ArticleNature genetics2022
Assessing the contribution of rare variants to complex trait heritability from whole-genome sequence data.
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Article in Nature genetics, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 219 papers, 7 of them syntheses that pooled it.
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219citing papers in PubMed, 7 pooled it
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Who cites it
219 citing papers in PubMed, 7 syntheses or guidelines pooled it.
- Alzheimer disease is (sometimes) highly heritable: Drivers of variation in heritability estimates for binary traits, a systematic review.PLoS genetics · 2025Pooled it
- Multi-ancestry sequencing-based genome-wide association study of C-reactive protein in 513,273 genomes.Nature communications · 2025Pooled it
- Rare variant analyses in 51,256 type 2 diabetes cases and 370,487 controls reveal the pathogenicity spectrum of monogenic diabetes genes.Nature genetics · 2024Pooled it
- Pooled it
- Genetics of Exercise and Diet-Induced Fat Loss Efficiency: A Systematic Review.Journal of sports science & medicine · 2024Pooled it
- Multi-ancestry study of the genetics of problematic alcohol use in over 1 million individuals.Nature medicine · 2023Pooled it
- Powerful, scalable and resource-efficient meta-analysis of rare variant associations in large whole genome sequencing studies.Nature genetics · 2023Pooled it
- A heritability-optimized method for functional prioritization of rare coding variants in complex traits.Nature genetics · 2026Article
- Genetic Risk in Multiple Sclerosis: Susceptibility, Modifiers and Unresolved Questions.Neurology and therapy · 2026Review
- Shared and distinct genetic architectures of eating disorders and obesity: From monogenic causes to polygenic risk.Reviews in endocrine & metabolic disorders · 2026Review
- Genome-wide association meta-analysis of eating behavior traits revealed one susceptibility locus for emotional eating.Molecular psychiatry · 2026Article
- The contribution of common and rare genetic variation to emotional and behavioural symptoms in childhood and adolescence.Molecular psychiatry · 2026Article
- Hiding in plain sight: uncovering the genetic basis of complex phenotypes through low-risk groups.Genetics · 2026Article
- Genetic variants in pulmonary hypertension associated with chronic obstructive pulmonary disease.Current opinion in pulmonary medicine · 2026Review
- Genetic and Environmental Effects on BMI Fluctuation Across the Adult Life Course and Its Associations With Baseline BMI and BMI Change: An Individual-Based Study of 14 Longitudinal Twin Cohorts.Diabetes, obesity & metabolism · 2026Article
- Identification of novel loci regulating circulating melatonin and its causal relationship with hypertension.Human genetics · 2026Article
- Convergent coexpression reveals shared biological mechanisms underlying common and rare variant risk in six neuropsychiatric disorders.Molecular psychiatry · 2026Article
- Rare Germline Variants in Key Pathways Contribute to Hepatocellular Carcinoma Risk in Hispanic Individuals.Cancers · 2026Article
- Exploring the use of machine and deep learning in genome-wide association studies: a comprehensive review.BioData mining · 2026Review
- UK Biobank whole-genome sequencing reveals robust contributions of rare variants to complex-trait heritability.Genome biology · 2026Article
159 more citing papers are in PubMed but not listed here.
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Authors and funding
52 authors.
Pierrick WainschteinInstitute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia. p.wainschtein@uq.edu.au.ORCID http://orcid.org/0000-0002-5203-6481
Deepti JainDepartment of Biostatistics, University of Washington, Seattle, WA, USA.
Zhili ZhengInstitute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.
TOPMed Anthropometry Working Group
NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium
L Adrienne CupplesDepartment of Biostatistics, Boston University School of Public Health, Boston, MA, USA.ORCID http://orcid.org/0000-0003-0273-7965
Aladdin H ShadyabHerbert Wertheim School of Public Health and Human Longevity Science, University of California San Diego, La Jolla, CA, USA.
Barbara McKnightDepartment of Biostatistics, University of Washington, Seattle, WA, USA.
Benjamin M ShoemakerDepartment of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
Braxton D MitchellDepartment of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
Bruce M PsatyCardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.ORCID http://orcid.org/0000-0002-7278-2190
Charles KooperbergDivision of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.ORCID http://orcid.org/0000-0002-7986-8560
Ching-Ti LiuDepartment of Biostatistics, Boston University School of Public Health, Boston, MA, USA.ORCID http://orcid.org/0000-0002-0703-0742
Christine M AlbertHarvard Medical School, Boston, MA, USA.
