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

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

Pierrick Wainschtein^{a b}✉, Deepti Jain^c, Zhili Zheng^b, TOPMed Anthropometry Working Group^d, Stella W. Aslibekyan^{d e}, Diane M. Becker^{e f}, Wenjian Bi^{f g}, Jennifer A. Brody^{g h}, Jenna C. Carlson^{h i}, Adolfo Correa^{i j}, Margaret Mengmeng Du^{j k},

Nature Genetics Nature Portfolio2022-03-01 514 citations53 references

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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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^aInstitute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia. p.wainschtein@uq.edu.au
^bInstitute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia
^cDepartment of Biostatistics, University of Washington, Seattle, WA, USA
^dUniversity of Alabama, Birmingham, AL, USA
^eMedicine, Johns Hopkins University, Baltimore, MD, USA
^fDepartment of Biostatistics, University of Michigan, Ann Arbor, MI, USA
^gUniversity of Washington, Seattle, WA, USA
^hDepartment of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA
ⁱPopulation Health Science, University of Mississippi, Jackson, MS, USA
^jPublic Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
^kDepartment of Biobehavioral Health, Pennsylvania State University, University Park, PA, USA
^lDepartment of Medicine, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA
^mDepartment of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
ⁿInstitute for Translational Genomics and Population Sciences, Department of Pediatrics, Lundquist Institute at Harbor-UCLA Medical Center, Torrance, CA, USA
^oTulane University, New Orleans, LA, USA
^pDepartment of Neurology, Boston University, Boston, MA, USA
^qProgram in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA
^rUniversity of Mississippi Medical Center, Jackson, MS, USA
^sDepartment of Epidemiology & Population Health, Albert Einstein College of Medicine, New York, NY, USA
^tDivision of Endocrinology, DIabetes and Metabolism, Internal Medicine, Ohio State University Medical Center, Columbus, OH, USA
^uDepartment of Animal Science, North Carolina State University, Raleigh, NC, USA
^vDivision of Intramural Research, National Institutes of Health, National Heart, Lung, and Blood Institute, Bethesda, MD, USA
^wBiomedical and Translational Informatics, Geisinger Health, Danville, PA, USA
^xDepartment of Medicine, Endocrinology, Diabetes and Metabolism, Johns Hopkins University School of Medicine, Baltimore, MD, USA
^yUniversity of Michigan, Ann Arbor, MI, USA
^zUniversity of Colorado at Denver, Denver, CO, USA
^aaBrigham & Women's Hospital, Boston, MA, USA
^abBrigham & Women’s Hospital, Boston, MA, USA
^acBaylor College of Medicine Human Genome Sequencing Center, Houston, TX, USA
^adDepartment of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA
✉Corresponding author