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Landscape of multi-nucleotide variants in 125,748 human exomes and 15,708 genomes

Qingbo Wang, Emma Pierce-Hoffman, Beryl B. Cummings, Konrad J. Karczewski, Jessica Alföldi, Laurent C. Francioli, Laura D. Gauthier, Andrew J. Hill, Anne H. O’Donnell-Luria, Genome Aggregation Database (gnomAD) Production Team, Genome Aggregation Database (gnomAD) Consortium, Daniel G. MacArthur
doi: https://doi.org/10.1101/573378

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doi 
https://doi.org/10.1101/573378
History 
  • March 10, 2019.

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Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.

Author Information

  1. Qingbo Wang1,2,4,
  2. Emma Pierce-Hoffman1,
  3. Beryl B. Cummings1,2,3,
  4. Konrad J. Karczewski1,2,
  5. Jessica Alföldi1,2,
  6. Laurent C. Francioli1,2,
  7. Laura D. Gauthier1,
  8. Andrew J. Hill1,5,
  9. Anne H. O’Donnell-Luria1,2,
  10. Genome Aggregation Database (gnomAD) Production Team, Genome Aggregation Database (gnomAD) Consortium and
  11. Daniel G. MacArthur1,2
      1. 1Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
      2. 2Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
      3. 3Program in Bioinformatics and Integrative Genomics, Harvard Medical School, Boston, MA, USA
      4. 4Program in Biomedical and Biological Sciences, Harvard Medical School, Boston, MA, USA
      5. 5Department of Genome Sciences, University of Washington, Seattle, WA 98105, USA
      6. 1Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
      7. 2Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
      8. 3European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SD, United Kingdom
      9. 4Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
      10. 5Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
      11. 6Program in Bioinformatics and Integrative Genomics, Harvard Medical School, Boston, MA 02115, USA
      12. 7Genomics Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
      13. 8Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA, 02115, USA
      14. 9Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
      15. 10Broad Genomics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
      16. 11Division of Genetics and Genomics, Boston Children’s Hospital, Boston, Massachusetts 02115, USA
      17. 12Department of Pediatrics, Harvard Medical School, Boston, Massachusetts 02115, USA
      18. 13Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK
      19. 14National Heart & Lung Institute and MRC London Institute of Medical Sciences, Imperial College London, London UK
      20. 15Cardiovascular Research Centre, Royal Brompton & Harefield Hospitals NHS Trust, London UK
      21. 1Unidad de Investigacion de Enfermedades Metabolicas. Instituto Nacional de Ciencias Medicas y Nutricion. Mexico City
      22. 2Peninsula College of Medicine and Dentistry, Exeter, UK
      23. 3Division of Preventive Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, USA
      24. 4Division of Cardiovascular Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA
      25. 5Department of Cardiology, University Hospital, 43100 Parma, Italy
      26. 6Department of Biology, Faculty of Natural Sciences, University of Haifa, Haifa, Israel
      27. 7Departments of Medicine and Genetics, Albert Einstein College of Medicine, Bronx, NY, USA, 10461
      28. 8Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44122, USA
      29. 9Sorbonne Université, APHP, Gastroenterology Department, Saint Antoine Hospital, Paris, France
      30. 10NHLBI and Boston University’s Framingham Heart Study, Framingham, Massachusetts, USA
      31. 11Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA
      32. 12Department of Epidemiology, Boston University School of Public Health, Boston, Massachusetts, USA
      33. 13Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan 48109
      34. 14National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
      35. 15The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
      36. 16Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA
      37. 17Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC, USA
      38. 18Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, NC, USA
      39. 19Department of Cardiovascular Sciences, University of Leicester, Leicester, UK
      40. 20NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, UK
      41. 21Department of Epidemiology and Biostatistics, Imperial College London, London, UK
      42. 22Department of Cardiology, Ealing Hospital NHS Trust, Southall, UK
      43. 23Imperial College Healthcare NHS Trust, Imperial College London, London, UK
      44. 24Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China
      45. 25Department of Medicine, Harvard Medical School, Boston, MA
      46. 26Departments of Cardiovascular Medicine, Cellular and Molecular Medicine, Molecular Cardiology, and Quantitative Health Sciences, Cleveland Clinic, Cleveland, Ohio, USA
      47. 27McLean Hospital, Belmont, MA
      48. 28Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi, USA
      49. 29Department of Epidemiology, Colorado School of Public Health, Aurora, Colorado, USA
