ArticleNature computational science2025
A statistical framework for multi-trait rare variant analysis in large-scale whole-genome sequencing studies.
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Article in Nature computational science, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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8citing papers in PubMed
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Who cites it
8 citing papers in PubMed.
- Genomics of drug target prioritization for complex diseases.Nature reviews. Genetics · 2026Review
- Application of qualifying variants for genomic analysis.Bioinformatics (Oxford, England) · 2026Article
- FAVOR 2.0: A reengineered functional annotation of variants online resource for interpreting genomic variation.Nucleic acids research · 2026Article
- Network construction using sparse Gaussian graphical model based on GWAS summary statistics.Scientific reports · 2025Article
- CNPI: Rapid Analyses of Human Copy Number Data.Journal of molecular biology · 2025Article
- Identification of Risk Loci for Radiotherapy-Induced Tinnitus and Hearing Loss Through Integrated Genomic Analysis.International journal of molecular sciences · 2025Article
- A statistical framework for multi-trait rare variant analysis in large-scale whole-genome sequencing studies.Nature computational science · 2025Article
- Scalable analysis of large multi-ancestry biobanks by leveraging sparse ancestry-adjusted sample-relatedness.Research square · 2024Article
Corrections and comments
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Authors and funding
84 authors.
Xihao LiDepartment of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.ORCID 0000-0001-8151-0106
Han ChenHuman Genetics Center, Department of Epidemiology, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA.ORCID 0000-0002-9510-4923
Margaret Sunitha SelvarajCenter for Genomic Medicine and Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.
Eric Van BurenDepartment of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
Hufeng ZhouDepartment of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
Yuxuan WangDepartment of Biostatistics, Boston University School of Public Health, Boston, MA, USA.ORCID 0000-0001-9117-0619
Ryan SunDepartment of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Zachary R McCawDepartment of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Zhi YuCenter for Genomic Medicine and Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.ORCID 0000-0003-4810-3474
Min-Zhi JiangDepartment of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.ORCID 0000-0001-5502-063X
Daniel DiCorpoDepartment of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
Sheila M GaynorDepartment of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
Rounak DeyDepartment of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
Donna K ArnettProvost Office, University of South Carolina, Columbia, SC, USA.
Emelia J BenjaminSection of Cardiovascular Medicine, Boston Medical Center, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA.ORCID 0000-0003-4076-2336
Joshua C BisCardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.ORCID 0000-0002-3409-1110
John BlangeroDepartment of Human Genetics and South Texas Diabetes and Obesity Institute, School of Medicine, The University of Texas Rio Grande Valley, Brownsville, TX, USA.ORCID 0000-0001-6250-5723
Eric BoerwinkleHuman Genetics Center, Department of Epidemiology, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA.
Donald W BowdenDepartment of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
Jennifer A BrodyCardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
Brian E CadeProgram in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
April P CarsonDepartment of Medicine, University of Mississippi Medical Center, Jackson, MS, USA.ORCID 0000-0002-7970-6756
Jenna C CarlsonDepartment of Human Genetics and Department of Biostatistics and Health Data Science, University of Pittsburgh, Pittsburgh, PA, USA.
Nathalie ChamiThe Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.ORCID 0000-0002-8547-6424
Yii-Der Ida ChenThe Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, 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, USA.
Paul S de VriesHuman Genetics Center, Department of Epidemiology, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA.
Myriam FornageHuman Genetics Center, Department of Epidemiology, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA.
Nora FranceschiniDepartment of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Barry I FreedmanDepartment of Internal Medicine, Nephrology, Wake Forest University School of Medicine, Winston-Salem, NC, USA.ORCID 0000-0003-0275-5530
Charles GuDivision of Biology & Biomedical Sciences, Washington University School of Medicine, St. Louis, MO, USA.ORCID 0000-0002-8527-8145
Nancy L Heard-CostaFramingham Heart Study, Framingham, MA, USA.ORCID 0000-0001-9730-0306
Jiang HeDepartment of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, USA.
Lifang HouDepartment of Preventive Medicine, Northwestern University, Chicago, IL, USA.
Yi-Jen HungDepartment of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
Marguerite R IrvinDepartment of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, AL, USA.
Robert C KaplanDepartment of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA.
Sharon L R KardiaDepartment of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
Tanika N KellyDepartment of Medicine, Division of Nephrology, University of Illinois Chicago, Chicago, IL, USA.
Iain KonigsbergDepartment of Biomedical Informatics, University of Colorado, Aurora, CO, USA.
Charles KooperbergDepartment of Medicine, Division of Nephrology, University of Illinois Chicago, Chicago, IL, USA.
Brian G KralDepartment of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Changwei LiDepartment of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, USA.
Yun LiDepartment of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Honghuang LinDepartment of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA.
Ching-Ti LiuDepartment of Biostatistics, Boston University School of Public Health, Boston, MA, USA.ORCID 0000-0002-0703-0742
Ruth J F LoosThe Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Michael C MahaneyDepartment of Human Genetics and South Texas Diabetes and Obesity Institute, School of Medicine, The University of Texas Rio Grande Valley, Brownsville, TX, USA.
Lisa W MartinSchool of Medicine and Health Sciences, George Washington University, Washington, DC, USA.ORCID 0000-0003-4352-0914
Rasika A MathiasDepartment of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Braxton D MitchellDepartment of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.ORCID 0000-0003-4920-4744
May E MontasserDepartment of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
Alanna C MorrisonHuman Genetics Center, Department of Epidemiology, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA.
Take NaseriNaseri & Associates Public Health Consultancy Firm and Family Health Clinic, Apia, Samoa.
