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Inferring compound heterozygosity from large-scale exome sequencing data

Nature Genetics volume 56, pages 152–161 (2024)Cite this article

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Abstract

Recessive diseases arise when both copies of a gene are impacted by a damaging genetic variant. When a patient carries two potentially causal variants in a gene, accurate diagnosis requires determining that these variants occur on different copies of the chromosome (that is, are in trans) rather than on the same copy (that is, in cis). However, current approaches for determining phase, beyond parental testing, are limited in clinical settings. Here we developed a strategy for inferring phase for rare variant pairs within genes, leveraging genotypes observed in the Genome Aggregation Database (v2, n = 125,748 exomes). Our approach estimates phase with 96% accuracy, both in trio data and in patients with Mendelian conditions and presumed causal compound heterozygous variants. We provide a public resource of phasing estimates for coding variants and counts per gene of rare variants in trans that can aid interpretation of rare co-occurring variants in the context of recessive disease.

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Fig. 1: Overview of phasing approach using the expectation–maximization method in gnomAD.
Fig. 2: Phasing accuracy as a function of variant AF.
Fig. 3: Phasing accuracy using population-specific versus cosmopolitan Ptrans estimates.
Fig. 4: Phasing accuracy as a function of distance between variant pairs.
Fig. 5: Counts of genes with variants in trans in gnomAD.

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Data availability

The gnomAD v2 dataset can be accessed at https://gnomad.broadinstitute.org. We made use of prior quality control processing of these and related data. In addition, we downloaded HapMap2 genetic maps from https://github.com/joepickrell/1000-genomes-genetic-maps.

We provide both web-based look-up tools and downloads for the data generated here. A look-up tool to find the likely co-occurrence pattern between two rare (global AF in gnomAD exomes <5%) coding, flanking intronic (from position −1 to −3 in acceptor sites and +1 to +8 in donor sites) or 5′/3′ UTR variants can be found at https://gnomad.broadinstitute.org/variant-cooccurrence

Additionally, we display the per-gene counts tables that provide the details of the number of individuals with two rare variants, stratified by AF and functional consequence, on each gene’s main page. One table provides the details of counts of individuals with two heterozygous variants and includes the predicted phase, while the second table provides the details of individuals with homozygous variants. Both can be found by clicking on the ‘Variant Co-occurrence’ tab on each gene’s main page.

All variant co-occurrence tables can be downloaded from https://gnomad.broadinstitute.org/downloads#v2-variant-cooccurrence

Code availability

The code used to estimate Ptrans estimates for variant pairs and to determine the number of individuals carrying rare, compound heterozygous variants can be found at https://github.com/broadinstitute/gnomad_chets

The code has also been uploaded to Zenodo (https://doi.org/10.5281/zenodo.10034663).

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Acknowledgements

We thank all members of the gnomAD team for helpful comments and suggestions, and we particularly recognize the members of the gnomAD methods and browser teams who worked hard over many years to provide cleaned datasets, easy-to-use browsers and visualizations. This work was supported by the National Human Genome Research Institute (NHGRI; U24HG011450 to H.L.R. and M.J.D.; UM1HG008900 to D.G.M. and H.L.R.; U01HG011755 to A.O.-L. and H.L.R.).

Author information

Author notes

  1. These authors contributed equally: Michael H. Guo, Laurent C. Francioli.

Authors and Affiliations

  1. Department of Neurology, Hospital of the University of the Pennsylvania, Philadelphia, PA, USA

    Michael H. Guo

  2. Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Michael H. Guo, Laurent C. Francioli, Sarah L. Stenton, Julia K. Goodrich, Nicholas A. Watts, Moriel Singer-Berk, Emily Groopman, Philip W. Darnowsky, Matthew Solomonson, Samantha Baxter, Jessica Alföldi, Irina M. Armean, Samantha M. Baxter, Sarah E. Calvo, Katherine R. Chao, Sinéad Chapman, Siwei Chen, Ryan L. Collins, Beryl Cummings, Stacey Donnelly, Patrick T. Ellinor, Eleina England, Tõnu Esko, Emily Evangelista, Sanna Gudmundsson, Namrata Gupta, Zan Koenig, Kristen M. Laricchia, Emily Lipscomb, Steven A. Lubitz, Alicia R. Martin, James B. Meigs, Eric V. Minikel, Vamsi K. Mootha, Anne H. O’Donnell-Luria, William Phu, Timothy Poterba, Dan Rhodes, Andrea Saltzman, Jeremiah Scharf, Molly Schleicher, Eleanor Seaby, Rachel G. Son, Christine Stevens, Michael E. Talkowski, Yekaterina Tarasova, Christopher Vittal, Arcturus Wang, Qingbo Wang, James S. Ware, Nicola Whiffin, Michael W. Wilson, Mary T. Yohannes, Grace Tiao, Benjamin M. Neale, Joel N. Hirschhorn, Heidi L. Rehm, Mark J. Daly, Anne O’Donnell-Luria, Konrad J. Karczewski, Daniel G. MacArthur & Kaitlin E. Samocha

