ArticleAmerican journal of human genetics2019
Efficient Variant Set Mixed Model Association Tests for Continuous and Binary Traits in Large-Scale Whole-Genome Sequencing Studies.
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Article in American journal of human genetics, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 88 papers, 4 of them syntheses that pooled it.
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Who cites it
88 citing papers in PubMed, 4 syntheses or guidelines pooled it.
- A cosmopolitan inversion facilitates seasonal adaptation in overwintering Drosophila.Genetics · 2024Pooled it
- Powerful, scalable and resource-efficient meta-analysis of rare variant associations in large whole genome sequencing studies.Nature genetics · 2023Pooled it
- Insights From a Large-Scale Whole-Genome Sequencing Study of Systolic Blood Pressure, Diastolic Blood Pressure, and Hypertension.Hypertension (Dallas, Tex. : 1979) · 2022Pooled it
- Gene-based whole genome sequencing meta-analysis of 250 circulating proteins in three isolated European populations.Molecular metabolism · 2022Pooled it
- Transcript-aware rare genetic variant association analyses of cardiopulmonary traits in participants from the All of Us Research Program.Nature communications · 2026Article
- HiFiMAP: High-resolution fast identity-by-descent mapping test.medRxiv : the preprint server for health sciences · 2026Article
- Interactions between genetic and epidemiological factors influencing mammographic density.American journal of epidemiology · 2026Article
- Scalable and accurate rare-variant association tests for whole genome sequencing time-to-event analysis in large biobanks.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Modeling and application of alzheimer's disease complex trait prediction based on multi-task learning.Scientific reports · 2026Article
- cellSTAAR: incorporating single-cell-sequencing-based functional data to boost power in rare variant association testing of noncoding regions.Nature methods · 2026Article
- Whole genome sequence analysis of pulmonary function and COPD in 44,287 multi-ancestry participants.Genome biology · 2026Article
- The Impact of Structural Variation on Alzheimer's Disease in the Alzheimer's Disease Sequencing Project.Research square · 2026Article
- Genome-wide association study (GWAS) provides insights into the genomic basis of reproduction-related traits in Chouardia litardierei (Asparagaceae).BMC plant biology · 2025Article
- BCG induced innate immune response heterogeneity and susceptibility to pediatric tuberculosis.Journal of immunology (Baltimore, Md. : 1950) · 2025Article
- Whole genome sequencing analysis of body mass index identifies novel African ancestry-specific risk allele.Nature communications · 2025Article
- Unveiling the Genetic Landscape of Coronary Artery Disease Through Common and Rare Structural Variants.Journal of the American Heart Association · 2025Article
- A statistical framework for multi-trait rare variant analysis in large-scale whole-genome sequencing studies.Nature computational science · 2025Article
- Dose-dependent role of AMH and AMHR2 signaling in male differentiation and regulation of sex determination in Spotted knifejaw (Oplegnathus punctatus) with XCell communication and signaling : CCS · 2025Article
- Uncovering the genomic basis of phenological traits inFrontiers in plant science · 2025Article
- Auto-branch multi-task learning for simultaneous prediction of multiple correlated traits associated with Alzheimer's disease.Frontiers in genetics · 2025Article
28 more citing papers are in PubMed but not listed here.
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Authors and funding
48 authors.
Han ChenHuman Genetics Center, Department of Epidemiology, Human Genetics and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA; Center for Precision Health, School of Public Health and School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
Jennifer E HuffmanCenter for Population Genomics, VA Boston Healthcare System, Jamaica Plain, MA 02130, USA.
Jennifer A BrodyCardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 98101, USA.
Chaolong WangDepartment of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
Seunggeun LeeDepartment of Biostatistics, University of Michigan, Ann Arbor, MI 48109, USA.
Zilin LiDepartment of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
Stephanie M GogartenDepartment of Biostatistics, University of Washington, Seattle, WA 98195, USA.
Tamar SoferDivision of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA 02115, USA; Division of Sleep Medicine, Harvard Medical School, Boston, MA 02115, USA.
Lawrence F BielakDepartment of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI 48109, USA.
Joshua C BisCardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 98101, USA.
John BlangeroDepartment of Human Genetics and South Texas Diabetes and Obesity Institute, School of Medicine, The University of Texas Rio Grande Valley, Brownsville, TX 78520, USA.
Russell P BowlerDivision of Pulmonary Medicine, Department of Medicine, National Jewish Health, Denver, CO 80206, USA.
Brian E CadeDivision of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA 02115, USA; Division of Sleep Medicine, Harvard Medical School, Boston, MA 02115, USA.
