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      • Record: found
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      Is Open Access

      The mutational constraint spectrum quantified from variation in 141,456 humans

      research-article
      1 , 2 , , 1 , 2 , 1 , 2 , 1 , 2 , 3 , 1 , 2 , 1 , 2 , 4 , 1 , 4 , 5 , 1 , 2 , 1 , 2 , 6 , 1 , 2 , 7 , 1 , 5 , 1 , 2 , 1 , 2 , 8 , 1 , 2 , 1 , 2 , 1 , 2 , 1 , 2 , 4 , 1 , 2 , 9 , 1 , 2 , 9 , 7 , 7 , 1 , 2 , 9 , 1 , 2 , 9 , 1 , 2 , 9 , 1 , 2 , 10 , 11 , 12 , 13 , 1 , 2 , 1 , 2 , 14 , 1 , 2 , 15 , 16 , 1 , 7 , 17 , 1 , 10 , 11 , 2 , 9 , 1 , 2 , 7 , 7 , 18 , 7 , 1 , 18 , 18 , 7 , 1 , 18 , 7 , 7 , 7 , 7 , 7 , 7 , 7 , 7 , 1 , 1 , 7 , 7 , 7 , 7 , 1 , 5 , 19 , Genome Aggregation Database Consortium, 1 , 2 , 9 , 1 , 2 , 6 , 9 , 1 , 2 , 149 , 150 ,
      Nature
      Nature Publishing Group UK
      Medical genomics, Rare variants

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          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Genetic variants that inactivate protein-coding genes are a powerful source of information about the phenotypic consequences of gene disruption: genes that are crucial for the function of an organism will be depleted of such variants in natural populations, whereas non-essential genes will tolerate their accumulation. However, predicted loss-of-function variants are enriched for annotation errors, and tend to be found at extremely low frequencies, so their analysis requires careful variant annotation and very large sample sizes 1 . Here we describe the aggregation of 125,748 exomes and 15,708 genomes from human sequencing studies into the Genome Aggregation Database (gnomAD). We identify 443,769 high-confidence predicted loss-of-function variants in this cohort after filtering for artefacts caused by sequencing and annotation errors. Using an improved model of human mutation rates, we classify human protein-coding genes along a spectrum that represents tolerance to inactivation, validate this classification using data from model organisms and engineered human cells, and show that it can be used to improve the power of gene discovery for both common and rare diseases.

          Abstract

          A catalogue of predicted loss-of-function variants in 125,748 whole-exome and 15,708 whole-genome sequencing datasets from the Genome Aggregation Database (gnomAD) reveals the spectrum of mutational constraints that affect these human protein-coding genes.

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          Most cited references27

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          • Abstract: found
          • Article: not found

          Genetic compensation triggered by mutant mRNA degradation

          Genetic robustness, or the ability of an organism to maintain fitness in the presence of mutations, can be achieved via protein feedback loops. Recent evidence suggests that organisms may also respond to mutations by upregulating related gene(s) independently of protein feedback loops, a phenomenon called transcriptional adaptation. However, the prevalence of transcriptional adaptation and its underlying molecular mechanisms are unknown. Here, by analyzing several models of transcriptional adaptation in zebrafish and mouse, we show a requirement for mRNA degradation. Alleles that fail to transcribe the mutated gene do not display transcriptional adaptation and exhibit more severe phenotypes than alleles displaying mutant mRNA decay. Transcriptome analysis reveals the upregulation of a substantial proportion of the genes that exhibit sequence similarity with the mutated gene’s mRNA, suggesting a sequence dependent mechanism. Besides implications for our understanding of disease-causing mutations, these findings will help design mutant alleles with minimal transcriptional adaptation-derived compensation.
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            • Record: found
            • Abstract: found
            • Article: found
            Is Open Access