Dan RodenDepartments of Medicine, Pharmacology and Bioinformatics, Vanderbilt University Medical Center, Nashville, TN, USA.
Daniel I ChasmanDivision of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, USA.ORCID http://orcid.org/0000-0003-3357-0862
Dawood DarbarDepartment of Medicine, University of Illinois-Chicago, Chicago, IL, USA.ORCID http://orcid.org/0000-0002-4103-5977
Donald M Lloyd-JonesDepartment of Preventive Medicine, Northwestern University, Chicago, IL, USA.
Donna K ArnettDean's Office, College of Public Health, University of Kentucky, Lexington, KY, USA.ORCID http://orcid.org/0000-0003-2219-657X
Elizabeth A ReganDepartment of Medicine, National Jewish Health, Denver, CO, USA.
Eric BoerwinkleHealth Science Center, University of Texas, Houston, TX, USA.
Jerome I RotterInstitute for Translational Genomics and Population Sciences, Department of Pediatrics, Lundquist Institute at Harbor-UCLA Medical Center, Torrance, CA, USA.ORCID http://orcid.org/0000-0001-7191-1723
Jeffrey R O'ConnellDepartment of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
Lisa R YanekDivision of General Internal Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.ORCID http://orcid.org/0000-0001-7117-1075
Mariza de AndradeDepartment of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
Matthew A AllisonDepartment of Family Medicine, University of California San Diego, La Jolla, CA, USA.
Merry-Lynn N McDonaldDivision of Pulmonary, Allergy and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
Mina K ChungDepartment of Molecular Cardiology, Cleveland Clinic, Cleveland, OH, USA.
Myriam FornageBrown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA.ORCID http://orcid.org/0000-0003-0677-8158
Nathalie ChamiCharles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Nicholas L SmithCardiovascular Health Research Unit and Department of Epidemiology, University of Washington, Seattle, WA, USA.
Patrick T EllinorHarvard Medical School, Boston, MA, USA.ORCID http://orcid.org/0000-0002-2067-0533
Ramachandran S VasanFramingham Heart Study, Framingham, MA, USA.ORCID http://orcid.org/0000-0001-7357-5970
Rasika A MathiasGeneSTAR Research Program, Divisions of Allergy and Clinical Immunology and General Internal Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.ORCID http://orcid.org/0000-0002-2282-9042
Ruth J F LoosCharles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.ORCID http://orcid.org/0000-0002-8532-5087
Stephen S RichCenter for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
Steven A LubitzCardiac Arrhythmia Service, Massachusetts General Hospital, Boston, MA, USA.ORCID http://orcid.org/0000-0002-9599-4866
Susan R HeckbertKaiser Permanente Washington Health Research Institute, Seattle, WA, USA.ORCID http://orcid.org/0000-0002-7100-512X
Susan RedlineDivision of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA, USA.
Xiuqing GuoInstitute for Translational Genomics and Population Sciences, Department of Pediatrics, Lundquist Institute at Harbor-UCLA Medical Center, Torrance, CA, USA.
Y -D Ida ChenInstitute for Translational Genomics and Population Sciences, Department of Pediatrics, Lundquist Institute at Harbor-UCLA Medical Center, Torrance, CA, USA.
Cecelia A LaurieDepartment of Biostatistics, University of Washington, Seattle, WA, USA.ORCID http://orcid.org/0000-0001-6569-2501
Ryan D HernandezDepartment of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA.
Stephen T McGarveyInternational Health Institute, Department of Epidemiology, Brown University School of Public Health, Providence, RI, USA.
Michael E GoddardCentre for AgriBioscience, Department of Economic Development, Jobs, Transport and Resources, Bundoora, Victoria, Australia.
Cathy C LaurieDepartment of Biostatistics, University of Washington, Seattle, WA, USA.ORCID http://orcid.org/0000-0003-2572-4040
Kari E NorthDepartment of Epidemiology and Carolina Center of Genome Sciences, University of North Carolina, Chapel Hill, NC, USA.
Leslie A LangeDepartment of Medicine, University of Colorado, Aurora, CO, USA.
Bruce S WeirDepartment of Biostatistics, University of Washington, Seattle, WA, USA.