  3. Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA

    Laurent C. Francioli, Sarah L. Stenton, Julia K. Goodrich, Nicholas A. Watts, Matthew Solomonson, Jessica Alföldi, Irina M. Armean, Sinéad Chapman, Siwei Chen, Sanna Gudmundsson, Kristen M. Laricchia, Anne H. O’Donnell-Luria, Aarno Palotie, Timothy Poterba, Cotton Seed, Christine Stevens, Christopher Vittal, Arcturus Wang, Michael W. Wilson, Grace Tiao, Benjamin M. Neale, Heidi L. Rehm, Mark J. Daly, Anne O’Donnell-Luria, Konrad J. Karczewski, Daniel G. MacArthur & Kaitlin E. Samocha

  4. Division of Genetics and Genomics, Boston Children’s Hospital, Boston, MA, USA

    Sarah L. Stenton, Emily Groopman, Sanna Gudmundsson, Anne H. O’Donnell-Luria, William Phu & Anne O’Donnell-Luria

  5. Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Benjamin M. Neale

  6. The Novo Nordisk Foundation Center for Genomic Mechanisms of Disease, Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Benjamin M. Neale & Konrad J. Karczewski

  7. Departments of Genetics and Pediatrics, Harvard Medical School, Boston, MA, USA

    Joel N. Hirschhorn

  8. Division of Endocrinology, Boston Children’s Hospital, Boston, MA, USA

    Daniel Chasman & Joel N. Hirschhorn

  9. Center for Basic and Translational Obesity Research, Boston Children’s Hospital, Boston, MA, USA

    Joel N. Hirschhorn

  10. Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA

    Heidi L. Rehm, Anne O’Donnell-Luria, Konrad J. Karczewski & Kaitlin E. Samocha

  11. Institute for Molecular Medicine Finland (FIMM), Helsinki, Finland

    Sinéad Chapman, Steven McCarroll, Aarno Palotie, Timothy Poterba, Jeremiah Scharf, Cotton Seed, Christine Stevens, Michael E. Talkowski, Arcturus Wang & Mark J. Daly

  12. Centre for Population Genomics, Garvan Institute of Medical Research and UNSW Sydney, Sydney, New South Wales, Australia

    Daniel G. MacArthur

  13. Centre for Population Genomics, Murdoch Children’s Research Institute, Melbourne, Victoria, Australia

    Daniel G. MacArthur

  14. University of Miami Miller School of Medicine, Gastroenterology, Miami, FL, USA

    Maria Abreu

  15. Unidad de Investigacion de Enfermedades Metabolicas, Instituto Nacional de Ciencias Medicas y Nutricion, Mexico City, Mexico

    Carlos A. Aguilar Salinas

  16. Peninsula College of Medicine and Dentistry, Exeter, UK

    Tariq Ahmad, Sarah E. Calvo, Ryan L. Collins, Sekar Kathiresan, Anne H. O’Donnell-Luria, Jeremiah Scharf & Michael E. Talkowski

  17. Division of Preventive Medicine, Brigham and Women’s Hospital, Boston, MA, USA

    Christine M. Albert

  18. Division of Cardiovascular Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA

    Christine M. Albert

  19. Department of Cardiology, Parma University Hospital, Parma, Italy

    Diego Ardissino

  20. European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, UK

    Irina M. Armean

  21. Department of Biology Faculty of Natural Sciences, University of Haifa, Haifa, Israel

    Gil Atzmon

  22. Departments of Medicine and Genetics, Albert Einstein College of Medicine, Bronx, NY, USA

    Gil Atzmon

  23. Data Science Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Eric Banks, David Benjamin, Louis Bergelson, Kristian Cibulskis, Miguel Covarrubias, James Emery, Yossi Farjoun, Kiran Garimella, Laura D. Gauthier, Jeff Gentry, Andrea Haessly, Thibault Jeandet, Diane Kaplan, Trevyn Langsford, Christopher Llanwarne, Ruchi Munshi, Sam Novod, Nikelle Petrillo, David Roazen, Valentin Ruano-Rubio, Nareh Sahakian, Megan Shand, Jonathan T. Smith, Jose Soto, Kathleen Tibbetts, Charlotte Tolonen, Gordon Wade & Ben Weisburd