            A structural variation reference for medical and population genetics

            Structural variants (SVs) rearrange large segments of DNA 1 and can have profound consequences in evolution and human disease 2,3 . As national biobanks, disease-association studies, and clinical genetic testing have grown increasingly reliant on genome sequencing, population references such as the Genome Aggregation Database (gnomAD) 4 have become integral in the interpretation of single-nucleotide variants (SNVs) 5 . However, there are no reference maps of SVs from high-coverage genome sequencing comparable to those for SNVs. Here we present a reference of sequence-resolved SVs constructed from 14,891 genomes across diverse global populations (54% non-European) in gnomAD. We discovered a rich and complex landscape of 433,371 SVs, from which we estimate that SVs are responsible for 25–29% of all rare protein-truncating events per genome. We found strong correlations between natural selection against damaging SNVs and rare SVs that disrupt or duplicate protein-coding sequence, which suggests that genes that are highly intolerant to loss-of-function are also sensitive to increased dosage 6 . We also uncovered modest selection against noncoding SVs in cis-regulatory elements, although selection against protein-truncating SVs was stronger than all noncoding effects. Finally, we identified very large (over one megabase), rare SVs in 3.9% of samples, and estimate that 0.13% of individuals may carry an SV that meets the existing criteria for clinically important incidental findings 7 . This SV resource is freely distributed via the gnomAD browser 8 and will have broad utility in population genetics, disease-association studies, and diagnostic screening.
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              Accurate classification of BRCA1 variants with saturation genome editing

              Variants of uncertain significance (VUS) fundamentally limit the clinical utility of genetic information. The challenge they pose is epitomized by BRCA1, a tumor suppressor in which germline loss-of-function variants predispose women to breast and ovarian cancer. Although BRCA1 has been sequenced in millions of women, the risk associated with most newly observed variants cannot be definitively assigned. Here, we employ saturation genome editing to assay 96.5% of all possible single nucleotide variants (SNVs) in 13 exons encoding functionally critical domains of BRCA1. Functional effects for nearly 4,000 SNVs are bimodally distributed and almost perfectly concordant with established assessments of pathogenicity. Over 400 non-functional missense SNVs are identified, as well as ~300 SNVs that disrupt expression. We predict that these results will be immediately useful for clinical interpretation of BRCA1 variants, and that this paradigm can be extended to overcome the challenge of VUS in additional clinically actionable genes.
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                Author and article information

