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Assessing the contribution of rare variants to complex trait heritability from whole-genome sequence data

Nature Genetics volume 54, pages 263–273 (2022)Cite this article

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Abstract

Analyses of data from genome-wide association studies on unrelated individuals have shown that, for human traits and diseases, approximately one-third to two-thirds of heritability is captured by common SNPs. However, it is not known whether the remaining heritability is due to the imperfect tagging of causal variants by common SNPs, in particular whether the causal variants are rare, or whether it is overestimated due to bias in inference from pedigree data. Here we estimated heritability for height and body mass index (BMI) from whole-genome sequence data on 25,465 unrelated individuals of European ancestry. The estimated heritability was 0.68 (standard error 0.10) for height and 0.30 (standard error 0.10) for body mass index. Low minor allele frequency variants in low linkage disequilibrium (LD) with neighboring variants were enriched for heritability, to a greater extent for protein-altering variants, consistent with negative selection. Our results imply that rare variants, in particular those in regions of low linkage disequilibrium, are a major source of the still missing heritability of complex traits and disease.

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Fig. 1: GREML-LDMS estimates with 8 bins (2 LD bins for each of the 4 MAF bins) correcting for 20 PCs (calculated from LD-pruned HM3 SNPs) after imputing SNPs from Illumina InfiniumCore24, GSA 24 and Affymetrix Axiom arrays using HRC reference panels for n = 25,465 samples.
Fig. 2: GREML-LDMS of height and BMI for n = 25,465 samples using 3 or 4 LD groups for each MAF bin, correcting for 48, 160 or 320 PCs computed from WGS variants.
Fig. 3: Variance explained per variant (the estimate of genetic variance divided by the number of variants in each bin) from GREML-LDMS with the low-LD and low-MAF (<0.1) variants partitioned into two distinct categories according to the SnpEff putative effect of the variant (protein-altering or non-protein-altering), correcting for 48 PCs from WGS variants for n = 25,465 samples.

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Data availability

The individual-level genotype and phenotype TOPMed data used in this study are available through dbGaP. The dbGaP accession numbers for all TOPMed studies referenced in this paper are listed in Supplementary Table 1. The genotypic data are under restricted access. This research was conducted under TOPMed proposal ID 3235. Individual-level genotype and phenotype data for the UKB are available through formal application (http://www.ukbiobank.ac.uk). The UK10K data are accessible at https://www.uk10k.org. The 1000 Genomes genotype data are available at https://www.internationalgenome.org.

Code availability

The code used for the main analysis and figures is available at https://github.com/CNSGenomics/Heritability_WGS. GRM computation, LD score calculations, PC projections and GREML analyses were performed using GCTA 1.92.4 (https://cnsgenomics.com/software/gcta/#Download). WGS analyses followed the steps described at https://cnsgenomics.com/software/gcta/#GREMLinWGSorimputeddata. Plink 1.9 (https://www.cog-genomics.org/plink/1.9) and 2.0 were used in the present study (https://www.cog-genomics.org/plink/2.0). R 3.4.1 (https://www.r-project.org) and Tidyverse packages (https://www.tidyverse.org) were used to generate figures and additional analyses. KING 2.2.6 was used for IBD calculations (https://www.kingrelatedness.com). All the parameters used for analyses are described in Methods.

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Acknowledgements

P.M.V. was supported by the Australian Research Council (grant nos. DP160102400 and FL180100072), the Australian National Health and Medical Research Council (grant nos. 1113400 and 1078037) and the US National Institutes of Health (NIH; grant no. R01MH100141). J.Y. was supported by the Australian Research Council (grant no. FT180100186), the Sylvia & Charles Viertel Charitable Foundation and the Westlake Education Foundation. L.Y. was supported by the Australian Research Council (grant no. DE200100425). The present study makes use of data from the TOPMed program, the UKB and the UK10K projects. WGS for the TOPMed program was supported by the NHLBI. A full list of acknowledgements is provided in the Supplementary Information.

Author information

Author notes

  1. These authors contributed equally: Jian Yang, Peter M. Visscher.

Authors and Affiliations

  1. Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia

    Pierrick Wainschtein, Zhili Zheng, Loic Yengo, Jian Yang & Peter M. Visscher

  2. Department of Biostatistics, University of Washington, Seattle, WA, USA

    Deepti Jain, Barbara McKnight, Cecelia A. Laurie, Cathy C. Laurie & Bruce S. Weir

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

    L. Adrienne Cupples & Ching-Ti Liu

  4. Framingham Heart Study, Framingham, MA, USA

    L. Adrienne Cupples & Ramachandran S. Vasan

  5. Herbert Wertheim School of Public Health and Human Longevity Science, University of California San Diego, La Jolla, CA, USA