Loic YengoInstitute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.ORCID http://orcid.org/0000-0002-4272-9305
Jian Yang *Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia. jian.yang@westlake.edu.cn.ORCID http://orcid.org/0000-0003-2001-2474
Peter M Visscher *Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia. peter.visscher@uq.edu.au.ORCID http://orcid.org/0000-0002-2143-8760
Funding
Tracking and Evaluation CoreU54GM115428 · NIGMS · UNIVERSITY OF MISSISSIPPI MED CTR · PI LIRETTE, SETH · 2016 to 2025
$38.2MUNC-CH CENTER FOR ENVIRONMENTAL HEALTH &SUSCEPTIBILITYP30ES010126 · NIEHS · UNIV OF NORTH CAROLINA CHAPEL HILL · PI Stephanie Engel · 2001 to 2026
$36.3MEpidemiology of Venous Thrombosis & Pulmonary EmbolismR01HL059367 · NHLBI · UNIVERSITY OF MINNESOTA TWIN CITIES · PI TANG, WEIHONG · 1998 to 2024
$11.8MExceptional Survival: Trajectories to Functional Aging (CHS All Stars)R01AG023629 · NIA · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI NEWMAN, ANNE B. · 2004 to 2016
$9.5MPhenotypic and Molecular Signatures for Sleep Apnea and Related MorbiditiesR35HL135818 · NHLBI · BRIGHAM AND WOMEN'S HOSPITAL · PI REDLINE, SUSAN S. · 2017 to 2023
$7.2MTraining Grant in Cancer BiologyT32CA154274 · NCI · UNIVERSITY OF MARYLAND BALTIMORE · PI Toni M Antalis, CURT I CIVIN · 2011 to 2026
$6.8MCHS research resources for the cardiovascular health of older adultsU01HL130114 · NHLBI · UNIVERSITY OF WASHINGTON · PI BURKE, GREGORY L, KRONMAL, RICHARD A · 2016 to 2019
$6.6MFunctional Genomics of Atrial Fibrillation in Human AtriaR01HL111314 · NHLBI · CLEVELAND CLINIC LERNER COM-CWRU · PI BARNARD, JOHN, CHUNG, MINA KAY · 2012 to 2019
$6.1MEstimating the genetic and environmental architecture of psychiatric disordersR01MH100141 · NIMH · UNIVERSITY OF COLORADO · PI KELLER, MATTHEW CHARLES · 2013 to 2022
$5.3MTheoretical Population Genetics SupplementR01GM075091 · NIGMS · UNIVERSITY OF WASHINGTON · PI WEIR, BRUCE S. · 2006 to 2020
$4.7MCHS Events Follow-up StudyU01HL080295 · NHLBI · UNIVERSITY OF WASHINGTON · PI PSATY, BRUCE M · 2005 to 2008
$4.6MRADIOMIC APPROACHES TO IMPROVE TARGETING FOR ATRIAL FIBRILLATION CATHETER ABLATIONR01HL158071 · NHLBI · CLEVELAND CLINIC LERNER COM-CWRU · PI BARNARD, JOHN, CHUNG, MINA KAY · 2021 to 2024
$2.9MBLRD VA IK6 BX006185NCI NIH HHS T32 CA154274NHLBI NIH HHS HHSN268200800007CNHLBI NIH HHS HHSN268201200036CNHLBI NIH HHS HHSN268201800001CNHLBI NIH HHS K08 HL141601NHLBI NIH HHS N01 HC085079NHLBI NIH HHS N01 HC085080NHLBI NIH HHS N01 HC085081NHLBI NIH HHS R01 HL059367NHLBI NIH HHS R01 HL111314NHLBI NIH HHS R01 HL158071NHLBI NIH HHS R35 HL135818NHLBI NIH HHS U01 HL080295NHLBI NIH HHS U01 HL130114NIA NIH HHS K01 AG059898NIA NIH HHS R01 AG023629NIDDK NIH HHS R01 DK110113NIDDK NIH HHS R01 DK124097NIEHS NIH HHS P30 ES010126NIGMS NIH HHS R01 GM075091NIGMS NIH HHS U54 GM115428NIMH NIH HHS R01 MH100141
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.
Indexed as
Genome-Wide Association StudyMultifactorial InheritanceAllelesHumansLinkage DisequilibriumPolymorphism, Single Nucleotide
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