                Contributors
                konradk@broadinstitute.org
                d.macarthur@garvan.org.au
                Journal
                Nature
                Nature
                Nature
                Nature Publishing Group UK (London )
                0028-0836
                1476-4687
                27 May 2020
                27 May 2020
                2020
                : 581
                : 7809
                : 434-443
                Affiliations
                [1 ]GRID grid.66859.34, Program in Medical and Population Genetics, , Broad Institute of MIT and Harvard, ; Cambridge, MA USA
                [2 ]ISNI 0000 0004 0386 9924, GRID grid.32224.35, Analytic and Translational Genetics Unit, , Massachusetts General Hospital, ; Boston, MA USA
                [3 ]ISNI 000000041936754X, GRID grid.38142.3c, Program in Biological and Biomedical Sciences, , Harvard Medical School, ; Boston, MA USA
                [4 ]ISNI 000000041936754X, GRID grid.38142.3c, Program in Bioinformatics and Integrative Genomics, , Harvard Medical School, ; Boston, MA USA
                [5 ]ISNI 0000 0004 0386 9924, GRID grid.32224.35, Center for Genomic Medicine, , Massachusetts General Hospital, ; Boston, MA USA
                [6 ]ISNI 0000 0004 0409 5350, GRID grid.452494.a, Institute for Molecular Medicine Finland, ; Helsinki, Finland
                [7 ]GRID grid.66859.34, Data Sciences Platform, , Broad Institute of MIT and Harvard, ; Cambridge, MA USA
                [8 ]ISNI 0000 0001 2171 1133, GRID grid.4868.2, Centre for Translational Bioinformatics, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, , Queen Mary University of London and Barts Health NHS Trust, ; London, UK
                [9 ]GRID grid.66859.34, Stanley Center for Psychiatric Research, , Broad Institute of MIT and Harvard, ; Cambridge, MA USA
                [10 ]ISNI 0000 0001 2113 8111, GRID grid.7445.2, National Heart & Lung Institute and MRC London Institute of Medical Sciences, , Imperial College London, ; London, UK
                [11 ]ISNI 0000 0004 0581 2008, GRID grid.451052.7, Cardiovascular Research Centre, , Royal Brompton & Harefield Hospitals NHS Trust, ; London, UK
                [12 ]ISNI 0000000122986657, GRID grid.34477.33, Department of Pediatrics, , University of Washington, ; Seattle, WA USA
                [13 ]Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge UK
                [14 ]ISNI 0000 0004 0384 7506, GRID grid.422219.e, Vertex Pharmaceuticals Inc, ; Boston, MA USA
                [15 ]ISNI 0000 0004 0378 8438, GRID grid.2515.3, Division of Genetics and Genomics, , Boston Children’s Hospital, ; Boston, MA USA
                [16 ]ISNI 000000041936754X, GRID grid.38142.3c, Department of Pediatrics, , Harvard Medical School, ; Boston, MA USA
                [17 ]ISNI 0000000419368710, GRID grid.47100.32, Department of Genetics, , Yale School of Medicine, ; New Haven, CT USA
                [18 ]GRID grid.66859.34, Broad Genomics, , Broad Institute of MIT and Harvard, ; Cambridge, MA USA
                [19 ]ISNI 000000041936754X, GRID grid.38142.3c, Department of Neurology, , Harvard Medical School, ; Boston, MA USA
                [149 ]ISNI 0000 0004 4902 0432, GRID grid.1005.4, Present Address: Centre for Population Genomics, , Garvan Institute of Medical Research, and UNSW Sydney, ; Sydney, New South Wales Australia
                [150 ]ISNI 0000 0000 9442 535X, GRID grid.1058.c, Centre for Population Genomics, , Murdoch Children’s Research Institute, ; Melbourne, Victoria Australia
                [20 ]ISNI 0000 0001 0698 4037, GRID grid.416850.e, Unidad de Investigacion de Enfermedades Metabolicas, Instituto Nacional de Ciencias Medicas y Nutricion, ; Mexico City, Mexico
                [21 ]ISNI 0000 0004 0367 1942, GRID grid.467855.d, Peninsula College of Medicine and Dentistry, ; Exeter, UK
                [22 ]ISNI 0000 0004 0378 8294, GRID grid.62560.37, Division of Preventive Medicine, , Brigham and Women’s Hospital, ; Boston, MA USA
                [23 ]ISNI 0000 0004 0378 8294, GRID grid.62560.37, Division of Cardiovascular Medicine, , Brigham and Women’s Hospital and Harvard Medical School, ; Boston, MA USA