    Aladdin H. Shadyab

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

    Benjamin M. Shoemaker

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

    Braxton D. Mitchell & Jeffrey R. O’Connell

  8. Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, Baltimore, MD, USA

    Braxton D. Mitchell

  9. Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA

    Bruce M. Psaty

  10. Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    Charles Kooperberg

  11. Harvard Medical School, Boston, MA, USA

    Jonathan Seidman, Christine M. Albert & Patrick T. Ellinor

  12. Division of Cardiovascular, Brigham and Women’s Hospital, Boston, MA, USA

    Christine M. Albert

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

    Christine M. Albert & Daniel I. Chasman

  14. Departments of Medicine, Pharmacology and Bioinformatics, Vanderbilt University Medical Center, Nashville, TN, USA

    Dan Roden

  15. Department of Medicine, University of Illinois-Chicago, Chicago, IL, USA

    Dawood Darbar

  16. Department of Preventive Medicine, Northwestern University, Chicago, IL, USA

    Donald M. Lloyd-Jones

  17. Dean’s Office, College of Public Health, University of Kentucky, Lexington, KY, USA

    Donna K. Arnett

  18. Department of Medicine, National Jewish Health, Denver, CO, USA

    Elizabeth A. Regan

  19. Health Science Center, University of Texas, Houston, TX, USA

    Eric Boerwinkle

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

    Jerome I. Rotter, Xiuqing Guo & Y. -D Ida Chen

  21. Division of General Internal Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Lisa R. Yanek

  22. Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA

    Mariza de Andrade

  23. Department of Family Medicine, University of California San Diego, La Jolla, CA, USA

    Matthew A. Allison

  24. Division of Pulmonary, Allergy and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, AL, USA

    Merry-Lynn N. McDonald

  25. Department of Molecular Cardiology, Cleveland Clinic, Cleveland, OH, USA

    Mina K. Chung

  26. Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA

    Myriam Fornage

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

    Nathalie Chami & Ruth J. F. Loos

  28. Mindich Institute for Child Health and Development, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Nathalie Chami & Ruth J. F. Loos

  29. Cardiovascular Health Research Unit and Department of Epidemiology, University of Washington, Seattle, WA, USA

    Nicholas L. Smith

  30. Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA

    Nicholas L. Smith & Susan R. Heckbert

  31. Seattle Epidemiologic Research and Information Center, Department of Veterans Affairs Office of Research and Development, Seattle, WA, USA

    Nicholas L. Smith & Susan R. Heckbert

  32. Cardiac Arrhythmia Service, Massachusetts General Hospital, Boston, MA, USA

    Patrick T. Ellinor & Steven A. Lubitz

  33. Sections of Preventive Medicine and Cardiovascular Medicine, Department of Medicine, Boston University School of Medicine, Boston, MA, USA

    Ramachandran S. Vasan

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

    Ramachandran S. Vasan

  35. GeneSTAR Research Program, Divisions of Allergy and Clinical Immunology and General Internal Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Rasika A. Mathias

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

    Stephen S. Rich

  37. Cardiovascular Disease Initiative, Broad Institute of Harvard and MIT, Cambridge, MA, USA

    Steven A. Lubitz

  38. Division of Sleep and Circadian Disorders, Brigham and Women’s Hospital, Boston, MA, USA

    Susan Redline

  39. Division of Sleep Medicine, Harvard Medical School, Boston, MA, USA

    Susan Redline

  40. Division of Pulmonary, Critical Care, and Sleep Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA

    Susan Redline

  41. Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA

    Ryan D. Hernandez

  42. Department of Human Genetics, McGill University, Montreal, Quebec, Canada

    Ryan D. Hernandez

  43. International Health Institute, Department of Epidemiology, Brown University School of Public Health, Providence, RI, USA

    Stephen T. McGarvey

  44. Centre for AgriBioscience, Department of Economic Development, Jobs, Transport and Resources, Bundoora, Victoria, Australia

    Michael E. Goddard

  45. Faculty of Veterinary and Agricultural Sciences, University of Melbourne, Parkville, Victoria, Australia

    Michael E. Goddard

  46. Department of Epidemiology and Carolina Center of Genome Sciences, University of North Carolina, Chapel Hill, NC, USA

    Kari E. North

  47. Department of Medicine, University of Colorado, Aurora, CO, USA

    Leslie A. Lange

  48. School of Life Sciences, Westlake University, Hangzhou Zhejiang, China

    Jian Yang

  49. Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia

    Peter M. Visscher

  50. University of Alabama, Birmingham, AL, USA

    Stella Aslibekyan, Bertha Hidalgo & Marguerite Ryan Irvin

  51. Medicine, Johns Hopkins University, Baltimore, MD, USA

    Diane Becker

  52. Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA

    Wenjian Bi & Seunggeun Lee

  53. University of Washington, Seattle, WA, USA

    Jennifer Brody, Peter Anderson, Jai Broome, Colleen Davis, Leslie Emery, Chris Frazar, Stephanie M. Fullerton, Stephanie Gogarten, Craig Johnson, Alyna Khan, David Levine, Ken Rice, Josh Smith, Nona Sotoodehnia, Adrienne M. Stilp, Adam Szpiro, Timothy A. Thornton, David Tirschwell, Fei Fei Wang & Quenna Wong

