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Recovery of trait heritability from whole genome sequence data

View ORCID ProfilePierrick Wainschtein, Deepti P. Jain, View ORCID ProfileLoic Yengo, Zhili Zheng, TOPMed Anthropometry Working Group, Trans-Omics for Precision Medicine Consortium, L. Adrienne Cupples, Aladdin H. Shadyab, Barbara McKnight, Benjamin M. Shoemaker, Braxton D. Mitchell, Bruce M. Psaty, Charles Kooperberg, Dan Roden, Dawood Darbar, Donna K. Arnett, Elizabeth A. Regan, Eric Boerwinkle, Jerome I. Rotter, Matthew A. Allison, Merry-Lynn N. McDonald, Mina K Chung, Nicholas L. Smith, Patrick T. Ellinor, Ramachandran S. Vasan, Rasika A. Mathias, Stephen S. Rich, Susan R. Heckbert, Susan Redline, Xiuqing Guo, Y.-D Ida Chen, Ching-Ti Liu, Mariza de Andrade, Lisa R. Yanek, Christine M. Albert, Ryan D. Hernandez, Stephen T. McGarvey, Kari E. North, Leslie A. Lange, Bruce S. Weir, Cathy C. Laurie, Jian Yang, Peter M. Visscher
doi: https://doi.org/10.1101/588020
Pierrick Wainschtein
Institute for Molecular Bioscience, The University of Queensland, Brisbane 4072, Australia
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Deepti P. Jain
Department of Biostatistics, University of Washington, Seattle, WA, USA
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Loic Yengo
Institute for Molecular Bioscience, The University of Queensland, Brisbane 4072, Australia
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Zhili Zheng
Institute for Molecular Bioscience, The University of Queensland, Brisbane 4072, Australia
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L. Adrienne Cupples
Boston University and the Framingham Heart Study
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Aladdin H. Shadyab
Department of Family Medicine and Public Health, University of California San Diego School of Medicine, La Jolla, CA
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Barbara McKnight
Department of Biostatistics, University of Washington, Seattle, WA, USA
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Benjamin M. Shoemaker
Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
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Braxton D. Mitchell
Department of Medicine, University of Maryland School of Medicine, Baltimore, USAGeriatrics Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, Baltimore, MD, USA
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Bruce M. Psaty
Cardiovascular Health Research Unit and Department of Epidemiology, University of Washington, Seattle, WA, USAKaiser Permanente Washington Health Research Institute, Seattle, WA, USA
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Charles Kooperberg
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
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Dan Roden
Departments of Medicine, Pharmacology and Bioinformatics, Vanderbilt University Medical Center, Nashville, TN, USA
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Dawood Darbar
Department of Medicine. University of Illinois-Chicago, Chicago, IL; USA
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Donna K. Arnett
Dean’s Office, College of Public Health, University of Kentucky, Lexington, KY, USA
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Elizabeth A. Regan
Department of Medicine, National Jewish Health, Denver, CO, USA
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Eric Boerwinkle
University of Texas, Health Science Center, Houston, TX, USA
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Jerome I. Rotter
The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA
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Matthew A. Allison
Department of Family Medicine and Public Health, University of California San Diego, La Jolla, CA, USA
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Merry-Lynn N. McDonald
Division of Pulmonary, Allergy and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
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Mina K Chung
Department of Molecular Cardiology, Cleveland Clinic, Cleveland, OH, USA
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Nicholas L. Smith
Cardiovascular Health Research Unit and Department of Epidemiology, University of Washington, Seattle, WA, USAKaiser Permanente Washington Health Research Institute, Seattle, WA, USASeattle Epidemiologic Research and Information Center, Department of Veterans Affairs Office of Research and Development, Seattle, WA, USA
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Patrick T. Ellinor
Harvard Medical School, Boston, MA, USACardiac Arrhythmia Service, Massachusetts General Hospital, Boston, MA, USA
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Ramachandran S. Vasan
Boston University and the Framingham Heart Study
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Rasika A. Mathias
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
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Stephen S. Rich
Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA
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Susan R. Heckbert
Cardiovascular Health Research Unit and Department of Epidemiology, University of Washington, Seattle, WA, USA
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Susan Redline
Division of Sleep and Circadian Disorders, Brigham and Women’s Hospital, Boston, MA, USA; Division of Sleep Medicine, Harvard Medical School, Boston, MA, USA; Division of Pulmonary, Critical Care, and Sleep Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA
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Xiuqing Guo
The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA
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Y.-D Ida Chen
The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA
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Ching-Ti Liu
Department of Biostatistics, Boston University School of Public Health Boston, MA, USA
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Mariza de Andrade
Department of Health Sciences Research, Mayo Clinic, Rochester, MN, 55905, USA
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Lisa R. Yanek
Division of General Internal Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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Christine M. Albert
Harvard Medical School, Boston, MA, USADivision of Cardiovascular, Brigham and Women’s Hospital, Boston, MA, USADivision of Preventive Medicine, Brigham and Women’s Hospital, Boston, MA, USA
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Ryan D. Hernandez
Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USADepartment of Human Genetics, McGill University, Montreal, QC, Canada
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Stephen T. McGarvey
International Health Institute, Department of Epidemiology, Brown University School of Public Health, Providence, USA
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Kari E. North
Department of Epidemiology and Carolina Center of Genome Sciences, University of North Carolina, Chapel Hill, NC, USA
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Leslie A. Lange
Department of Medicine, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA
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Bruce S. Weir
Department of Biostatistics, University of Washington, Seattle, WA, USA
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Cathy C. Laurie
Department of Biostatistics, University of Washington, Seattle, WA, USA
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Jian Yang
Institute for Molecular Bioscience, The University of Queensland, Brisbane 4072, AustraliaInstitute for Advanced Research, Wenzhou Medical University, Wenzhou, Zhejiang, ChinaQueensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia
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Peter M. Visscher
Institute for Molecular Bioscience, The University of Queensland, Brisbane 4072, AustraliaQueensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia
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  • For correspondence: peter.visscher@uq.edu.au
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Abstract