                [24 ]GRID grid.411482.a, Department of Cardiology, , University Hospital, ; Parma, Italy
                [25 ]ISNI 0000 0004 1937 0562, GRID grid.18098.38, Department of Biology, Faculty of Natural Sciences, , University of Haifa, ; Haifa, Israel
                [26 ]ISNI 0000000121791997, GRID grid.251993.5, Department of Medicine, , Albert Einstein College of Medicine, ; Bronx, NY USA
                [27 ]ISNI 0000000121791997, GRID grid.251993.5, Department of Genetics, , Albert Einstein College of Medicine, ; Bronx, NY USA
                [28 ]ISNI 0000 0001 0675 4725, GRID grid.239578.2, Department of Quantitative Health Sciences, , Lerner Research Institute, Cleveland Clinic, ; Cleveland, OH USA
                [29 ]Sorbonne Université, APHP, Gastroenterology Department, Saint Antoine Hospital, Paris, France
                [30 ]ISNI 0000 0004 1936 7558, GRID grid.189504.1, Framingham Heart Study, National Heart, , Lung, & Blood Institute and Boston University, ; Framingham, MA USA
                [31 ]ISNI 0000 0004 0367 5222, GRID grid.475010.7, Department of Medicine, , Boston University School of Medicine, ; Boston, MA USA
                [32 ]ISNI 0000 0004 1936 7558, GRID grid.189504.1, Department of Epidemiology, , Boston University School of Public Health, ; Boston, MA USA
                [33 ]ISNI 0000000086837370, GRID grid.214458.e, Department of Biostatistics, Center for Statistical Genetics, , University of Michigan, ; Ann Arbor, MI USA
                [34 ]ISNI 0000 0001 2297 5165, GRID grid.94365.3d, National Human Genome Research Institute, , National Institutes of Health, ; Bethesda, MD USA
                [35 ]ISNI 0000 0001 0670 2351, GRID grid.59734.3c, The Charles Bronfman Institute for Personalized Medicine, , Icahn School of Medicine at Mount Sinai, ; New York, NY USA
                [36 ]ISNI 0000 0001 2185 3318, GRID grid.241167.7, Department of Biochemistry, , Wake Forest School of Medicine, ; Winston-Salem, NC USA
                [37 ]ISNI 0000 0001 2185 3318, GRID grid.241167.7, Center for Genomics and Personalized Medicine Research, , Wake Forest School of Medicine, ; Winston-Salem, NC USA
                [38 ]ISNI 0000 0001 2185 3318, GRID grid.241167.7, Center for Diabetes Research, , Wake Forest School of Medicine, ; Winston-Salem, NC USA
                [39 ]ISNI 0000 0004 1936 8411, GRID grid.9918.9, Department of Cardiovascular Sciences and NIHR Leicester Biomedical Research Centre, , University of Leicester, ; Leicester, UK
                [40 ]ISNI 0000 0004 0400 6581, GRID grid.412925.9, NIHR Leicester Biomedical Research Centre, , Glenfield Hospital, ; Leicester, UK
                [41 ]ISNI 0000 0001 2113 8111, GRID grid.7445.2, Department of Epidemiology and Biostatistics, , Imperial College London, ; London, UK
                [42 ]GRID grid.412922.e, Department of Cardiology, , Ealing Hospital NHS Trust, ; Southall, UK
                [43 ]ISNI 0000 0001 2113 8111, GRID grid.7445.2, Imperial College Healthcare NHS Trust, , Imperial College London, ; London, UK
                [44 ]ISNI 0000 0004 1937 0482, GRID grid.10784.3a, Department of Medicine and Therapeutics, , The Chinese University of Hong Kong, ; Hong Kong, China
                [45 ]ISNI 000000041936754X, GRID grid.38142.3c, Department of Medicine, , Harvard Medical School, ; Boston, MA USA
                [46 ]ISNI 0000 0000 8795 072X, GRID grid.240206.2, Program for Neuropsychiatric Research, , McLean Hospital, ; Belmont, MA USA
                [47 ]ISNI 0000 0004 1937 0407, GRID grid.410721.1, Department of Medicine, , University of Mississippi Medical Center, ; Jackson, MI USA
                [48 ]ISNI 0000 0004 0401 9614, GRID grid.414594.9, Department of Epidemiology, , Colorado School of Public Health, ; Aurora, CO USA
                [49 ]ISNI 0000 0001 2175 0319, GRID grid.185648.6, Department of Medicine and Pharmacology, , University of Illinois at Chicago, ; Chicago, IL USA
                [50 ]ISNI 0000 0001 2215 0219, GRID grid.250889.e, Department of Genetics, , Texas Biomedical Research Institute, ; San Antonio, TX USA