  54. Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA

    Jenna C. Carlson & Emily M. Russell

  55. Population Health Science, University of Mississippi, Jackson, MS, USA

    Adolfo Correa

  56. Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    Margaret Mengmeng Du

  57. Department of Biobehavioral Health, Pennsylvania State University, University Park, PA, USA

    Lindsay Fernandez-Rhodes

  58. Department of Medicine, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA

    Kendra R. Ferrier, Sharon Graw, Luisa Mestroni & Matthew Taylor

  59. Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Misa Graff, Heather M. Highland, Mohammad Yaser & Sachiko Yoneyama

  60. Lundquist Institute, Torrance, CA, USA

    Xiuqing Guo, Xiaohui Li & Henry Lin

  61. Tulane University, New Orleans, LA, USA

    Jiang He

  62. Department of Neurology, Boston University, Boston, MA, USA

    Nancy L. Heard-Costa

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

    Joel N. Hirschhorn

  64. University of Mississippi Medical Center, Jackson, MS, USA

    Candace M. Howard-Claudio

  65. Department of Epidemiology & Population Health, Albert Einstein College of Medicine, New York, NY, USA

    Carmen R. Isasi, Qibin Qi & Tao Wang

  66. Division of Endocrinology, DIabetes and Metabolism, Internal Medicine, Ohio State University Medical Center, Columbus, OH, USA

    Rebecca Jackson

  67. Department of Animal Science, North Carolina State University, Raleigh, NC, USA

    Jicai Jiang

  68. Division of Intramural Research, National Institutes of Health, National Heart, Lung, and Blood Institute, Bethesda, MD, USA

    Roby Joehanes

  69. Biomedical and Translational Informatics, Geisinger Health, Danville, PA, USA

    Anne E. Justice

  70. Department of Medicine, Endocrinology, Diabetes and Metabolism, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Rita R. Kalyani

  71. University of Michigan, Ann Arbor, MI, USA

    Sharon Kardia, Jennifer Smith, Sebastian Zoellner, Gonçalo Abecasis, Larry Bielak, Thomas Blackwell, Jeffrey Curtis, Matthew Flickinger, Colin Gross, Jonathon LeFaive, Patricia Peyser, Jacob Pleiness, Albert Vernon Smith, Daniel Taliun, Peter VandeHaar, Jiongming Wang & Ketian Yu

  72. University of Colorado at Denver, Denver, CO, USA

    Ethan Lange, Jonathan Cardwell, Sameer Chavan, Michelle Daya, Shanshan Gao, Daniel Grine, John Hokanson, Susan Mathai, Bonnie Neltner, Meher Preethi Boorgula, Pamela Russell, David Schwartz, Aniket Shetty, Tarik Walker, Avram Walts & Ivana Yang

  73. Brigham & Women’s Hospital, Boston, MA, USA

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  74. Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA

    Xihao Li, Zilin Li, Jingwen Zhang & Hufeng Zhou

  75. Department of Biostatistics, Boston University, Boston, MA, USA

    Elise Lim, Hanfei Xu & Gina Peloso

  76. Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Danyu Lin

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

    Xihong Lin

  78. Epidemiology and Medicine, Brown University, Providence, RI, USA

    Simin Liu

  79. Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA

    Yingchang Lu

  80. Cardiology, George Washington University, Washington DC, USA

    Lisa Martin

  81. Department of Biostatistics, University of Washington, Seattle, WA, USA

    Caitlin McHugh & Catherine Tong

  82. National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA

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  83. Department of Medicine, University of Mississippi, Jackson, MS, USA

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  84. Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN, USA

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  85. Department of Genome Sciences, University of Washington, Seattle, WA, USA

    Deborah Nickerson & Machiko Threlkeld

  86. Wake Forest Baptist Health, Winston-Salem, NC, USA

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

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

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  90. Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

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  91. Northwestern University, Chicago, IL, USA

    Laura Rasmussen-Torvik

  92. Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA, USA

    Alex Reiner

  93. Cardiovascular Health Research Unit, University of Washington, Seattle, WA, USA

    Colleen Sitlani & Joshua Bis

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

    Zhe Wang

  95. Epidemiology, Indiana University, Indianapolis, IN, USA

    Jennifer Wessel

  96. Department of Epidemiology, University of Colorado, Aurora, CO, USA

    Kendra A. Young

  97. Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA

    Xiaofeng Zhu

  98. New York Genome Center, New York, NY, USA

    Namiko Abe, Karen Bunting, Bo-Juen Chen, Soren Germer, Tanja Smith & Michael Zody

  99. Broad Institute, Cambridge, MA, USA

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  100. Children’s Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA, USA

    Laura Almasy

  101. Emory University, Atlanta, GA, USA

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  102. University of Mississippi, Jackson, MS, USA

    Pramod Anugu, Lynette Ekunwe, Yan Gao, Hao Mei & Nancy Min

  103. National Institutes of Health, Bethesda, MD, USA

    Deborah Applebaum-Bowden

  104. Johns Hopkins University, Baltimore, MD, USA

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  105. Duke University, Durham, NC, USA

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  106. Stanford University, Stanford, CA, USA

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  107. Medical College of Wisconsin, Milwaukee, WI, USA