Heritability, the proportion of phenotypic variance explained by genetic factors, can be estimated from pedigree data 1, but such estimates are uninformative with respect to the underlying genetic architecture. Analyses of data from genome-wide association studies (GWAS) on unrelated individuals have shown that for human traits and disease, approximately one-third to two-thirds of heritability is captured by common SNPs 2–5. It is not known whether the remaining heritability is due to the imperfect tagging of causal variants by common SNPs, in particular if the causal variants are rare, or other reasons such as over-estimation of heritability from pedigree data. Here we show that pedigree heritability for height and body mass index (BMI) appears to be fully recovered from whole-genome sequence (WGS) data on 21,620 unrelated individuals of European ancestry. We assigned 47.1 million genetic variants to groups based upon their minor allele frequencies (MAF) and linkage disequilibrium (LD) with variants nearby, and estimated and partitioned variation accordingly. The estimated heritability was 0.79 (SE 0.09) for height and 0.40 (SE 0.09) for BMI, consistent with pedigree estimates. Low-MAF variants in low LD with neighbouring variants were enriched for heritability, to a greater extent for protein altering variants, consistent with negative selection thereon. Cumulatively variants in the MAF range of 0.0001 to 0.1 explained 0.54 (SE 0.05) and 0.51 (SE 0.11) of heritability for height and BMI, respectively. Our results imply that the still missing heritability of complex traits and disease is accounted for by rare variants, in particular those in regions of low LD.

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Posted March 25, 2019.
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Recovery of trait heritability from whole genome sequence data
Pierrick Wainschtein, Deepti P. Jain, Loic Yengo, Zhili Zheng, TOPMed Anthropometry Working Group, Trans-Omics for Precision Medicine Consortium, L. Adrienne Cupples, Aladdin H. Shadyab, Barbara McKnight, Benjamin M. Shoemaker, Braxton D. Mitchell, Bruce M. Psaty, Charles Kooperberg, Dan Roden, Dawood Darbar, Donna K. Arnett, Elizabeth A. Regan, Eric Boerwinkle, Jerome I. Rotter, Matthew A. Allison, Merry-Lynn N. McDonald, Mina K Chung, Nicholas L. Smith, Patrick T. Ellinor, Ramachandran S. Vasan, Rasika A. Mathias, Stephen S. Rich, Susan R. Heckbert, Susan Redline, Xiuqing Guo, Y.-D Ida Chen, Ching-Ti Liu, Mariza de Andrade, Lisa R. Yanek, Christine M. Albert, Ryan D. Hernandez, Stephen T. McGarvey, Kari E. North, Leslie A. Lange, Bruce S. Weir, Cathy C. Laurie, Jian Yang, Peter M. Visscher
bioRxiv 588020; doi: https://doi.org/10.1101/588020
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Recovery of trait heritability from whole genome sequence data
Pierrick Wainschtein, Deepti P. Jain, Loic Yengo, Zhili Zheng, TOPMed Anthropometry Working Group, Trans-Omics for Precision Medicine Consortium, L. Adrienne Cupples, Aladdin H. Shadyab, Barbara McKnight, Benjamin M. Shoemaker, Braxton D. Mitchell, Bruce M. Psaty, Charles Kooperberg, Dan Roden, Dawood Darbar, Donna K. Arnett, Elizabeth A. Regan, Eric Boerwinkle, Jerome I. Rotter, Matthew A. Allison, Merry-Lynn N. McDonald, Mina K Chung, Nicholas L. Smith, Patrick T. Ellinor, Ramachandran S. Vasan, Rasika A. Mathias, Stephen S. Rich, Susan R. Heckbert, Susan Redline, Xiuqing Guo, Y.-D Ida Chen, Ching-Ti Liu, Mariza de Andrade, Lisa R. Yanek, Christine M. Albert, Ryan D. Hernandez, Stephen T. McGarvey, Kari E. North, Leslie A. Lange, Bruce S. Weir, Cathy C. Laurie, Jian Yang, Peter M. Visscher
bioRxiv 588020; doi: https://doi.org/10.1101/588020

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