                [51 ]ISNI 0000 0004 1936 7558, GRID grid.189504.1, Department of Biostatistics, , Boston University School of Public Health, ; Boston, MA USA
                [52 ]ISNI 0000 0004 0386 9924, GRID grid.32224.35, Cardiac Arrhythmia Service and Cardiovascular Research Center, , Massachusetts General Hospital, ; Boston, MA USA
                [53 ]ISNI 0000 0004 1767 9005, GRID grid.20522.37, Cardiovascular Epidemiology and Genetics, , Hospital del Mar Medical Research Institute (IMIM), ; Barcelona, Catalonia Spain
                [54 ]ISNI 0000 0000 9314 1427, GRID grid.413448.e, Centro de Investigación Biomédica en Red Enfermedades Cardiovaculares (CIBERCV), ; Barcelona, Catalonia Spain
                [55 ]GRID grid.440820.a, Department of Medicine, Medical School, , University of Vic-Central University of Catalonia, ; Vic, Catalonia Spain
                [56 ]ISNI 0000 0001 0057 2672, GRID grid.4562.5, Institute for Cardiogenetics, University of Lübeck, ; Lübeck, Germany
                [57 ]DZHK (German Research Centre for Cardiovascular Research), partner site Hamburg/Lübeck/Kiel, Lübeck, Germany
                [58 ]University Heart Center Lübeck, Lübeck, Germany
                [59 ]ISNI 0000 0001 0943 7661, GRID grid.10939.32, Estonian Genome Center, Institute of Genomics, , University of Tartu, ; Tartu, Estonia
                [60 ]ISNI 0000 0004 0410 2071, GRID grid.7737.4, Helsinki University and Helsinki University Hospital, Clinic of Gastroenterology, ; Helsinki, Finland
                [61 ]ISNI 0000 0004 0386 9924, GRID grid.32224.35, Diabetes Unit, , Massachusetts General Hospital, ; Boston, MA USA
                [62 ]ISNI 0000 0004 0386 9924, GRID grid.32224.35, Center for Genomic Medicine, , Massachusetts General Hospital, ; Boston, MA USA
                [63 ]GRID grid.66859.34, Program in Metabolism, , Broad Institute of MIT and Harvard, ; Cambridge, MA USA
                [64 ]ISNI 0000 0001 2153 9986, GRID grid.9764.c, Institute of Clinical Molecular Biology (IKMB), , Christian-Albrechts-University of Kiel, ; Kiel, Germany
                [65 ]ISNI 0000 0004 0386 9924, GRID grid.32224.35, Bioinformatics Consortium, , Massachusetts General Hospital, ; Boston, MA USA
                [66 ]GRID grid.66859.34, Cancer Genome Computational Analysis Group, , Broad Institute of MIT and Harvard, ; Cambridge, MA USA
                [67 ]ISNI 0000 0004 0386 9924, GRID grid.32224.35, Department of Pathology, , Massachusetts General Hospital, ; Boston, MA USA
                [68 ]ISNI 0000 0004 0386 9924, GRID grid.32224.35, Cancer Center, , Massachusetts General Hospital, ; Boston, MA USA
                [69 ]ISNI 0000 0001 2221 2926, GRID grid.17788.31, Endocrinology and Metabolism Department, , Hadassah-Hebrew University Medical Center, ; Jerusalem, Israel
                [70 ]ISNI 0000 0000 9159 4457, GRID grid.411023.5, Department of Psychiatry and Behavioral Sciences, , SUNY Upstate Medical University, ; Syracuse, NY USA
                [71 ]ISNI 0000 0001 2285 2675, GRID grid.239585.0, Institute for Genomic Medicine, , Columbia University Medical Center, Hammer Health Sciences, ; New York, NY USA
                [72 ]ISNI 0000 0001 2285 2675, GRID grid.239585.0, Department of Genetics and Development, , Columbia University Medical Center, Hammer Health Sciences, ; New York, NY USA
                [73 ]ISNI 0000 0004 1773 4764, GRID grid.415771.1, Centro de Investigacion en Salud Poblacional, Instituto Nacional de Salud Publica, ; Cuernavaca, Mexico
                [74 ]ISNI 0000 0001 0930 2361, GRID grid.4514.4, Genomics, Diabetes and Endocrinology, , Lund University, ; Lund, Sweden
                [75 ]ISNI 0000 0001 0930 2361, GRID grid.4514.4, Lund University Diabetes Centre, ; Malmö, Sweden
                [76 ]ISNI 0000 0000 9206 2401, GRID grid.267308.8, Human Genetics Center, , University of Texas Health Science Center at Houston, ; Houston, TX USA
                [77 ]ISNI 0000000419368729, GRID grid.21729.3f, Department of Neurology, , Columbia University, ; New York, NY USA
                [78 ]ISNI 0000000419368729, GRID grid.21729.3f, Institute of Genomic Medicine, , Columbia University, ; New York, NY USA