    Paul Auer

  108. Medicine, Providence Health Care Vancouver, Vancouver, British Columbia, Canada

    Najib Ayas

  109. Baylor College of Medicine Human Genome Sequencing Center, Houston, TX, USA

    Adithya Balasubramanian, Huyen Dinh, Harsha Doddapaneni, Shannon Dugan-Perez, Jesse Farek, Richard Gibbs, Yi Han, Jianhong Hu, Ziad Khan, Sandra Lee, Vipin Menon, Ginger Metcalf, Zeineen Momin, Donna Muzny, Caitlin Nessner, Osuji Nkechinyere, Geoffrey Okwuonu, Mahitha Rajendran, Sejal Salvi, Jireh Santibanez & Jennifer Watt

  110. Cleveland Clinic, Cleveland, OH, USA

    John Barnard & Serpil Erzurum

  111. Tempus, University of Colorado, Aurora, CO, USA

    Kathleen Barnes

  112. Columbia University, New York, NY, USA

    R. Graham Barr & Danish Saleheen

  113. The Emmes Corporation, LTRC, Rockville, MD, USA

    Lucas Barwick

  114. Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH, USA

    Gerald Beck

  115. Boston University, Massachusetts General Hospital, Boston University School of Medicine, Boston, MA, USA

    Emelia Benjamin

  116. University of Pittsburgh, Pittsburgh, PA, USA

    Takis Benos, Mark Geraci, Mark Gladwin, Ryan L. Minster, Frank Sciurba & Daniel E. Weeks

  117. Fundação de Hematologia e Hemoterapia de Pernambuco—Hemope, Recife, Brazil

    Marcos Bezerra

  118. Human Genetics, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX, USA

    John Blangero

  119. Department of Biochemistry, Wake Forest Baptist Health, Winston-Salem, NC, USA

    Donald W. Bowden

  120. National Jewish Health, Denver, CO, USA

    Russell Bowler, James Crapo & Snow Xueyan Zhao

  121. Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA

    Ulrich Broeckel

  122. Pediatrics, University of Texas Health at Houston, Houston, TX, USA

    Deborah Brown

  123. University of California San Francisco, San Francisco, CA, USA

    Esteban Burchard & Shannon Kelly

  124. Biomedical Data Science, Stanford University, Stanford, CA, USA

    Carlos Bustamante

  125. Biostatistics, University of Washington, Seattle, WA, USA

    Erin Buth, Matthew Conomos, Ben Heavner, Susanne May, Sarah C. Nelson & Kayleen Williams

  126. Brigham and Women’s Hospital, Boston, MA, USA

    Brian Cade

  127. University of Montreal, Montreal, Quebe, Canada

    Julie Carrier

  128. Medicine, University of Mississippi, Jackson, MS, USA

    April Carson

  129. Washington State University, Washington DC, USA

    Cara Carty

  130. University of California Los Angeles, Los Angeles, CA, USA

    Richard Casaburi, Carolyn Crandall & Karol Watson

  131. Brigham & Women’s Hospital, Medicine, Boston, MA, USA

    Juan P. Casas Romero, Peter Castaldi & Matt Moll

  132. National Taiwan University, Taipei, Taiwan

    Yi-Cheng Chang

  133. University of Virginia, Charlottesville, VA, USA

    Wei-Min Chen, Charles Farber, Ani Manichaikul, Josyf C. Mychaleckyj & Aakrosh Ratan

  134. National Taiwan University, National Taiwan University Hospital, Taipei, Taiwan

    Lee-Ming Chuang

  135. National Health Research Institute Taiwan, Miaoli County, Taiwan

    Ren-Hua Chung

  136. Metabolomics Platform, Broad Institute, Cambridge, MA, USA

    Clary Clish

  137. Immunity and Immunology, Cleveland Clinic, Cleveland, OH, USA

    Suzy Comhair

  138. University of Vermont, Burlington, VT, USA

    Elaine Cornell & Jon Peter Durda

  139. University of Texas Rio Grande Valley School of Medicine, Brownsville, TX, USA

    Joanne Curran & Michael Mahaney

  140. Vitalant Research Institute, San Francisco, CA, USA

    Brian Custer

  141. University of Illinois at Chicago, Chicago, IL, USA

    Dawood Darbar

  142. University of Chicago, Chicago, IL, USA

    Sean David

  143. Department of Medicine, Cardiovascular Division, Washington University in St. Louis, St. Louis, MO, USA

    Lisa de las Fuentes

  144. Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, University of Texas Health at Houston, Houston, TX, USA