  24. Department of Quantitative Health Sciences, Lerner Research Institute Cleveland Clinic, Cleveland, OH, USA

    John Barnard

  25. Sorbonne Université, APHP, Gastroenterology Department Saint Antoine Hospital, Paris, France

    Laurent Beaugerie

  26. NHLBI and Boston University’s Framingham Heart Study, Framingham, MA, USA

    Emelia J. Benjamin

  27. Department of Medicine, Boston University Chobanian and Avedisian School of Medicine, Boston, MA, USA

    Emelia J. Benjamin

  28. Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA

    Emelia J. Benjamin

  29. Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA

    Michael Boehnke

  30. National Human Genome Research Institute, National Institutes of Health Bethesda, Bethesda, MD, USA

    Lori L. Bonnycastle

  31. The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York City, NY, USA

    Erwin P. Bottinger, Judy Cho & Ruth J. F. Loos

  32. Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA

    Donald W. Bowden

  33. Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC, USA

    Donald W. Bowden

  34. Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, NC, USA

    Donald W. Bowden

  35. Department of Cardiovascular Sciences, University of Leicester, Leicester, UK

    Matthew J. Bown & Nilesh J. Samani

  36. NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, UK

    Matthew J. Bown & Nilesh J. Samani

  37. John Hopkins Bloomberg School of Public Health, Baltimore, MD, USA

    Steven Brant

  38. Harvard School of Public Health, Boston, MA, USA

    Hannia Campos

  39. Central American Population Center, San Pedro, Costa Rica

    Hannia Campos

  40. Department of Epidemiology and Biostatistics, Imperial College London, London, UK

    John C. Chambers

  41. Department of Cardiology, Ealing Hospital, NHS Trust, Southall, UK

    John C. Chambers & Jaspal Kooner

  42. Imperial College Healthcare NHS Trust, Imperial College London, London, UK

    John C. Chambers & Jaspal Kooner

  43. Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China

    Juliana C. Chan & Ronald C. W. Ma

  44. Department of Medicine, Harvard Medical School, Boston, MA, USA

    Daniel Chasman, Bruce Cohen, Jose Florez, Gad Getz, Sekar Kathiresan, James B. Meigs & Dost Ongur

  45. Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    Rex L. Chisholm

  46. University of Cambridge, Cambridge, UK

    Rajiv Chowdhury & John Danesh

  47. Departments of Cardiovascular, Medicine Cellular and Molecular Medicine Molecular Cardiology, Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH, USA

    Mina K. Chung

  48. Department of Pediatrics, Columbia University Irving Medical Center, New York City, NY, USA

    Wendy K. Chung

  49. Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York City, NY, USA

    Wendy K. Chung

  50. Department of Medicine, Columbia University Medical Center, New York City, NY, USA

    Wendy K. Chung

  51. McLean Hospital, Belmont, MA, USA

    Bruce Cohen & Dost Ongur

  52. Division of Medical Sciences, Harvard Medical School, Boston, MA, USA

    Ryan L. Collins & Beryl Cummings

  53. Genomics Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Kristen M. Connolly

  54. Department of Medicine, University of Mississippi Medical Center, Jackson, MI, USA

    Adolfo Correa

  55. Department of Epidemiology, Colorado School of Public Health, Aurora, CO, USA

    Dana Dabelea

  56. Department of Medicine and Pharmacology, University of Illinois at Chicago, Chicago, IL, USA

    Dawood Darbar

  57. Vanderbilt University Medical Center, Nashville, TN, USA

    Joshua Denny

  58. Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX, USA

    Ravindranath Duggirala

  59. Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA

    Josée Dupuis

  60. National Heart Lung and Blood Institute’s Framingham Heart Study, Framingham, MA, USA

    Josée Dupuis

  61. Cardiac Arrhythmia Service and Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA

    Patrick T. Ellinor & Steven A. Lubitz

  62. Cardiovascular Epidemiology and Genetics Hospital del Mar Medical Research Institute (IMIM), Barcelona, Catalonia, Spain

