boston, USA (GRID:grid.32224.35) (ISNI:0000 0004 0386 9924); Harvard Medical School, Department of Genetics, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X) 
75  University of Oxford, Churchill Hospital, Oxford Centre for Diabetes, Endocrinology and Metabolism, Oxford, UK (GRID:grid.4991.5) (ISNI:0000 0004 1936 8948); University of Oxford, Roosevelt Drive, Wellcome Centre for Human Genetics, Oxford, UK (GRID:grid.4991.5) (ISNI:0000 0004 1936 8948); Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford NIHR Biomedical Research Centre, Oxford, UK (GRID:grid.8348.7) (ISNI:0000 0001 2306 7492) 
76  Cedars-Sinai Medical Center, F Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Los Angeles, USA (GRID:grid.50956.3f) (ISNI:0000 0001 2152 9905) 
77  University of Ottawa Heart Institute, Atherogenomics Laboratory, Ottawa, Canada (GRID:grid.28046.38) (ISNI:0000 0001 2182 2255) 
78  The Broad Institute of MIT and Harvard, Program in Medical and Population Genetics, Cambridge, USA (GRID:grid.66859.34); Harvard Medical School, Department of Medicine, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X); Massachusetts General Hospital, Division of General Internal Medicine, Boston, USA (GRID:grid.32224.35) (ISNI:0000 0004 0386 9924) 
79  University Hospital Malmo Clinical Research Center, Lund University, Department of Clinical Sciences, Malmo, Sweden (GRID:grid.4514.4) (ISNI:0000 0001 0930 2361) 
80  University of Tartu, Estonian Genome Center, Institute of Genomics, Tartu, Estonia (GRID:grid.10939.32) (ISNI:0000 0001 0943 7661) 
81  Skane University Hospital, Lund University, Department of Clinical Sciences, Malmo, Sweden (GRID:grid.411843.b) (ISNI:0000 0004 0623 9987) 
82  Instituto Nacional de Medicina Genómica (INMEGEN), Mexico City, Mexico (GRID:grid.452651.1) (ISNI:0000 0004 0627 7633) 
83  University of Dundee, Medical Research Institute, Ninewells Hospital and Medical School, Dundee, UK (GRID:grid.8241.f) (ISNI:0000 0004 0397 2876) 
84  The Broad Institute of MIT and Harvard, Program in Medical and Population Genetics, Cambridge, USA (GRID:grid.66859.34); Broad Institute of MIT and Harvard, Stanley Center for Psychiatric Research, Cambridge, USA (GRID:grid.66859.34); University of Helsinki, Institute for Molecular Medicine Finland (FIMM), HiLIFE, Helsinki, Finland (GRID:grid.7737.4) (ISNI:0000 0004 0410 2071) 
85  Seoul National University Hospital, Department of Internal Medicine, Seoul, Republic of Korea (GRID:grid.412484.f) (ISNI:0000 0001 0302 820X); Seoul National University, Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul, Republic of Korea (GRID:grid.31501.36) (ISNI:0000 0004 0470 5905) 
86  Keck School of Medicine at the University of Southern California, Department of Psychiatry, Los Angeles, USA (GRID:grid.42505.36) (ISNI:0000 0001 2156 6853) 
87  Johns Hopkins University School of Medicine, Department of Psychiatry and Behavioral Sciences, Baltimore, USA (GRID:grid.21107.35) (ISNI:0000 0001 2171 9311) 
88  Institute of Cancer Research, Division of Genetics and Epidemiology, London, UK (GRID:grid.18886.3f) (ISNI:0000 0001 1271 4623) 
89  University of Oulu, Medical Research Center, Oulu University Hospital, Oulu, Finland and Research Unit of Clinical Neuroscience, Neurology, Oulu, Finland (GRID:grid.10858.34) (ISNI:0000 0001 0941 4873) 
90  Montreal Heart Institute, Montreal, Research Center, Quebec, Canada (GRID:grid.482476.b) (ISNI:0000 0000 8995 9090); Université de Montréal, Department of Medicine, Faculty of Medicine, Québec, Canada (GRID:grid.14848.31) (ISNI:0000 0001 2292 3357) 
