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Nature. 2016 Aug 18;536(7616):285-91. doi: 10.1038/nature19057.

Analysis of protein-coding genetic variation in 60,706 humans.

Collaborators (175)

Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T, O'Donnell-Luria AH, Ware JS, Hill AJ, Cummings BB, Tukiainen T, Birnbaum DP, Kosmicki JA, Duncan LE, Estrada K, Zhao F, Zou J, Pierce-Hoffman E, Berghout J, Cooper DN, Deflaux N, DePristo M, Do R, Flannick J, Fromer M, Gauthier L, Goldstein J, Gupta N, Howrigan D, Kiezun A, Kurki MI, Moonshine AL, Natarajan P, Orozco L, Peloso GM, Poplin R, Rivas MA, Ruano-Rubio V, Rose SA, Ruderfer DM, Shakir K, Stenson PD, Stevens C, Thomas BP, Tiao G, Tusie-Luna MT, Weisburd B, Won HH, Yu D, Altshuler DM, Ardissino D, Boehnke M, Danesh J, Donnelly S, Elosua R, Florez JC, Gabriel SB, Getz G, Glatt SJ, Hultman CM, Kathiresan S, Laakso M, McCarroll S, McCarthy MI, McGovern D, McPherson R, Neale BM, Palotie A, Purcell SM, Saleheen D, Scharf JM, Sklar P, Sullivan PF, Tuomilehto J, Tsuang MT, Watkins HC, Wilson JG, Daly MJ, MacArthur DG, Abboud HE, Abecasis G, Aguilar-Salinas CA, Arellano-Campos O, Atzmon G, Aukrust I, Barr CL, Bell GI, Bell GI, Bergen S, Bjørkhaug L, Blangero J, Bowden DW, Budman CL, Burtt NP, Centeno-Cruz F, Chambers JC, Chambert K, Clarke R, Collins R, Coppola G, Córdova EJ, Cortes ML, Cox NJ, Duggirala R, Farrall M, Fernandez-Lopez JC, Fontanillas P, Frayling TM, Freimer NB, Fuchsberger C, García-Ortiz H, Goel A, Gómez-Vázquez MJ, González-Villalpando ME, González-Villalpando C, Grados MA, Groop L, Haiman CA, Hanis CL, Hanis CL, Hattersley AT, Henderson BE, Hopewell JC, Huerta-Chagoya A, Islas-Andrade S, Jacobs SB, Jalilzadeh S, Jenkinson CP, Moran J, Jiménez-Morale S, Kähler A, King RA, Kirov G, Kooner JS, Kyriakou T, Lee JY, Lehman DM, Lyon G, MacMahon W, Magnusson PK, Mahajan A, Marrugat J, Martínez-Hernández A, Mathews CA, McVean G, Meigs JB, Meitinger T, Mendoza-Caamal E, Mercader JM, Mohlke KL, Moreno-Macías H, Morris AP, Najmi LA, Njølstad PR, O'Donovan MC, Ordóñez-Sánchez ML, Owen MJ, Park T, Pauls DL, Posthuma D, Revilla-Monsalve C, Riba L, Ripke S, Rodríguez-Guillén R, Rodríguez-Torres M, Sandor P, Seielstad M, Sladek R, Soberón X, Spector TD, Tai SE, Teslovich TM, Walford G, Wilkens LR, Williams AL.