    Roberto Elosua

  63. CIBER CV, Barcelona, Spain

    Roberto Elosua

  64. Department of Medicine, Medical School University of Vic-Central, University of Catalonia, Barcelona, Spain

    Roberto Elosua & Jaume Marrugat

  65. Institute for Cardiogenetics, University of Lübeck, Lübeck, Germany

    Jeanette Erdmann

  66. German Research Centre for Cardiovascular Research, Hamburg/Lübeck/Kiel, Lübeck, Germany

    Jeanette Erdmann

  67. University Heart Center Lübeck, Lübeck, Germany

    Jeanette Erdmann

  68. Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia

    Tõnu Esko & Andres Metspalu

  69. Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia

    Diane Fatkin

  70. Faculty of Medicine, UNSW Sydney, Kensington, New South Wales, Australia

    Diane Fatkin

  71. Cardiology Department, St Vincent’s Hospital, Darlinghurst, New South Wales, Australia

    Diane Fatkin

  72. Broad Genomics, Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Steven Ferriera & Namrata Gupta

  73. Diabetes Unit and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA

    Jose Florez

  74. Programs in Metabolism and Medical & Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Jose Florez

  75. Institute of Clinical Molecular Biology (IKMB), Christian-Albrechts-University of Kiel, Kiel, Germany

    Andre Franke

  76. Helsinki University and Helsinki University Hospital Clinic of Gastroenterology, Helsinki, Finland

    Martti Färkkilä

  77. Bioinformatics Program MGH Cancer Center and Department of Pathology, Boston, MA, USA

    Stacey Gabriel & Gad Getz

  78. Cancer Genome Computational Analysis, Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Gad Getz

  79. Department of Psychiatry and Behavioral Sciences, Boston Children’s Hospital and Harvard Medical School, Boston, MA, USA

    David C. Glahn

  80. Harvard Medical School Teaching Hospital, Boston, MA, USA

    David C. Glahn

  81. Department of Endocrinology and Metabolism, Hadassah Medical Center and Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel

    Benjamin Glaser

  82. Department of Psychiatry and Behavioral Sciences, SUNY Upstate Medical University, Syracuse, NY, USA

    Stephen J. Glatt

  83. Institute for Genomic Medicine, Columbia University Medical Center Hammer Health Sciences, New York City, NY, USA

    David Goldstein

  84. Department of Genetics & Development, Columbia University Medical Center, Hammer Health Sciences, New York City, NY, USA

    David Goldstein

  85. Centro de Investigacion en Salud Poblacional, Instituto Nacional de Salud Publica, Cuernavaca, Mexico

    Clicerio Gonzalez

  86. Lund University, Lund, Sweden

    Leif Groop

  87. Institute for Molecular Medicine Finland (FIMM), HiLIFE University of Helsinki, Helsinki, Finland

    Leif Groop, Jaakko Kaprio, Aarno Palotie, Samuli Ripatti, Tiinamaija Tuomi & Maija Wessman

  88. Lund University Diabetes Centre, Malmö, Sweden

    Christopher Haiman

  89. Washington School of Medicine, St Louis, MO, USA

    Ira Hall & Nathan Stitziel

  90. Human Genetics Center University of Texas Health Science Center at Houston, Houston, TX, USA

    Craig Hanis

  91. Department of Neurology, Columbia University, New York City, NY, USA

    Matthew Harms

  92. Institute of Genomic Medicine, Columbia University, New York City, NY, USA

    Matthew Harms

  93. Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland

    Mikko Hiltunen

  94. Department of Psychiatry, Helsinki University Central Hospital Lapinlahdentie, Helsinki, Finland

    Matti M. Holi

  95. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden

    Christina M. Hultman & Patrick F. Sullivan

  96. Icahn School of Medicine at Mount Sinai, New York City, NY, USA

    Christina M. Hultman & Eimear Kenny

  97. Bonei Olam, Center for Rare Jewish Genetic Diseases, Brooklyn, NY, USA

    Chaim Jalas

  98. Department of Neurology, Helsinki University, Central Hospital, Helsinki, Finland

    Mikko Kallela

  99. Cardiovascular Disease Initiative and Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Sekar Kathiresan

  100. Charles Bronfman Institute for Personalized Medicine, New York City, NY, USA

    Eimear Kenny

  101. Division of Genome Science, Department of Precision Medicine, National Institute of Health, Cheongju, Republic of Korea

    Bong-Jo Kim & Young Jin Kim

  102. MRC Centre for Neuropsychiatric Genetics & Genomics, Cardiff University School of Medicine, Cardiff, UK

    George Kirov, Michael C. O’Donovan & Michael J. Owen

  103. National Heart and Lung Institute Cardiovascular Sciences, Hammersmith Campus, Imperial College London, London, UK

    Jaspal Kooner

  104. Department of Health THL-National Institute for Health and Welfare, Helsinki, Finland

    Seppo Koskinen

  105. Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, Center for Outcomes Research and Evaluation Yale-New Haven Hospital, New Haven, CT, USA

    Harlan M. Krumholz

  106. Division of Pediatric Gastroenterology, Emory University School of Medicine, Atlanta, GA, USA

    Subra Kugathasan

  107. Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea

    Soo Heon Kwak & Kyong Soo Park

  108. The University of Eastern Finland, Institute of Clinical Medicine, Kuopio, Finland

    Markku Laakso

  109. Kuopio University Hospital, Kuopio, Finland

    Markku Laakso

  110. Department of Genetics, Yale School of Medicine, New Haven, CT, USA

    Nicole Lake & Monkol Lek

  111. Department of Clinical Chemistry Fimlab Laboratories and Finnish Cardiovascular Research Center-Tampere Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland

    Terho Lehtimäki & Kari M. Mattila

  112. The Mindich Child Health and Development, Institute Icahn School of Medicine at Mount Sinai, New York City, NY, USA

    Ruth J. F. Loos

  113. National Autonomous University of Mexico, Mexico City, Mexico

    Teresa Tusie Luna

  114. Salvador Zubirán National Institute of Health Sciences and Nutrition, Mexico City, Mexico

    Teresa Tusie Luna

  115. Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China

    Ronald C. W. Ma

  116. Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Hong Kong, China

    Ronald C. W. Ma

  117. University of California San Francisco Parnassus Campus, San Francisco, CA, USA

    Gregory M. Marcus

  118. Cardiovascular Research REGICOR Group, Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain

    Jaume Marrugat

  119. Department of Genetics, Harvard Medical School, Boston, MA, USA

    Steven McCarroll

  120. Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK

    Mark I. McCarthy

  121. Welcome Centre for Human Genetics, University of Oxford, Oxford, UK

    Mark I. McCarthy

  122. Oxford NIHR Biomedical Research Centre, Oxford University Hospitals, NHS Foundation Trust, John Radcliffe Hospital, Oxford, UK

    Mark I. McCarthy

  123. John P. Hussman Institute for Human Genomics, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA

    Jacob McCauley

  124. The Dr. John T. Macdonald Foundation Department of Human Genetics, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA

    Jacob McCauley

  125. F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute Cedars-Sinai Medical Center, Los Angeles, CA, USA

    Dermot McGovern

  126. Atherogenomics Laboratory University of Ottawa, Heart Institute, Ottawa, Ontario, Canada

    Ruth McPherson

  127. Division of General Internal Medicine, Massachusetts General Hospital, Boston, MA, USA

    James B. Meigs

  128. Department of Clinical Sciences University, Hospital Malmo Clinical Research Center, Lund University, Malmö, Sweden

    Olle Melander

  129. University of Arizona Health Science, Tuscon, AZ, USA

    Deborah Meyers

  130. Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA

    Braxton D. Mitchell

  131. Howard Hughes Medical Institute and Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA

    Vamsi K. Mootha

  132. International Centre for Diarrhoeal Disease Research, Dhaka, Bangladesh

    Aliya Naheed

  133. Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Saman Nazarian & Dan Rader

  134. Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA

    Saman Nazarian

  135. Lund University, Department of Clinical Sciences, Skåne University Hospital, Malmö, Sweden

    Peter M. Nilsson

  136. Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan

    Yukinori Okada & Qingbo Wang

  137. Laboratory of Statistical Immunology, Immunology Frontier Research Center (WPI-IFReC), Osaka University, Suita, Japan

    Yukinori Okada

  138. Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Suita, Japan

    Yukinori Okada

  139. Instituto Nacional de Medicina Genómica, (INMEGEN), Mexico City, Mexico

    Lorena Orozco

  140. Medical Research Institute, Ninewells Hospital and Medical School University of Dundee, Dundee, UK

    Colin Palmer

  141. Wake Forest School of Medicine, Winston-Salem, NC, USA

    Nicholette D. Palmer

  142. Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Republic of Korea

    Kyong Soo Park

  143. Department of Psychiatry Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    Carlos Pato

  144. Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Ann E. Pulver

  145. Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    Dan Rader

  146. Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK

    Nazneen Rahman

  147. University of Washington, Seattle, WA, USA

    Alex Reiner

  148. Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    Alex Reiner

  149. Medical Research Center, Oulu University Hospital, Oulu Finland and Research Unit of Clinical Neuroscience Neurology University of Oulu, Oulu, Finland

    Anne M. Remes

  150. Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA

    Stephen Rich

  151. Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA

    Stephen Rich

  152. Research Center Montreal Heart Institute, Montreal, Québec, Canada

    John D. Rioux

  153. Department of Medicine, Faculty of Medicine Université de Montréal, Montreal, Québec, Canada

    John D. Rioux

  154. Department of Public Health, Faculty of Medicine, University of Helsinki, Helsinki, Finland

    Samuli Ripatti & Erkki Vartiainen

  155. Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Samuli Ripatti & J. Gustav Smith

  156. Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA

    Dan M. Roden

  157. Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA

    Dan M. Roden

  158. The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA

    Jerome I. Rotter & Kent D. Taylor

  159. Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Danish Saleheen

  160. Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA

    Danish Saleheen

  161. Center for Non-Communicable Diseases, Karachi, Pakistan

    Danish Saleheen

  162. National Institute for Health and Welfare, Helsinki, Finland

    Veikko Salomaa & Jaana Suvisaari

  163. Deutsches Herzzentrum, München, Germany

    Heribert Schunkert

  164. Technische Universität München, München, Germany

    Heribert Schunkert

  165. Institute of Genetic Epidemiology, Department of Genetics and Pharmacology, Medical University of Innsbruck, Innsbruck, Austria