91  The Broad Institute of MIT and Harvard, Program in Medical and Population Genetics, Cambridge, USA (GRID:grid.66859.34); University of Helsinki, Institute for Molecular Medicine Finland (FIMM), HiLIFE, Helsinki, Finland (GRID:grid.7737.4) (ISNI:0000 0004 0410 2071); University of Helsinki, Department of Public Health, Faculty of Medicine, Helsinki, Finland (GRID:grid.7737.4) (ISNI:0000 0004 0410 2071) 
92  Vanderbilt University Medical Center, Department of Biomedical Informatics, Nashville, USA (GRID:grid.412807.8) (ISNI:0000 0004 1936 9916); Vanderbilt University Medical Center, Department of Medicine, Nashville, USA (GRID:grid.412807.8) (ISNI:0000 0004 1936 9916) 
93  Perelman School of Medicine at the University of Pennsylvania, Department of Biostatistics and Epidemiology, Philadelphia, USA (GRID:grid.25879.31) (ISNI:0000 0004 1936 8972); Perelman School of Medicine at the University of Pennsylvania, Department of Medicine, Philadelphia, USA (GRID:grid.25879.31) (ISNI:0000 0004 1936 8972); Center for Non-Communicable Diseases, Karachi, Pakistan (GRID:grid.497620.e) 
94  National Institute for Health and Welfare, Helsinki, Finland (GRID:grid.14758.3f) (ISNI:0000 0001 1013 0499) 
95  The Broad Institute of MIT and Harvard, Program in Medical and Population Genetics, Cambridge, USA (GRID:grid.66859.34); Massachusetts General Hospital, Center for Genomic Medicine, Boston, USA (GRID:grid.32224.35) (ISNI:0000 0004 0386 9924); Broad Institute of MIT and Harvard, Stanley Center for Psychiatric Research, Cambridge, USA (GRID:grid.66859.34) 
96  Deutsches Herzzentrum München, München, Germany (GRID:grid.472754.7) (ISNI:0000 0001 0695 783X); Technische Universität München, München, Germany (GRID:grid.6936.a) (ISNI:0000000123222966) 
97  Division of Cardiovascular Medicine, Nashville VA Medical Center and Vanderbilt University, School of Medicine, Nashville, USA (GRID:grid.152326.1) (ISNI:0000 0001 2264 7217) 
98  Icahn School of Medicine at Mount Sinai, Department of Psychiatry, New York, USA (GRID:grid.59734.3c) (ISNI:0000 0001 0670 2351); Icahn School of Medicine at Mount Sinai, Department of Genetics and Genomic Sciences, New York, USA (GRID:grid.59734.3c) (ISNI:0000 0001 0670 2351); Icahn School of Medicine at Mount Sinai, Institute for Genomics and Multiscale Biology, New York, USA (GRID:grid.59734.3c) (ISNI:0000 0001 0670 2351) 
99  University of Eastern Finland, Institute of Clinical Medicine, Neurology, Kuopio, Finland (GRID:grid.9668.1) (ISNI:0000 0001 0726 2490) 
100  King’s College London, Department of Twin Research and Genetic Epidemiology, London, UK (GRID:grid.13097.3c) (ISNI:0000 0001 2322 6764) 
101  Helsinki University Central Hospital, Department of Neurology, Helsinki, Finland (GRID:grid.15485.3d) (ISNI:0000 0000 9950 5666); University of North Carolina, Departments of Genetics and Psychiatry, Chapel Hill, USA (GRID:grid.410711.2) (ISNI:0000 0001 1034 1720) 
102  National University of Singapore, National University Health System, Saw Swee Hock School of Public Health, Singapore, Singapore (GRID:grid.4280.e) (ISNI:0000 0001 2180 6431); National University of Singapore, Department of Medicine, Yong Loo Lin School of Medicine, Singapore, Singapore (GRID:grid.4280.e) (ISNI:0000 0001 2180 6431); Duke-NUS Graduate Medical School, Singapore, Singapore (GRID:grid.428397.3) (ISNI:0000 0004 0385 0924) 