    Paul de Vries

  145. Vanderbilt University, Nashville, TN, USA

    Michael DeBaun

  146. University of Cincinnati, Cincinnati, OH, USA

    Ranjan Deka

  147. University of North Carolina, Chapel Hill, NC, USA

    Qing Duan & Yun Li

  148. University of Texas Rio Grande Valley School of Medicine, Edinburgh, TX, USA

    Ravi Duggirala & Juan Manuel Peralta

  149. Genetics, Washington University in St. Louis, St. Louis, MO, USA

    Susan K. Dutcher

  150. Brown University, Providence, RI, USA

    Charles Eaton

  151. Channing Division of Network Medicine, Harvard University, Boston, MA, USA

    Adel El Boueiz

  152. Center for Genes, Environment and Health, National Jewish Health, Denver, CO, USA

    Tasha Fingerlin

  153. Epidemiology, University of North Carolina, Chapel Hill, NC, USA

    Nora Franceschini

  154. Washington University in St. Louis, St. Louis, MO, USA

    Lucinda Fulton, C. Charles Gu, D. C. Rao, Karen Schwander & Yun Ju Sung

  155. New York Genome Center, New York City, NY, USA

    Heather Geiger, Melissa Marton, Catherine Reeves, Nicolas Robine, Alexi Runnels & Lara Winterkorn