    Sebastian Schönherr

  166. Duke Molecular Physiology Institute, Durham, NC, USA

    Svati H. Shah

  167. Division of Cardiovascular Medicine, Nashville VA Medical Center, Vanderbilt University School of Medicine, Nashville, TN, USA

    Moore B. Shoemaker

  168. Division of Endocrinology, National University Hospital, Singapore City, Singapore

    Tai Shyong

  169. NUS Saw Swee Hock School of Public Health, Singapore City, Singapore

    Tai Shyong

  170. Channing Division of Network Medicine, Brigham and Women’s Hospital, Boston, MA, USA

    Edwin K. Silverman

  171. Harvard Medical School, Boston, MA, USA

    Edwin K. Silverman

  172. Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York City, NY, USA

    Pamela Sklar

  173. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York City, NY, USA

    Pamela Sklar

  174. Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York City, NY, USA

    Pamela Sklar

  175. The Wallenberg Laboratory/Department of Molecular and Clinical Medicine, Institute of Medicine, Gothenburg University and the Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden

    J. Gustav Smith

  176. Department of Cardiology, Wallenberg Center for Molecular Medicine and Lund University Diabetes Center, Clinical Sciences, Lund University and Skåne University Hospital, Lund, Sweden

    J. Gustav Smith

  177. Institute of Clinical Medicine Neurology, University of Eastern Finad, Kuopio, Finland

    Hilkka Soininen

  178. Gastroenterology Department, Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, CRSA, AP-HP, Saint Antoine Hospital, Paris, France

    Harry Sokol

  179. INRA, UMR1319 Micalis & AgroParisTech, Jouy en Josas, France

    Harry Sokol

  180. Paris Center for Microbiome Medicine (PaCeMM), FHU, Paris, France

    Harry Sokol

  181. Department of Twin Research and Genetic Epidemiology, King’s College London, London, UK

    Tim Spector

  182. The McDonnell Genome Institute at Washington University, Seattle, WA, USA

    Nathan Stitziel

  183. Departments of Genetics and Psychiatry, University of North Carolina, Chapel Hill, NC, USA

    Patrick F. Sullivan

  184. Saw Swee Hock School of Public Health National University of Singapore, National University Health System, Singapore City, Singapore

    E. Shyong Tai & Yik Ying Teo

  185. Department of Medicine, Yong Loo Lin School of Medicine National University of Singapore, Singapore City, Singapore

    E. Shyong Tai

  186. Duke-NUS Graduate Medical School, Singapore City, Singapore

    E. Shyong Tai

  187. Life Sciences Institute, National University of Singapore, Singapore City, Singapore

    Yik Ying Teo

  188. Department of Statistics and Applied Probability, National University of Singapore, Singapore City, Singapore

    Yik Ying Teo

  189. Center for Behavioral Genomics, Department of Psychiatry, University of California, San Diego, San Diego, CA, USA

    Ming Tsuang

  190. Institute of Genomic Medicine, University of California, San Diego, San Diego, CA, USA

    Ming Tsuang

  191. Endocrinology, Abdominal Center, Helsinki University Hospital, Helsinki, Finland

    Tiinamaija Tuomi

  192. Institute of Genetics, Folkhalsan Research Center, Helsinki, Finland

    Tiinamaija Tuomi

  193. Juliet Keidan Institute of Pediatric Gastroenterology Shaare Zedek Medical Center, The Hebrew University of Jerusalem, Jerusalem, Israel

    Dan Turner

  194. Instituto de Investigaciones Biomédicas, UNAM, Mexico City, Mexico

    Teresa Tusie-Luna

  195. Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico

    Teresa Tusie-Luna

  196. Department of Psychiatry and Human Behavior, University of California Irvine, Irvine, CA, USA

    Marquis Vawter

  197. National Heart & Lung Institute & MRC London Institute of Medical Sciences, Imperial College London, London, UK

    James S. Ware

  198. Royal Brompton & Harefield Hospitals, Guy’s and St. Thomas’ NHS Foundation Trust, London, UK

    James S. Ware

  199. Radcliffe Department of Medicine, University of Oxford, Oxford, UK

    Hugh Watkins

  200. Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands

    Rinse K. Weersma

  201. Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland

    Maija Wessman

  202. National Heart & Lung Institute and MRC London Institute of Medical Sciences, Imperial College London, London, UK

    Nicola Whiffin

  203. Cardiovascular Research Centre, Royal Brompton & Harefield Hospitals NHS Trust, London, UK

    Nicola Whiffin

  204. Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA

    James G. Wilson

  205. Program in Infectious Disease and Microbiome, Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Ramnik J. Xavier

  206. Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA, USA

    Ramnik J. Xavier

Authors
  1. Michael H. Guo
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  2. Laurent C. Francioli
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  19. Kaitlin E. Samocha
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Consortia