103  National University of Singapore, National University Health System, Saw Swee Hock School of Public Health, Singapore, Singapore (GRID:grid.4280.e) (ISNI:0000 0001 2180 6431); National University of Singapore, Life Sciences Institute, Singapore, Singapore (GRID:grid.4280.e) (ISNI:0000 0001 2180 6431); National University of Singapore, Department of Statistics and Applied Probability, Singapore, Singapore (GRID:grid.4280.e) (ISNI:0000 0001 2180 6431) 
104  University of Helsinki, Institute for Molecular Medicine Finland (FIMM), HiLIFE, Helsinki, Finland (GRID:grid.7737.4) (ISNI:0000 0004 0410 2071); Folkhälsan Research Center, Folkhälsan Institute of Genetics, Helsinki, Finland (GRID:grid.428673.c) (ISNI:0000 0004 0409 6302); Helsinki University Hospital, HUCH Abdominal Center, Helsinki, Finland (GRID:grid.15485.3d) (ISNI:0000 0000 9950 5666) 
105  University of California, Center for Behavioral Genomics, Department of Psychiatry, San Diego, USA (GRID:grid.266100.3) (ISNI:0000 0001 2107 4242); University of California, Institute of Genomic Medicine, San Diego, USA (GRID:grid.266100.3) (ISNI:0000 0001 2107 4242) 
106  University of California, Institute of Genomic Medicine, San Diego, USA (GRID:grid.266100.3) (ISNI:0000 0001 2107 4242); The Hebrew University of Jerusalem, Juliet Keidan Institute of Pediatric Gastroenterology, Shaare Zedek Medical Center, Jerusalem, Israel (GRID:grid.9619.7) (ISNI:0000 0004 1937 0538) 
107  Instituto de Investigaciones Biomédicas UNAM, Mexico City, Mexico (GRID:grid.9486.3) (ISNI:0000 0001 2159 0001); Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán Mexico City, Mexico City, Mexico (GRID:grid.416850.e) (ISNI:0000 0001 0698 4037) 
108  University of Helsinki, Department of Public Health, Faculty of Medicine, Helsinki, Finland (GRID:grid.7737.4) (ISNI:0000 0004 0410 2071) 
109  University of Oxford, Radcliffe Department of Medicine, Oxford, UK (GRID:grid.4991.5) (ISNI:0000 0004 1936 8948) 
110  University of Groningen and University Medical Center Groningen, Department of Gastroenterology and Hepatology, Groningen, The Netherlands (GRID:grid.4494.d) (ISNI:0000 0000 9558 4598) 
111  University of Helsinki, Institute for Molecular Medicine Finland (FIMM), HiLIFE, Helsinki, Finland (GRID:grid.7737.4) (ISNI:0000 0004 0410 2071); Folkhälsan Research Center, Folkhälsan Institute of Genetics, Helsinki, Finland (GRID:grid.428673.c) (ISNI:0000 0004 0409 6302) 
112  University of Mississippi Medical Center, Department of Physiology and Biophysics, Jackson, USA (GRID:grid.410721.1) (ISNI:0000 0004 1937 0407) 
113  Broad Institute of MIT and Harvard, Program in Infectious Disease and Microbiome, Cambridge, USA (GRID:grid.66859.34); Massachusetts General Hospital, Center for Computational and Integrative Biology, Boston, USA (GRID:grid.32224.35) (ISNI:0000 0004 0386 9924) 
114  University of California Irvine, Department of Psychiatry and Human Behavior, Irvine, USA (GRID:grid.266093.8) (ISNI:0000 0001 0668 7243) 
115  The Broad Institute of MIT and Harvard, Program in Medical and Population Genetics, Cambridge, USA (GRID:grid.66859.34); Massachusetts General Hospital, Analytic and Translational Genetics Unit, Boston, USA (GRID:grid.32224.35) (ISNI:0000 0004 0386 9924); Garvan Institute of Medical Research, and UNSW Sydney, Centre for Population Genomics, Sydney, Australia (GRID:grid.1005.4) (ISNI:0000 0004 4902 0432); Murdoch Children’s Research Institute, Centre for Population Genomics, Melbourne, Australia (GRID:grid.1058.c) (ISNI:0000 0000 9442 535X) 
Publication year
2020
Publication date
2020
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-019-12438-5
ProQuest document ID
2484413507
Copyright
© The Author(s) 2020. corrected publication 2021. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.