      50. 30Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
      51. 31Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
      52. 32Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA
      53. 33Department of Medicine and Pharmacology, University of Illinois at Chicago
      54. 34Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX, USA
      55. 35Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA
      56. 36National Heart, Lung, and Blood Institute’s Framingham Heart Study, Framingham, MA 01702, USA
      57. 37Cardiac Arrhythmia Service and Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA
      58. 38Cardiovascular Epidemiology and Genetics, Hospital del Mar Medical Research Institute (IMIM). Barcelona, Catalonia, Spain
      59. 39CIBER CV, Barcelona, Catalonia, Spain
      60. 40Departament of Medicine, Medical School, University of Vic-Central University of Catalonia. Vic, Catalonia, Spain
      61. 41Institute for Cardiogenetics, University of Lübeck, Lübeck, Germany
      62. 421. DZHK (German Research Centre for Cardiovascular Research), partner site Hamburg/Lübeck/Kiel, 23562 Lübeck, Germany
      63. 43University Heart Center Lübeck, 23562 Lübeck, Germany
      64. 44Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia
      65. 45Helsinki University and Helsinki University Hospital, Clinic of Gastroenterology, Helsinki, Finland
      66. 46Diabetes Unit and Center for Genomic Medicine, Massachusetts General Hospital; Programs in Metabolism and Medical & Population Genetics, Broad Institute; Department of Medicine, Harvard Medical School
      67. 47Institute of Clinical Molecular Biology (IKMB), Christian-Albrechts-University of Kiel, Kiel, Germany
      68. 48Bioinformatics Program, MGH Cancer Center and Department of Pathology
      69. 49Cancer Genome Computational Analysis, Broad Institute
      70. 50Endocrinology and Metabolism Department, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
      71. 51Department of Psychiatry and Behavioral Sciences; SUNY Upstate Medical University
      72. 52Institute for Genomic Medicine, Columbia University Medical Center, Hammer Health Sciences, 1408, 701 West 168th Street, New York, New York 10032, USA
      73. 53Department of Genetics & Development, Columbia University Medical Center, Hammer Health Sciences, 1602, 701 West 168th Street, New York, New York 10032, USA
      74. 54Centro de Investigacion en Salud Poblacional. Instituto Nacional de Salud Publica MEXICO
      75. 55Lund University, Sweden
      76. 56Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland
      77. 57Lund University Diabetes Centre
      78. 58Human Genetics Center, University of Texas Health Science Center at Houston, Houston, TX 77030
      79. 59Departmentg of Neurology, Columbia University
      80. 60Institute of Genomic Medicine, Columbia University
      81. 61Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland
      82. 62Department of Psychiatry, PL 320, Helsinki University Central Hospital, Lapinlahdentie, 00 180 Helsinki, Finland
      83. 63Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
      84. 64Icahn School of Medicine at Mount Sinai, New York, NY, USA
      85. 65Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland
      86. 66Department of Public Health, Faculty of Medicine, University of Helsinki, Finland
      87. 67Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
      88. 68Cardiovascular Disease Initiative and Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
      89. 69Center for Genome Science, Korea National Institute of Health, Chungcheongbuk-do, Republic of Korea
      90. 70MRC Centre for Neuropsychiatric Genetics & Genomics, Cardiff University School of Medicine, Hadyn Ellis Building, Maindy Road, Cardiff CF24 4HQ
      91. 71National Heart and Lung Institute, Cardiovascular Sciences, Hammersmith Campus, Imperial College London, London, UK
      92. 72Department of Health, THL-National Institute for Health and Welfare, 00271 Helsinki, Finland
      93. 73Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut3Center for Outcomes Research and Evaluation, Yale-New Haven Hospital, New Haven, Connecticut
      94. 74Division of Pediatric Gastroenterology, Emory University School of Medicine, Atlanta, Georgia, USA
      95. 75Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea
      96. 76The University of Eastern Finland, Institute of Clinical Medicine, Kuopio, Finland
      97. 77Kuopio University Hospital, Kuopio, Finland
      98. 78Department of Clinical Chemistry, Fimlab Laboratories and Finnish Cardiovascular Research Center-Tampere, Faculty of Medicine and Health Technology, Tampere University, Finland
      99. 79The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY
      100. 80Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
      101. 81Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Hong Kong, China
      102. 82Cardiovascular Research REGICOR Group, Hospital del Mar Medical Research Institute (IMIM). Barcelona, Catalonia
      103. 83Department of Genetics, Harvard Medical School, Boston, MA, USA
      104. 84Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Old Road, Headington, Oxford, OX3 7LJ UK
      105. 85Wellcome Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK
      106. 86Oxford NIHR Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford OX3 9DU, UK
      107. 87F Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
      108. 88Atherogenomics Laboratory, University of Ottawa Heart Institute, Ottawa, Canada
      109. 89Division of General Internal Medicine, Massachusetts General Hospital, Boston, MA, 02114
      110. 90Program in Population and Medical Genetics, Broad Institute, Cambridge, MA
      111. 91Department of Clinical Sciences, University Hospital Malmo Clinical Research Center, Lund University, Malmo, Sweden
      112. 92Lund University, Dept. Clinical Sciences, Skane University Hospital, Malmo, Sweden
      113. 93Instituto Nacional de Medicina Genómica (INMEGEN), Mexico City, 14610, Mexico
      114. 94Medical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK
      115. 95Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Republic of Korea
      116. 96Department of Psychiatry, Keck School of Medicine at the University of Southern California, Los Angeles, California, USA
      117. 97Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
      118. 98Division of Genetics and Epidemiology, Institute of Cancer Research, London SM2 5NG
      119. 99Medical Research Center, Oulu University Hospital, Oulu, Finland and Research Unit of Clinical Neuroscience, Neurology, University of Oulu, Oulu, Finland
      120. 100Research Center, Montreal Heart Institute, Montreal, Quebec, Canada, H1T 1C8
      121. 101Department of Medicine, Faculty of Medicine, Université de Montréal, Québec, Canada
      122. 102Broad Institute of MIT and Harvard, Cambridge MA, USA
      123. 103Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee, USA
      124. 104Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
      125. 105Department of Biostatistics and Epidemiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
      126. 106Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
      127. 107Center for Non-Communicable Diseases, Karachi, Pakistan
      128. 108National Institute for Health and Welfare, Helsinki, Finland
      129. 109Deutsches Herzzentrum München, Germany
      130. 110Technische Universität München
      131. 111Division of Cardiovascular Medicine, Nashville VA Medical Center and Vanderbilt University, School of Medicine, Nashville, TN 37232-8802, USA
      132. 112Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA
      133. 113Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
      134. 114Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
      135. 115Institute of Clinical Medicine, neurology, University of Eastern Finad, Kuopio, Finland
      136. 116Department of Twin Research and Genetic Epidemiology, King’s College London, London UK
      137. 117Departments of Genetics and Psychiatry, University of North Carolina, Chapel Hill, NC, USA
      138. 118Saw Swee Hock School of Public Health, National University of Singapore, National University Health System, Singapore
      139. 119Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
      140. 120Duke-NUS Graduate Medical School, Singapore
      141. 121Life Sciences Institute, National University of Singapore, Singapore
      142. 122Department of Statistics and Applied Probability, National University of Singapore, Singapore
      143. 123Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland
      144. 124HUCH Abdominal Center, Helsinki University Hospital, Helsinki, Finland
      145. 125Center for Behavioral Genomics, Department of Psychiatry, University of California, San Diego
      146. 126Institute of Genomic Medicine, University of California, San Diego
      147. 127Juliet Keidan Institute of Pediatric Gastroenterology, Shaare Zedek Medical Center, The Hebrew University of Jerusalem, Israel
      148. 128Instituto de Investigaciones Biomédicas UNAM Mexico City
      149. 129Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán Mexico City
      150. 130National Heart & Lung Institute & MRC London Institute of Medical Sciences, Imperial College London, London UK
      151. 131Cardiovascular Research Centre, Royal Brompton & Harefield Hospitals NHS Trust, London UK
      152. 132Radcliffe Department of Medicine, University of Oxford, Oxford UK
      153. 133Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, the Netherlands
      154. 134Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216, USA
      155. 135Program in Infectious Disease and Microbiome, Broad Institute of MIT and Harvard, Cambridge, MA, USA
      156. 136Center for Computational and Integrative Biology, Massachusetts General Hospital
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      Posted March 10, 2019.
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      Landscape of multi-nucleotide variants in 125,748 human exomes and 15,708 genomes
      Qingbo Wang, Emma Pierce-Hoffman, Beryl B. Cummings, Konrad J. Karczewski, Jessica Alföldi, Laurent C. Francioli, Laura D. Gauthier, Andrew J. Hill, Anne H. O’Donnell-Luria, Genome Aggregation Database (gnomAD) Production Team, Genome Aggregation Database (gnomAD) Consortium, Daniel G. MacArthur
      bioRxiv 573378; doi: https://doi.org/10.1101/573378
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