gnomAD Project Consortium

  • Maria Abreu
  • , Carlos A. Aguilar Salinas
  • , Tariq Ahmad
  • , Christine M. Albert
  • , Jessica Alföldi
  • , Diego Ardissino
  • , Irina M. Armean
  • , Gil Atzmon
  • , Eric Banks
  • , John Barnard
  • , Samantha M. Baxter
  • , Laurent Beaugerie
  • , Emelia J. Benjamin
  • , David Benjamin
  • , Louis Bergelson
  • , Michael Boehnke
  • , Lori L. Bonnycastle
  • , Erwin P. Bottinger
  • , Donald W. Bowden
  • , Matthew J. Bown
  • , Steven Brant
  • , Sarah E. Calvo
  • , Hannia Campos
  • , John C. Chambers
  • , Juliana C. Chan
  • , Katherine R. Chao
  • , Sinéad Chapman
  • , Daniel Chasman
  • , Siwei Chen
  • , Rex L. Chisholm
  • , Judy Cho
  • , Rajiv Chowdhury
  • , Mina K. Chung
  • , Wendy K. Chung
  • , Kristian Cibulskis
  • , Bruce Cohen
  • , Ryan L. Collins
  • , Kristen M. Connolly
  • , Adolfo Correa
  • , Miguel Covarrubias
  • , Beryl Cummings
  • , Dana Dabelea
  • , Mark J. Daly
  • , John Danesh
  • , Dawood Darbar
  • , Joshua Denny
  • , Stacey Donnelly
  • , Ravindranath Duggirala
  • , Josée Dupuis
  • , Patrick T. Ellinor
  • , Roberto Elosua
  • , James Emery
  • , Eleina England
  • , Jeanette Erdmann
  • , Tõnu Esko
  • , Emily Evangelista
  • , Yossi Farjoun
  • , Diane Fatkin
  • , Steven Ferriera
  • , Jose Florez
  • , Laurent C. Francioli
  • , Andre Franke
  • , Martti Färkkilä
  • , Stacey Gabriel
  • , Kiran Garimella
  • , Laura D. Gauthier
  • , Jeff Gentry
  • , Gad Getz
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  • , Benjamin Glaser
  • , Stephen J. Glatt
  • , David Goldstein
  • , Clicerio Gonzalez
  • , Julia K. Goodrich
  • , Leif Groop
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  • , Diane Kaplan
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  • , Emily Lipscomb
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  • , Ruth J. F. Loos
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  • , Jaume Marrugat
  • , Alicia R. Martin
  • , Kari M. Mattila
  • , Steven McCarroll
  • , Mark I. McCarthy
  • , Jacob McCauley
  • , Dermot McGovern
  • , Ruth McPherson
  • , James B. Meigs
  • , Olle Melander
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  • , Eric V. Minikel
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  • , Aliya Naheed
  • , Saman Nazarian
  • , Benjamin M. Neale
  • , Peter M. Nilsson
  • , Sam Novod
  • , Anne H. O’Donnell-Luria
  • , Michael C. O’Donovan
  • , Yukinori Okada
  • , Dost Ongur
  • , Lorena Orozco
  • , Michael J. Owen
  • , Colin Palmer
  • , Nicholette D. Palmer
  • , Aarno Palotie
  • , Kyong Soo Park
  • , Carlos Pato
  • , Nikelle Petrillo
  • , William Phu
  • , Timothy Poterba
  • , Ann E. Pulver
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  • , Nazneen Rahman
  • , Heidi L. Rehm
  • , Alex Reiner
  • , Anne M. Remes
  • , Dan Rhodes
  • , Stephen Rich
  • , John D. Rioux
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  • , Jerome I. Rotter
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  • , Danish Saleheen
  • , Veikko Salomaa
  • , Andrea Saltzman
  • , Nilesh J. Samani
  • , Kaitlin E. Samocha
  • , Jeremiah Scharf
  • , Molly Schleicher
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  • , Cotton Seed
  • , Svati H. Shah
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  • , Tai Shyong
  • , Edwin K. Silverman
  • , Moriel Singer-Berk
  • , Pamela Sklar
  • , J. Gustav Smith
  • , Jonathan T. Smith
  • , Hilkka Soininen
  • , Harry Sokol
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  • , Rachel G. Son
  • , Jose Soto
  • , Tim Spector
  • , Christine Stevens
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  • , Arcturus Wang
  • , Qingbo Wang
  • , James S. Ware
  • , Hugh Watkins
  • , Nicholas A. Watts
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  • , Michael W. Wilson
  • , James G. Wilson
  • , Ramnik J. Xavier
  •  & Mary T. Yohannes