  156. Beth Israel Deaconess Medical Center, Boston, MA, USA

    Robert Gerszten

  157. Department of Psychiatry, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA

    David Glahn

  158. University of Texas Rio Grande Valley School of Medicine, San Antonio, TX, USA

    Harald Goring

  159. Obstetrics and Gynecology, Mass General Brigham, Boston, MA, USA

    Kathryn J. Gray

  160. OB/GYN, Indiana University, Indianapolis, IN, USA

    David M. Haas

  161. Cardiology, University of Mississippi, Jackson, MS, USA

    Michael Hall

  162. Medicine, University of Calgary, Calgary, Alberta, Canada

    Patrick Hanly

  163. Genetics, University of Maryland, Philadelphia, PA, USA

    Daniel Harris

  164. Department of Chronic Disease Epidemiology, Yale University, New Haven, CT, USA

    Nicola L. Hawley

  165. Wake Forest Baptist Health, Winston-Salem, NC, USA

    David Herrington

  166. Channing Division of Network Medicine, Brigham & Women’s Hospital, Boston, MA, USA

    Craig Hersh

  167. University of Texas Health at Houston, Houston, TX, USA

    James Hixson

  168. University of Iowa, Iowa City, IA, USA

    Karin Hoth & Robert Wallace

  169. National Health Research Institute Taiwan, Institute of Population Health Sciences, NHRI, Miaoli County, Taiwan

    Chao Agnes Hsiung

  170. Tri-Service General Hospital National Defense Medical Center, Taipei, Taiwan

    Yi-Jen Hung

  171. Blood Works Northwest, Seattle, WA, USA

    Haley Huston, Barbara Konkle & Sarah Ruuska

  172. Taichung Veterans General Hospital Taiwan, Taichung City, Taiwan

    Chii Min Hwu, Wen-Jane Lee & Wayne Hui-Heng Sheu

  173. Research Institute, Blood Works Northwest, Seattle, WA, USA

    Jill Johnsen

  174. Biostatistics, University of Michigan, Ann Arbor, MI, USA

    Hyun Min Kang & Joshua Weinstock

  175. Albert Einstein College of Medicine, New York, NY, USA

    Robert Kaplan & Sylvia Smoller

  176. Harvard University, Cambridge, MA, USA

    Wonji Kim & Sean McFarland

  177. McGill University, Montréal, Quebec, Canada

    John Kimoff

  178. Epidemiology, University of Colorado at Denver, Aurora, CO, USA

    Greg Kinney

  179. Public Health, Sciences Loyola University, Maywood, IL, USA

    Holly Kramer

  180. Biostats, Harvard School of Public Health, Boston, MA, USA

    Christoph Lange

  181. Boston University, Boston, MA, USA

    Honghuang Lin & Kathryn Lunetta

  182. Cardiology, Duke University, Durham, NC, USA

    Yongmei Liu

  183. Stanford University, Cardiovascular Institute, Stanford, CA, USA

    Yu Liu

  184. Division of Pulmonary, Critical Care and Sleep Medicine, Ohio State University, Columbus, OH, USA

    Ulysses Magalang

  185. Broad Institute, Harvard University, Massachusetts General Hospital, Boston, MA, USA

    Alisa Manning

  186. Genome Sciences, University of Washington, Seattle, WA, USA

    Daniel McGoldrick

  187. RTI International, Research Triangle Park, Durham, NC, USA

    Becky McNeil

  188. Medicine, Massachusetts General Hospital, Boston, MA, USA

    James Meigs

  189. University of Arizona, Tucson, AZ, USA

    Deborah A. Meyers

  190. Center For Sleep Sciences and Medicine, Stanford University, Palo Alto, CA, USA

    Emmanuel Mignot

  191. National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA

    Mollie Minear

  192. Genes and Human Disease, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA

    Courtney Montgomery

  193. Ministry of Health, Government of Samoa, Apia, Samoa

    Take Naseri

  194. Howard University, Washington, DC, USA

    Sergei Nekhai

  195. University at Buffalo, Buffalo, NY, USA

    Heather Ochs-Balcom

  196. Division of Sleep Medicine/Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Allan Pack

  197. Stanford University, Stanford Cardiovascular Institute, Stanford, CA, USA

    David T. Paik & Joseph Wu

  198. University of Minnesota, Minneapolis, MN, USA

    James Pankow, Michael Tsai & Scott Vrieze

  199. Biostatistics and Epidemiology Division, RTI International, Research Triangle Park, Durham, NC, USA

    Cora Parker

  200. Cardiology/Medicine, Johns Hopkins University, Baltimore, MD, USA

    Wendy Post

  201. Medicine, University of Colorado at Denver, Denver, CO, USA

    Julia Powers Becker

  202. CCPM, University of Colorado at Denver, Denver, CO, USA

    Nicholas Rafaels

  203. Lutia I Puava Ae Mapu I Fagalele, Apia, Samoa

    Muagututi‘a Sefuiva Reupena

  204. Sleep Research Unit, University of Ottawa Institute for Mental Health Research, University of Ottawa, Ottawa, Ontario, Canada

    Rebecca Robillard

  205. Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, Brazil

    Ester Cerdeira Sabino

  206. Lundquist Institute, Institute for Translational Genomics and Population Sciences, Torrance, CA, USA

    Kevin Sandow

  207. Division of Hematology/Oncology, Harvard University, Boston, MA, USA

    Vijay G. Sankaran

  208. Genetics, Harvard Medical School, Boston, MA, USA

    Christine Seidman

  209. Pediatrics, Emory University, Atlanta, GA, USA

    Vivien Sheehan

  210. Human Genetics, Emory University, Atlanta, GA, USA

    Stephanie L. Sherman

  211. UMass Memorial Medical Center, Worcester, MA, USA

    Brian Silver

  212. University of Saskatchewan, Saskatoon, Saskatchewan, Canada

    Robert Skomro

  213. Genomic Cardiology, University of Colorado at Denver, Aurora, CO, USA

    Garrett Storm

  214. Channing Department of Medicine, Brigham & Women’s Hospital, Boston, MA, USA

    Jessica Lasky Su

  215. Genetics, Stanford University, Stanford, CA, USA

    Hua Tang

  216. Lundquist Institute, Institute for Translational Genomics and Population Sciences, Torrance, CA, USA

    Kent D. Taylor

  217. Fred Hutchinson Cancer Research Center, Cancer Prevention Division of Public Health Sciences, Seattle, WA, USA

    Lesley Tinker

  218. Genetics, University of Pennsylvania, Philadelphia, PA, USA

    Sarah Tishkoff

  219. Biostatistics, University of Alabama, Birmingham, AL, USA

    Hemant Tiwari

  220. Pathology & Laboratory Medicine, University of Vermont, Burlington, VT, USA

    Russell Tracy

  221. USC Methylation Characterization Center, University of Southern California, Los Angeles, CA, USA

    David Van Den Berg

  222. Brigham & Women’s Hospital, Mass General Brigham, Boston, MA, USA

    Heming Wang

  223. Channing Division of Network Medicine, Department of Medicine, Brigham & Women’s Hospital, Boston, MA, USA

    Scott T. Weiss

  224. Massachusetts General Hospital, Boston, MA, USA

    Lu-Chen Weng

  225. Internal Medicine, University of Michigan, Ann Arbor, MI, USA

    Cristen Willer

  226. Henry Ford Health System, Detroit, MI, USA

    L. Keoki Williams

  227. Cardiology, Beth Israel Deaconess Medical Center, Cambridge, MA, USA

    James Wilson

  228. Medicine, University of Pittsburgh, Pittsburgh, PA, USA

    Yingze Zhang

  229. Department of Epidemiology, University of Michigan, Ann Arbor, MI, USA

    Wei Zhao

Authors
  1. Pierrick Wainschtein
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  2. Deepti Jain
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  3. Zhili Zheng
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  4. L. Adrienne Cupples
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  5. Aladdin H. Shadyab
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  6. Barbara McKnight
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  7. Benjamin M. Shoemaker
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  9. Bruce M. Psaty
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  10. Charles Kooperberg
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  11. Ching-Ti Liu
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  12. Christine M. Albert
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  13. Dan Roden
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  15. Dawood Darbar
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  28. Nathalie Chami
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  29. Nicholas L. Smith
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  30. Patrick T. Ellinor
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  31. Ramachandran S. Vasan
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  32. Rasika A. Mathias
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  33. Ruth J. F. Loos
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  34. Stephen S. Rich
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  35. Steven A. Lubitz
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  36. Susan R. Heckbert
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  37. Susan Redline
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  40. Cecelia A. Laurie
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  41. Ryan D. Hernandez
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  50. Peter M. Visscher
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Consortia