Michael H ChoChanning Division of Network Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Adolfo CorreaJackson Heart Study, Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA.
Joanne E CurranDepartment of Human Genetics and South Texas Diabetes and Obesity Institute, School of Medicine, The University of Texas Rio Grande Valley, Brownsville, TX 78520, USA.
Paul S de VriesHuman Genetics Center, Department of Epidemiology, Human Genetics and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
David C GlahnDepartment of Psychiatry, Yale University School of Medicine, New Haven, CT 06510, USA; Olin Neuropsychiatric Research Center, Institute of Living, Hartford Hospital, Hartford, CT 06106, USA.
Xiuqing GuoThe Institute for Translational Genomics and Population Sciences, Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
Andrew D JohnsonFramingham Heart Study, National Heart, Lung, and Blood Institute and Boston University, Framingham, MA 01702, USA.
Sharon KardiaDepartment of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI 48109, USA.
Charles KooperbergDivision of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Joshua P LewisDepartment of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Xiaoming LiuUSF Genomics, College of Public Health, University of South Florida, Tampa, FL 33612, USA.
Rasika A MathiasDepartment of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Braxton D MitchellDepartment of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA; Geriatrics Research and Education Clinical Center, Baltimore VA Medical Center, Baltimore, MD 21201, USA.
Jeffrey R O'ConnellDepartment of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Patricia A PeyserDepartment of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI 48109, USA.
Wendy S PostDivision of Cardiology, Johns Hopkins University, Baltimore, MD 21287, USA.
Alex P ReinerDivision of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Stephen S RichCenter for Public Health Genomics, University of Virginia, Charlottesville, VA 22908, USA.
Jerome I RotterThe Institute for Translational Genomics and Population Sciences, Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
Edwin K SilvermanChanning Division of Network Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Jennifer A SmithDepartment of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI 48109, USA.
Ramachandran S VasanFramingham Heart Study, National Heart, Lung, and Blood Institute and Boston University, Framingham, MA 01702, USA; Sections of Preventive Medicine and Epidemiology, and of Cardiology, Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA; Department of Epidemiology, Boston University School of Public Health, Boston, MA 02118, USA.
James G WilsonDepartment of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216, USA.
Lisa R YanekDepartment of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium
TOPMed Hematology and Hemostasis Working Group
Susan RedlineDivision of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA 02115, USA; Division of Sleep Medicine, Harvard Medical School, Boston, MA 02115, USA; Division of Pulmonary, Critical Care, and Sleep Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA.
Nicholas L SmithCardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 98101, USA; Kaiser Permanente Washington Health Research Institute, Seattle, WA 98101, USA; Seattle Epidemiologic Research and Information Center, Department of Veterans Affairs Office of Research and Development, Seattle, WA 98108, USA; Department of Epidemiology, University of Washington, Seattle, WA 98195, USA.
Eric BoerwinkleHuman Genetics Center, Department of Epidemiology, Human Genetics and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
Ingrid B BoreckiDepartment of Biostatistics, University of Washington, Seattle, WA 98195, USA.
L Adrienne CupplesFramingham Heart Study, National Heart, Lung, and Blood Institute and Boston University, Framingham, MA 01702, USA; Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA.
Cathy C LaurieDepartment of Biostatistics, University of Washington, Seattle, WA 98195, USA.
Alanna C MorrisonHuman Genetics Center, Department of Epidemiology, Human Genetics and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
Kenneth M RiceDepartment of Biostatistics, University of Washington, Seattle, WA 98195, USA.
Xihong LinDepartment of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Department of Statistics, Harvard University, Cambridge, MA 02138, USA. Electronic address: xlin@hsph.harvard.edu.