Contributions

M.H.G., L.C.F., S.L.S., J.K.G., A.O.-L., K.J.K., D.G.M. and K.E.S. conceived and designed experiments. M.H.G., L.C.F., S.L.S. and J.K.G. performed the analyses. N.A.W., P.W.D. and M.S. developed visualizations for the web browser. E.G. and M.S.-B. performed variant curation. S.B., G.T., B.M.N., J.N.H., H.L.R., M.J.D., A.O.-L. and K.J.K. provided data and analysis suggestions. J.N.H., D.G.M. and K.E.S. supervised the work. M.H.G., L.C.F., S.L.S., J.K.G. and K.E.S. completed the primary writing of the manuscript with input and approval of the final version from all other authors.

Corresponding author

Correspondence to Kaitlin E. Samocha.

Ethics declarations

Competing interests

L.C.F. is currently an employee of, and owns stock in, Vertex Pharmaceuticals. B.M.N. is a member of the scientific advisory board at Deep Genomics and Neumora (f/k/a RBNC Therapeutics). H.L.R. has received support from Illumina and Microsoft to support rare disease gene discovery and diagnosis. M.J.D. is a founder of Maze Therapeutics and Neumora Therapeutics (f/k/a RBNC Therapeutics). A.O.-L. has consulted for Tome Biosciences and Ono Pharma USA and is a member of the scientific advisory board for Congenica and the Simons Foundation SPARK for Autism study. K.J.K. is a consultant for Tome Biosciences and Vor Biosciences and a member of the Scientific Advisory Board of Nurture Genomics. D.G.M. is a paid advisor to GlaxoSmithKline, Insitro, Variant Bio and Overtone Therapeutics and has received research support from AbbVie, Astellas, Biogen, BioMarin, Eisai, Google, Merck, Microsoft, Pfizer and Sanofi-Genzyme. K.E.S. has received support from Microsoft for work related to rare disease diagnostics. The remaining authors declare no competing interests.

Peer review

Peer review information

Nature Genetics thanks Arnaldur Gylfason, Tobias Marschall and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Peer reviewer reports are available.

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Extended data

Extended Data Fig. 1 Publicly available browser for sharing phasing data.

a, Sample gnomAD browser output for two variants (GRCh37 1-55505647-G-T and 1-55523855-G-A) in the gene PCSK9. On the top, a table subdivided by genetic ancestry group displays how many individuals in gnomAD v2 from that genetic ancestry are consistent with the two variants occurring on different haplotypes (trans), and how many individuals are consistent with their occurring on the same haplotype (cis). Below that, there is a 3×3 table that contains the 9 possible combinations of genotypes for the two variants of interest. The number of individuals in gnomAD v2 that fall in each of these combinations are shown and are colored by whether they are consistent with variants falling on different haplotypes (red) or the same haplotype (blue), or whether they are indeterminate (purple). The estimated haplotype counts for the four possible haplotypes for the two variants as calculated by the EM algorithm is displayed on the bottom right. The probability of being in trans for this particular pair of variants is >99%. b, Variant co-occurrence tables on the gene landing page. For each gene (GBA1 shown), the top table lists the number of individuals carrying pairs of rare heterozygous variants by inferred phase, allele frequency (AF), and predicted functional consequence. The number of individuals with homozygous variants are tabulated in the same manner and presented as a comparison below. AF thresholds of ≤ 5%, ≤ 1%, and ≤ 0.5% are displayed across six predicted functional consequences (combinations of pLoF, various evidence strengths of predicted pathogenicity for missense variants, and synonymous variants). Both variants in the variant pair must be annotated with a consequence at least as severe as the consequence listed (that is, pLoF + strong missense also includes pLoF + pLoF).

Supplementary information

Supplementary Information

Supplementary Note and Supplementary Figs. 1–9.

Reporting Summary

Peer Review File

Supplementary Tables

Supplementary Tables 1 and 2: The dataset includes phasing information for diagnostic variants from CMG patients and manual curation of rare, compound heterozygous loss-of-function variants.

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Guo, M.H., Francioli, L.C., Stenton, S.L. et al. Inferring compound heterozygosity from large-scale exome sequencing data. Nat Genet 56, 152–161 (2024). https://doi.org/10.1038/s41588-023-01608-3

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