                [79 ]ISNI 0000 0001 0726 2490, GRID grid.9668.1, Institute of Biomedicine, , University of Eastern Finland, ; Kuopio, Finland
                [80 ]ISNI 0000 0000 9950 5666, GRID grid.15485.3d, Department of Psychiatry, , Helsinki University Central Hospital, Lapinlahdentie, ; Helsinki, Finland
                [81 ]ISNI 0000 0004 1937 0626, GRID grid.4714.6, Department of Medical Epidemiology and Biostatistics, , Karolinska Institutet, ; Stockholm, Sweden
                [82 ]ISNI 0000 0001 0670 2351, GRID grid.59734.3c, Icahn School of Medicine at Mount Sinai, ; New York, NY USA
                [83 ]ISNI 0000 0000 9950 5666, GRID grid.15485.3d, Department of Neurology, , Helsinki University Central Hospital, ; Helsinki, Finland
                [84 ]ISNI 0000 0004 0410 2071, GRID grid.7737.4, Department of Public Health, Faculty of Medicine, , University of Helsinki, ; Helsinki, Finland
                [85 ]GRID grid.66859.34, Cardiovascular Disease Initiative and Program in Medical and Population Genetics, , Broad Institute of MIT and Harvard, ; Cambridge, MA USA
                [86 ]ISNI 0000 0004 0647 4899, GRID grid.415482.e, Center for Genome Science, , Korea National Institute of Health, ; Chungcheongbuk-do, South Korea
                [87 ]ISNI 0000 0001 0807 5670, GRID grid.5600.3, MRC Centre for Neuropsychiatric Genetics & Genomics, , Cardiff University School of Medicine, ; Cardiff, UK
                [88 ]ISNI 0000 0001 1013 0499, GRID grid.14758.3f, Department of Health, , National Institute for Health and Welfare (THL), ; Helsinki, Finland
                [89 ]ISNI 0000000419368710, GRID grid.47100.32, Section of Cardiovascular Medicine, Department of Internal Medicine, , Yale School of Medicine, ; New Haven, CT USA
                [90 ]ISNI 0000 0001 0941 6502, GRID grid.189967.8, Division of Pediatric Gastroenterology, , Emory University School of Medicine, ; Atlanta, GA USA
                [91 ]ISNI 0000 0001 0302 820X, GRID grid.412484.f, Department of Internal Medicine, , Seoul National University Hospital, ; Seoul, South Korea
                [92 ]ISNI 0000 0001 0726 2490, GRID grid.9668.1, Institute of Clinical Medicine, , The University of Eastern Finland, ; Kuopio, Finland
                [93 ]ISNI 0000 0004 0628 207X, GRID grid.410705.7, Kuopio University Hospital, ; Kuopio, Finland
                [94 ]ISNI 0000 0001 2314 6254, GRID grid.502801.e, Department of Clinical Chemistry, Fimlab Laboratories and Finnish Cardiovascular Research Center-Tampere, Faculty of Medicine and Health Technology, , Tampere University, ; Tampere, Finland
                [95 ]ISNI 0000 0001 0670 2351, GRID grid.59734.3c, The Mindich Child Health and Development Institute, , Icahn School of Medicine at Mount Sinai, ; New York, NY USA
                [96 ]ISNI 0000 0004 1937 0482, GRID grid.10784.3a, Li Ka Shing Institute of Health Sciences, , The Chinese University of Hong Kong, ; Hong Kong, China
                [97 ]ISNI 0000 0004 1937 0482, GRID grid.10784.3a, Hong Kong Institute of Diabetes and Obesity, , The Chinese University of Hong Kong, ; Hong Kong, China
                [98 ]ISNI 0000 0004 1767 9005, GRID grid.20522.37, Cardiovascular Research REGICOR Group, , Hospital del Mar Medical Research Institute (IMIM), ; Barcelona, Catalonia Spain
                [99 ]ISNI 000000041936754X, GRID grid.38142.3c, Department of Genetics, , Harvard Medical School, ; Boston, MA USA
                [100 ]ISNI 0000 0004 1936 8948, GRID grid.4991.5, Oxford Centre for Diabetes, Endocrinology and Metabolism, , University of Oxford, Churchill Hospital, ; Headington, Oxford UK
                [101 ]ISNI 0000 0004 1936 8948, GRID grid.4991.5, Wellcome Centre for Human Genetics, , University of Oxford, ; Oxford, UK
                [102 ]ISNI 0000 0001 2306 7492, GRID grid.8348.7, Oxford NIHR Biomedical Research Centre, , Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, ; Oxford, UK
                [103 ]ISNI 0000 0001 2152 9905, GRID grid.50956.3f, F Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, , Cedars-Sinai Medical Center, ; Los Angeles, CA USA
                [104 ]ISNI 0000 0001 2182 2255, GRID grid.28046.38, Atherogenomics Laboratory, , University of Ottawa Heart Institute, ; Ottawa, Canada