TOPMed Anthropometry Working Group

  • Stella Aslibekyan
  • , Diane Becker
  • , Wenjian Bi
  • , Jennifer Brody
  • , Jenna C. Carlson
  • , Adolfo Correa
  • , Margaret Mengmeng Du
  • , Lindsay Fernandez-Rhodes
  • , Kendra R. Ferrier
  • , Misa Graff
  • , Xiuqing Guo
  • , Jiang He
  • , Nancy L. Heard-Costa
  • , Heather M. Highland
  • , Joel N. Hirschhorn
  • , Candace M. Howard-Claudio
  • , Carmen R. Isasi
  • , Rebecca Jackson
  • , Jicai Jiang
  • , Roby Joehanes
  • , Anne E. Justice
  • , Rita R. Kalyani
  • , Sharon Kardia
  • , Ethan Lange
  • , Meryl LeBoff
  • , Seunggeun Lee
  • , Xihao Li
  • , Zilin Li
  • , Elise Lim
  • , Danyu Lin
  • , Xihong Lin
  • , Simin Liu
  • , Yingchang Lu
  • , JoAnn Manson
  • , Lisa Martin
  • , Caitlin McHugh
  • , Julie Mikulla
  • , Solomon K. Musani
  • , Maggie Ng
  • , Deborah Nickerson
  • , Nicholette Palmer
  • , James Perry
  • , Ulrike Peters
  • , Michael Preuss
  • , Qibin Qi
  • , Laura Raffield
  • , Laura Rasmussen-Torvik
  • , Alex Reiner
  • , Emily M. Russell
  • , Colleen Sitlani
  • , Jennifer Smith
  • , Cassandra N. Spracklen
  • , Tao Wang
  • , Zhe Wang
  • , Jennifer Wessel
  • , Hanfei Xu
  • , Mohammad Yaser
  • , Sachiko Yoneyama
  • , Kendra A. Young
  • , Jingwen Zhang
  • , Xinruo Zhang
  • , Hufeng Zhou
  • , Xiaofeng Zhu
  •  & Sebastian Zoellner

NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium

  • Namiko Abe
  • , Gonçalo Abecasis
  • , Francois Aguet
  • , Laura Almasy
  • , Alvaro Alonso
  • , Seth Ament
  • , Peter Anderson
  • , Pramod Anugu
  • , Deborah Applebaum-Bowden
  • , Kristin Ardlie
  • , Dan Arking
  • , Allison Ashley-Koch
  • , Stella Aslibekyan
  • , Tim Assimes
  • , Paul Auer
  • , Dimitrios Avramopoulos
  • , Najib Ayas
  • , Adithya Balasubramanian
  • , John Barnard
  • , Kathleen Barnes
  • , R. Graham Barr
  • , Emily Barron-Casella
  • , Lucas Barwick
  • , Terri Beaty
  • , Gerald Beck
  • , Diane Becker
  • , Lewis Becker
  • , Rebecca Beer
  • , Amber Beitelshees
  • , Emelia Benjamin
  • , Takis Benos
  • , Marcos Bezerra
  • , Larry Bielak
  • , Joshua Bis
  • , Thomas Blackwell
  • , John Blangero
  • , Donald W. Bowden
  • , Russell Bowler
  • , Jennifer Brody
  • , Ulrich Broeckel
  • , Jai Broome
  • , Deborah Brown
  • , Karen Bunting
  • , Esteban Burchard
  • , Carlos Bustamante
  • , Erin Buth
  • , Brian Cade
  • , Jonathan Cardwell
  • , Vincent Carey
  • , Julie Carrier
  • , April Carson
  • , Cara Carty
  • , Richard Casaburi
  • , Juan P. Casas Romero
  • , James Casella
  • , Peter Castaldi
  • , Mark Chaffin
  • , Christy Chang
  • , Yi-Cheng Chang
  • , Sameer Chavan
  • , Bo-Juen Chen
  • , Wei-Min Chen
  • , Michael Cho
  • , Seung Hoan Choi
  • , Lee-Ming Chuang
  • , Ren-Hua Chung
  • , Clary Clish
  • , Suzy Comhair
  • , Matthew Conomos
  • , Elaine Cornell
  • , Adolfo Correa
  • , Carolyn Crandall
  • , James Crapo
  • , Joanne Curran
  • , Jeffrey Curtis
  • , Brian Custer
  • , Coleen Damcott
  • , Dawood Darbar
  • , Sean David
  • , Colleen Davis
  • , Michelle Daya
  • , Lisa de las Fuentes
  • , Paul de Vries
  • , Michael DeBaun
  • , Ranjan Deka
  • , Dawn DeMeo
  • , Scott Devine
  • , Huyen Dinh
  • , Harsha Doddapaneni
  • , Qing Duan
  • , Shannon Dugan-Perez
  • , Ravi Duggirala
  • , Jon Peter Durda
  • , Susan K. Dutcher
  • , Charles Eaton
  • , Lynette Ekunwe
  • , Adel El Boueiz
  • , Leslie Emery
  • , Serpil Erzurum
  • , Charles Farber
  • , Jesse Farek
  • , Tasha Fingerlin
  • , Matthew Flickinger
  • , Nora Franceschini
  • , Chris Frazar
  • , Mao Fu
  • , Stephanie M. Fullerton
  • , Lucinda Fulton
  • , Stacey Gabriel
  • , Weiniu Gan
  • , Shanshan Gao
  • , Yan Gao
  • , Margery Gass
  • , Heather Geiger
  • , Bruce Gelb
  • , Mark Geraci
  • , Soren Germer
  • , Robert Gerszten
  • , Auyon Ghosh
  • , Richard Gibbs
  • , Chris Gignoux
  • , Mark Gladwin
  • , David Glahn
  • , Stephanie Gogarten
  • , Da-Wei Gong
  • , Harald Goring
  • , Sharon Graw
  • , Kathryn J. Gray
  • , Daniel Grine
  • , Colin Gross
  • , C. Charles Gu
  • , Yue Guan
  • , Namrata Gupta
  • , David M. Haas
  • , Jeff Haessler
  • , Michael Hall
  • , Yi Han
  • , Patrick Hanly
  • , Daniel Harris
  • , Nicola L. Hawley
  • , Jiang He
  • , Ben Heavner
  • , David Herrington
  • , Craig Hersh
  • , Bertha Hidalgo
  • , James Hixson
  • , Brian Hobbs
  • , John Hokanson
  • , Elliott Hong
  • , Karin Hoth
  • , Chao Agnes Hsiung
  • , Jianhong Hu
  • , Yi-Jen Hung
  • , Haley Huston
  • , Chii Min Hwu
  • , Marguerite Ryan Irvin
  • , Rebecca Jackson
  • , Cashell Jaquish
  • , Jill Johnsen
  • , Andrew Johnson
  • , Craig Johnson
  • , Rich Johnston
  • , Kimberly Jones
  • , Hyun Min Kang
  • , Robert Kaplan
  • , Sharon Kardia
  • , Shannon Kelly
  • , Eimear Kenny
  • , Michael Kessler
  • , Alyna Khan
  • , Ziad Khan
  • , Wonji Kim
  • , John Kimoff
  • , Greg Kinney
  • , Barbara Konkle
  • , Holly Kramer
  • , Christoph Lange
  • , Ethan Lange
  • , Meryl LeBoff
  • , Jiwon Lee
  • , Sandra Lee
  • , Wen-Jane Lee
  • , Jonathon LeFaive
  • , David Levine
  • , Dan Levy
  • , Joshua Lewis
  • , Xiaohui Li
  • , Yun Li
  • , Henry Lin
  • , Honghuang Lin
  • , Xihong Lin
  • , Simin Liu
  • , Yongmei Liu
  • , Yu Liu
  • , Kathryn Lunetta
  • , James Luo
  • , Ulysses Magalang
  • , Michael Mahaney
  • , Barry Make
  • , Ani Manichaikul
  • , Alisa Manning
  • , JoAnn Manson
  • , Lisa Martin
  • , Melissa Marton
  • , Susan Mathai
  • , Susanne May
  • , Patrick McArdle
  • , Sean McFarland
  • , Daniel McGoldrick
  • , Caitlin McHugh
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Contributions