Funding
Tracking and Evaluation CoreU54GM115428 · NIGMS · UNIVERSITY OF MISSISSIPPI MED CTR · PI GOMEZ-SANCHEZ, CELSO ENRIQUE · 2016 to 2025
$38.2MRole of obesity in preeclamptic pregnancy.P20GM121334 · NIGMS · UNIVERSITY OF MISSISSIPPI MED CTR · PI Pier Paolo Claudio, Babbette LaMarca · 2017 to 2026
$26.4MCardiovascular Genomics and Bioinformatics projectsZIAHL006170 · NHLBI · NATIONAL HEART, LUNG, AND BLOOD INSTITUTE · PI JOHNSON, ANDREW · 2013 to 2025
$25.3MTranslating Molecular and Clinical Data to Population Lung Cancer Risk AssessmentU19CA203654 · NCI · UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR · PI Christopher I. Amos, Rayjean J. Hung · 2017 to 2026
$23.7MStatistical Methods for Analysis of Massive Genetic and Genomic Data in Cancer ResearchR35CA197449 · NCI · HARVARD UNIVERSITY D/B/A HARVARD SCHOOL OF PUBLIC HEALTH · PI XIHONG LIN · 2015 to 2026
$10.9MPhenotypic and Molecular Signatures for Sleep Apnea and Related MorbiditiesR35HL135818 · NHLBI · BRIGHAM AND WOMEN'S HOSPITAL · PI REDLINE, SUSAN S. · 2017 to 2023
$7.2MStatistical Methods for the Spatio-Temporal Assessment of Social Disparities in CancerP01CA134294 · NCI · HARVARD SCHOOL OF PUBLIC HEALTH · PI COULL, BRENT ANDREW, DOMINICI, FRANCESCA · 2008 to 2017
$6.8MRare variants and NHLBI traits in deeply phenotyped cohortsU01HL120393 · NHLBI · UNIVERSITY OF WASHINGTON · PI PSATY, BRUCE M, RICE, KENNETH M. · 2017 to 2018
$5.6MPowering whole genome sequence-based genetic discovery for common human diseases- Extended 2021-2022.U01HG009088 · NHGRI · HARVARD SCHOOL OF PUBLIC HEALTH · PI LIN, XIHONG, NEALE, BENJAMIN MICHAEL · 2016 to 2021
$5.1MSOLAR-Eclipse Computational Tools for Imaging GeneticsR01EB015611 · NIBIB · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · PI KOCHUNOV, PETER V. · 2012 to 2024
$5.0MAnalysis of Whole Genome Sequence and Hemostasis PhenotypesR01HL139553 · NHLBI · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · PI PAUL STEFAN DE VRIES, Alanna C Morrison · 2018 to 2026
$5.0MLeveraging Family Data to Identify Genetic Variants for Sleep ApneaR01HL113338 · NHLBI · BRIGHAM AND WOMEN'S HOSPITAL · PI LIN, XIHONG, REDLINE, SUSAN S. · 2012 to 2016
$4.4MNCI NIH HHS P01 CA134294NCI NIH HHS R35 CA197449NCI NIH HHS U19 CA203654NHGRI NIH HHS U01 HG009088NHLBI NIH HHS K01 HL135405NHLBI NIH HHS R00 HL130593NHLBI NIH HHS R01 HL113338NHLBI NIH HHS R01 HL119443NHLBI NIH HHS R01 HL131136NHLBI NIH HHS R01 HL137922NHLBI NIH HHS R01 HL139553NHLBI NIH HHS R35 HL135818NHLBI NIH HHS U01 HL120393NHLBI NIH HHS U01 HL137162NIGMS NIH HHS P20 GM121334NIGMS NIH HHS U54 GM115428
Abstract
With advances in whole-genome sequencing (WGS) technology, more advanced statistical methods for testing genetic association with rare variants are being developed. Methods in which variants are grouped for analysis are also known as variant-set, gene-based, and aggregate unit tests. The burden test and sequence kernel association test (SKAT) are two widely used variant-set tests, which were originally developed for samples of unrelated individuals and later have been extended to family data with known pedigree structures. However, computationally efficient and powerful variant-set tests are needed to make analyses tractable in large-scale WGS studies with complex study samples. In this paper, we propose the variant-set mixed model association tests (SMMAT) for continuous and binary traits using the generalized linear mixed model framework. These tests can be applied to large-scale WGS studies involving samples with population structure and relatedness, such as in the National Heart, Lung, and Blood Institute's Trans-Omics for Precision Medicine (TOPMed) program. SMMATs share the same null model for different variant sets, and a virtue of this null model, which includes covariates only, is that it needs to be fit only once for all tests in each genome-wide analysis. Simulation studies show that all the proposed SMMATs correctly control type I error rates for both continuous and binary traits in the presence of population structure and relatedness. We also illustrate our tests in a real data example of analysis of plasma fibrinogen levels in the TOPMed program (n = 23,763), using the Analysis Commons, a cloud-based computing platform.
Indexed as
Genetic Association StudiesModels, GeneticWhole Genome SequencingChromosomes, Human, Pair 4Cloud ComputingFemaleFibrinogenGenetics, PopulationHumansMaleNational Heart, Lung, and Blood Institute (U.S.)Precision MedicineResearch DesignTime FactorsUnited StatesFibrinogengeneralized linear mixed modelpopulation structurerare variantsrelatednessTOPMedvariant set association testwhole-genome sequencing
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