                [105 ]ISNI 0000 0004 0386 9924, GRID grid.32224.35, Division of General Internal Medicine, , Massachusetts General Hospital, ; Boston, MA USA
                [106 ]ISNI 0000 0001 0930 2361, GRID grid.4514.4, Department of Clinical Sciences, , University Hospital Malmo Clinical Research Center, Lund University, ; Malmo, Sweden
                [107 ]Department of Clinical Sciences, Lund University, Skane University Hospital, Malmo, Sweden
                [108 ]ISNI 0000 0004 0627 7633, GRID grid.452651.1, Instituto Nacional de Medicina Genómica (INMEGEN), ; Mexico City, Mexico
                [109 ]ISNI 0000 0004 0397 2876, GRID grid.8241.f, Medical Research Institute, Ninewells Hospital and Medical School, , University of Dundee, ; Dundee, UK
                [110 ]ISNI 0000 0004 0470 5905, GRID grid.31501.36, Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, , Seoul National University, ; Seoul, South Korea
                [111 ]ISNI 0000 0001 2156 6853, GRID grid.42505.36, Department of Psychiatry, , Keck School of Medicine at the University of Southern California, ; Los Angeles, CA USA
                [112 ]ISNI 0000 0001 2171 9311, GRID grid.21107.35, Department of Psychiatry and Behavioral Sciences, , Johns Hopkins University School of Medicine, ; Baltimore, MD USA
                [113 ]ISNI 0000 0001 1271 4623, GRID grid.18886.3f, Division of Genetics and Epidemiology, , Institute of Cancer Research, ; London, UK
                [114 ]ISNI 0000 0001 0941 4873, GRID grid.10858.34, Medical Research Center, Oulu University Hospital, Oulu, Finland and Research Unit of Clinical Neuroscience, Neurology, , University of Oulu, ; Oulu, Finland
                [115 ]ISNI 0000 0000 8995 9090, GRID grid.482476.b, Research Center, , Montreal Heart Institute, ; Montreal, Quebec Canada
                [116 ]ISNI 0000 0001 2292 3357, GRID grid.14848.31, Department of Medicine, Faculty of Medicine, , Université de Montréal, ; Quebec, Canada
                [117 ]ISNI 0000 0004 1936 9916, GRID grid.412807.8, Department of Biomedical Informatics, , Vanderbilt University Medical Center, ; Nashville, TN USA
                [118 ]ISNI 0000 0004 1936 9916, GRID grid.412807.8, Department of Medicine, , Vanderbilt University Medical Center, ; Nashville, TN USA
                [119 ]ISNI 0000 0004 1936 8972, GRID grid.25879.31, Department of Biostatistics and Epidemiology, , Perelman School of Medicine at the University of Pennsylvania, ; Philadelphia, PA USA
                [120 ]ISNI 0000 0004 1936 8972, GRID grid.25879.31, Department of Medicine, , Perelman School of Medicine at the University of Pennsylvania, ; Philadelphia, PA USA
                [121 ]GRID grid.497620.e, Center for Non-Communicable Diseases, ; Karachi, Pakistan
                [122 ]ISNI 0000 0001 1013 0499, GRID grid.14758.3f, National Institute for Health and Welfare, ; Helsinki, Finland
                [123 ]ISNI 0000 0001 0695 783X, GRID grid.472754.7, Deutsches Herzzentrum München, ; Munich, Germany
                [124 ]ISNI 0000000123222966, GRID grid.6936.a, Technische Universität München, ; Munich, Germany
                [125 ]ISNI 0000 0001 2264 7217, GRID grid.152326.1, Division of Cardiovascular Medicine, , Nashville VA Medical Center and Vanderbilt University, School of Medicine, ; Nashville, TN USA
                [126 ]ISNI 0000 0001 0670 2351, GRID grid.59734.3c, Department of Psychiatry, , Icahn School of Medicine at Mount Sinai, ; New York, NY USA
                [127 ]ISNI 0000 0001 0670 2351, GRID grid.59734.3c, Department of Genetics and Genomic Sciences, , Icahn School of Medicine at Mount Sinai, ; New York, NY USA
                [128 ]ISNI 0000 0001 0670 2351, GRID grid.59734.3c, Institute for Genomics and Multiscale Biology, , Icahn School of Medicine at Mount Sinai, ; New York, NY USA
                [129 ]Institute of Clinical Medicine, Neurology, University of Eastern Finlad, Kuopio, Finland
                [130 ]ISNI 0000 0001 2322 6764, GRID grid.13097.3c, Department of Twin Research and Genetic Epidemiology, , King’s College London, ; London, UK