P.M.V. and J.Y. conceived the study. P.W. performed the analyses, contributed to methods and interpretations of results, and wrote the first draft of the manuscript and supplementary materials. P.M.V., J.Y. and L.Y. provided supervision and contributed to analyses, and writing and revising the manuscript. M.E.G. contributed to supervision and analysis methods. D.J. and Z.Z. contributed to the analyses. C.A.L, R.D.H., S.T.M, C.C.L, K.E.N., L.A.L. and B.S.W. provided suggestions on the analyses and details of the phenotype data. L.A.C., A.H.S., B. MK., B.M.S., B.D.M., B.M.P., C.K., C.-T. L., C.M.A., D.R., D.I.C., D.D., D.M.L.-J., D.K.A., E.A.R., E.B., J.I.R., J.R.O., L.R.Y., M.A., M.A.A., M.-L.N.M., M.K.C., M.F., N.C., N.L.S., P.T.E., R.S.V., R.A.M., R.J.F.L., S.S.R., S.A.L., S.R.H., S.R., X.G. and Y.-D.I.C. provided phenotypic and/or WGS data through the TOPMed Consortium. All authors reviewed the manuscript, suggested revisions as needed and approved the final version. A full list of members and affiliations of the NHLBI TOPMed Consortium is available at https://topmed.nhlbi.nih.gov/topmed-banner-authorship.

Corresponding authors

Correspondence to Pierrick Wainschtein, Jian Yang or Peter M. Visscher.

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Competing interests

P.T.E. is supported by a grant from Bayer AG to the Broad Institute focused on the genetics and therapeutics of cardiovascular diseases. He has also served on advisory boards or consulted for Bayer AG, Quest Diagnostics and Novartis. S.A.L. receives sponsored research support from Bristol Myers Squibb/Pfizer, Bayer AG, Boehringer Ingelheim, Fitbit and IBM, and has consulted for Bristol Myers Squibb/Pfizer, Bayer AG and Blackstone Life Sciences. The other authors declare no competing interests.

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Supplementary Notes 1–3, Acknowledgements, Tables 1–8 and Figs. 1–43.

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Wainschtein, P., Jain, D., Zheng, Z. et al. Assessing the contribution of rare variants to complex trait heritability from whole-genome sequence data. Nat Genet 54, 263–273 (2022). https://doi.org/10.1038/s41588-021-00997-7

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