Author information

1
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
2
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
3
School of Paediatrics and Child Health, University of Sydney, Sydney, New South Wales 2145, Australia.
4
Institute for Neuroscience and Muscle Research, Children's Hospital at Westmead, Sydney, New South Wales 2145, Australia.
5
Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, Massachusetts 02115, USA.
6
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
7
Division of Genetics and Genomics, Boston Children's Hospital, Boston, Massachusetts 02115, USA.
8
Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
9
National Heart and Lung Institute, Imperial College London, London SW7 2AZ, UK.
10
NIHR Royal Brompton Cardiovascular Biomedical Research Unit, Royal Brompton Hospital, London SW3 6NP, UK.
11
MRC Clinical Sciences Centre, Imperial College London, London SW7 2AZ, UK.
12
Genome Sciences, University of Washington, Seattle, Washington 98195, USA.
13
Program in Bioinformatics and Integrative Genomics, Harvard Medical School, Boston, Massachusetts 02115, USA.
14
Mouse Genome Informatics, Jackson Laboratory, Bar Harbor, Maine 04609, USA.
15
Center for Biomedical Informatics and Biostatistics, University of Arizona, Tucson, Arizona 85721, USA.
16
Institute of Medical Genetics, Cardiff University, Cardiff CF10 3XQ, UK.
17
Google, Mountain View, California 94043, USA.
18
Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
19
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
20
Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
21
The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
22
The Center for Statistical Genetics, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
23
Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
24
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
25
Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
26
Harvard Medical School, Boston, Massachusetts 02115, USA.
27
Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
28
Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
29
Immunogenomics and Metabolic Disease Laboratory, Instituto Nacional de Medicina Genómica, Mexico City 14610, Mexico.
30
Molecular Biology and Genomic Medicine Unit, Instituto Nacional de Ciencias Médicas y Nutrición, Mexico City 14080, Mexico.
31
Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Sungkyunkwan University, Samsung Medical Center, Seoul, South Korea.
32
Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
33
Vertex Pharmaceuticals, Boston, Massachusetts 02210, USA.
34
Department of Cardiology, University Hospital, 43100 Parma, Italy.
35
Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan 48109, USA.
36
Department of Public Health and Primary Care, Strangeways Research Laboratory, Cambridge CB1 8RN, UK.
37
Cardiovascular Epidemiology and Genetics, Hospital del Mar Medical Research Institute, 08003 Barcelona, Spain.
38
Department of Pathology and Cancer Center, Massachusetts General Hospital, Boston, Massachusetts, 02114 USA.
39
Psychiatric Genetic Epidemiology &Neurobiology Laboratory, State University of New York, Upstate Medical University, Syracuse, New York 13210, USA.
40
Department of Psychiatry and Behavioral Sciences, State University of New York, Upstate Medical University, Syracuse, New York 13210, USA.
41
Department of Neuroscience and Physiology, State University of New York, Upstate Medical University, Syracuse, New York 13210, USA.
42
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
43
Department of Medicine, University of Eastern Finland and Kuopio University Hospital, 70211 Kuopio, Finland.
44
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX1 2JD, UK.
45
Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford OX1 2JD, UK.
46
Oxford NIHR Biomedical Research Centre, Oxford University Hospitals Foundation Trust, Oxford OX1 2JD, UK.
47
Inflammatory Bowel Disease and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA.
48
Atherogenomics Laboratory, University of Ottawa Heart Institute, Ottawa, Ontario K1Y 4W7, Canada.
49
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, 00100 Helsinki, Finland.
50
Department of Biostatistics and Epidemiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
51
Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
52
Center for Non-Communicable Diseases, Karachi, Pakistan.
53
Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
54
Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
55
Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
56
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet SE-171 77 Stockholm, Sweden.
57
Department of Public Health, University of Helsinki, 00100 Helsinki, Finland.
58
Department of Psychiatry, University of California, San Diego, California 92093, USA.
59
Radcliffe Department of Medicine, University of Oxford, Oxford OX1 2JD, UK.
60
Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi 39216, USA.

Abstract

Large-scale reference data sets of human genetic variation are critical for the medical and functional interpretation of DNA sequence changes. Here we describe the aggregation and analysis of high-quality exome (protein-coding region) DNA sequence data for 60,706 individuals of diverse ancestries generated as part of the Exome Aggregation Consortium (ExAC). This catalogue of human genetic diversity contains an average of one variant every eight bases of the exome, and provides direct evidence for the presence of widespread mutational recurrence. We have used this catalogue to calculate objective metrics of pathogenicity for sequence variants, and to identify genes subject to strong selection against various classes of mutation; identifying 3,230 genes with near-complete depletion of predicted protein-truncating variants, with 72% of these genes having no currently established human disease phenotype. Finally, we demonstrate that these data can be used for the efficient filtering of candidate disease-causing variants, and for the discovery of human 'knockout' variants in protein-coding genes.

PMID:
27535533
PMCID:
PMC5018207
DOI:
10.1038/nature19057
[Indexed for MEDLINE]
Free PMC Article

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