                [131 ]ISNI 0000 0001 1034 1720, GRID grid.410711.2, Departments of Genetics and Psychiatry, , University of North Carolina, ; Chapel Hill, NC USA
                [132 ]ISNI 0000 0001 2180 6431, GRID grid.4280.e, Saw Swee Hock School of Public Health, , National University of Singapore, National University Health System, ; Singapore, Singapore
                [133 ]ISNI 0000 0001 2180 6431, GRID grid.4280.e, Department of Medicine, Yong Loo Lin School of Medicine, , National University of Singapore, ; Singapore, Singapore
                [134 ]ISNI 0000 0004 0385 0924, GRID grid.428397.3, Duke-NUS Graduate Medical School, ; Singapore, Singapore
                [135 ]ISNI 0000 0001 2180 6431, GRID grid.4280.e, Life Sciences Institute, , National University of Singapore, ; Singapore, Singapore
                [136 ]ISNI 0000 0001 2180 6431, GRID grid.4280.e, Department of Statistics and Applied Probability, , National University of Singapore, ; Singapore, Singapore
                [137 ]ISNI 0000 0004 0410 2071, GRID grid.7737.4, Folkhälsan Institute of Genetics, Folkhälsan Research Center, ; Helsinki, Finland
                [138 ]ISNI 0000 0000 9950 5666, GRID grid.15485.3d, HUCH Abdominal Center, , Helsinki University Hospital, ; Helsinki, Finland
                [139 ]ISNI 0000 0001 2107 4242, GRID grid.266100.3, Center for Behavioral Genomics, Department of Psychiatry, , University of California, ; San Diego, CA USA
                [140 ]ISNI 0000 0001 2107 4242, GRID grid.266100.3, Institute of Genomic Medicine, , University of California, ; San Diego, CA USA
                [141 ]ISNI 0000 0004 1937 0538, GRID grid.9619.7, Juliet Keidan Instit.ute of Pediatric Gastroenterology, Shaare Zedek Medical Center, , The Hebrew University of Jerusalem, ; Jerusalem, Israel
                [142 ]ISNI 0000 0001 2159 0001, GRID grid.9486.3, Instituto de Investigaciones Biomédicas UNAM, ; Mexico City, Mexico
                [143 ]ISNI 0000 0001 0698 4037, GRID grid.416850.e, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, ; Mexico City, Mexico
                [144 ]ISNI 0000 0004 1936 8948, GRID grid.4991.5, Radcliffe Department of Medicine, , University of Oxford, ; Oxford, UK
                [145 ]ISNI 0000 0000 9558 4598, GRID grid.4494.d, Department of Gastroenterology and Hepatology, , University of Groningen and University Medical Center Groningen, ; Groningen, The Netherlands
                [146 ]ISNI 0000 0004 1937 0407, GRID grid.410721.1, Department of Physiology and Biophysics, , University of Mississippi Medical Center, ; Jackson, MS USA
                [147 ]GRID grid.66859.34, Program in Infectious Disease and Microbiome, , Broad Institute of MIT and Harvard, ; Cambridge, MA USA
                [148 ]ISNI 0000 0004 0386 9924, GRID grid.32224.35, Center for Computational and Integrative Biology, , Massachusetts General Hospital, ; Boston, MA USA
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                http://orcid.org/0000-0002-3039-8895
                http://orcid.org/0000-0001-9713-6200
                http://orcid.org/0000-0002-9110-5830
                http://orcid.org/0000-0003-1268-9995
                http://orcid.org/0000-0001-8422-6530
                http://orcid.org/0000-0002-7002-2868
                http://orcid.org/0000-0002-1704-3352
                http://orcid.org/0000-0001-6418-9592
                http://orcid.org/0000-0002-6110-5880
                http://orcid.org/0000-0002-1043-4756
                http://orcid.org/0000-0003-2889-0992
                http://orcid.org/0000-0003-1513-6077
                http://orcid.org/0000-0002-5771-2290
                Article
                2308
                10.1038/s41586-020-2308-7
                7334197
                32461654
                3f89e772-988d-4a71-abf9-3727407e6998
                © The Author(s) 2020

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                : 27 January 2019
                : 26 March 2020
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                medical genomics,rare variants
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                medical genomics, rare variants

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