Kari E NorthDepartment of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.ORCID 0000-0002-8903-0366
Nicholette D PalmerDepartment of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
Patricia A PeyserDepartment of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
Bruce M PsatyCardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
Susan RedlineDivision of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA, USA.
Alexander P ReinerDivision of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA.
Stephen S RichDepartment of Genome Sciences, University of Virginia, Charlottesville, VA, USA.ORCID 0000-0003-3872-7793
Colleen M SitlaniCardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
Jennifer A SmithDepartment of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
Kent D TaylorThe Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
Hemant K TiwariDepartment of Biostatistics, School of Public Health, University of Alabama at Birmingham, Birmingham, AL, USA.
Ramachandran S VasanFramingham Heart Study, Framingham, MA, USA.
Satupa'itea VialiSchool of Medicine, National University of Samoa, Apia, Samoa.ORCID 0000-0002-4829-8403
Zhe WangThe Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.ORCID 0000-0002-8046-4969
Jennifer WesselDepartment of Epidemiology, Fairbanks School of Public Health, Indiana University, Indianapolis, IN, USA.
Lisa R YanekDepartment of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Bing YuHuman Genetics Center, Department of Epidemiology, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA.
NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium
Josée DupuisDepartment of Biostatistics, Boston University School of Public Health, Boston, MA, USA.ORCID 0000-0003-2871-3603
James B MeigsProgram in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
Paul L AuerDivision of Biostatistics, Data Science Institute, and Cancer Center, Medical College of Wisconsin, Milwaukee, WI, USA.
Laura M RaffieldDepartment of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Alisa K ManningDepartment of Medicine, Harvard Medical School, Boston, MA, USA.
Kenneth M RiceDepartment of Biostatistics, University of Washington, Seattle, WA, USA.
Jerome I RotterThe Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
Gina M PelosoDepartment of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
Pradeep NatarajanCenter for Genomic Medicine and Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.
Zilin LiDepartment of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA. li@hsph.harvard.edu.ORCID 0000-0003-1521-8945
Zhonghua LiuDepartment of Biostatistics, Mailman School of Public Health, Columbia University, New York, NY, USA. zl2509@cumc.columbia.edu.ORCID 0000-0003-3048-9823
Xihong LinProgram in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA. xlin@hsph.harvard.edu.ORCID 0000-0001-7067-7752
Funding
UCLA Clinical Translational Science InstituteUL1TR001881 · NCATS · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI ARLEEN F. BROWN, ARASH NAEIM · 2016 to 2026
$118.1MInstitute for Clinical and Translational ResearchUL1TR001079 · NCATS · JOHNS HOPKINS UNIVERSITY · PI FORD, DANIEL ERNEST · 2013 to 2017
$60.1MTransgenic & Knock-out MouseP30DK063491 · NIDDK · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI MILES Frome WILKINSON · 2003 to 2026
$40.4MSleep Disorders in Adults with Sickle Cell Disease: Frequency, Associations with Cardiovascular and Pain Indicators, and Responses to TreatmentU54MD007597 · NIMHD · HOWARD UNIVERSITY · PI William M. Southerland · 2019 to 2026
$37.7MZINC AND CA EDTA THERAPY OF PLUMBISMM01RR000052 · NCRR · JOHNS HOPKINS UNIVERSITY · PI VINING, EILEEN PATRICE · 1985 to 2007
$37.3MWORKER PROTECTION AGAINST AIRBORNE INFLUENZA - A PILOT STUDYM01RR007122 · NCRR · WAKE FOREST UNIVERSITY HEALTH SCIENCES · PI WASHBURN, LISA K · 1992 to 2010
$35.2MWake Forest Clinical and Translational Science AwardUL1TR001420 · NCATS · WAKE FOREST UNIVERSITY HEALTH SCIENCES · PI ARD, JAMY D, FOLEY, KRISTIE L · 2015 to 2023
$32.3MROLE OF DIETARY CONSTITUENTS ON GENE EXPRESSION IN INTESTINAL EPITHELIUMP30DK040561 · NIDDK · MASSACHUSETTS GENERAL HOSPITAL · PI Elizabeth Austen Lawson, Takara Leah Stanley · 1994 to 2026
$31.6MFRAMINGHAM HEART STUDY - YEAR 5 EXAM75N92019D00031 · NHLBI · BOSTON UNIVERSITY MEDICAL CAMPUS · 2019 to 2024
$29.8MPEDIGREE ANALYSIS OF LIPOPROTEIN PHENOTYPESP01HL045522 · NHLBI · TEXAS BIOMEDICAL RESEARCH INSTITUTE · PI BLANGERO, JOHN · 1991 to 2012
$27.6MClinical and Translational Science AwardUL1TR000040 · NCATS · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI GINSBERG, HENRY N · 2012 to 2015
$26.2MTranslating Molecular and Clinical Data to Population Lung Cancer Risk AssessmentU19CA203654 · NCI · UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR · PI Christopher I. Amos · 2017 to 2026
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Abstract
Large-scale whole-genome sequencing (WGS) studies have improved our understanding of the contributions of coding and noncoding rare variants to complex human traits. Leveraging association effect sizes across multiple traits in WGS rare variant association analysis can improve statistical power over single-trait analysis, and also detect pleiotropic genes and regions. Existing multi-trait methods have limited ability to perform rare variant analysis of large-scale WGS data. We propose MultiSTAAR, a statistical framework and computationally scalable analytical pipeline for functionally informed multi-trait rare variant analysis in large-scale WGS studies. MultiSTAAR accounts for relatedness, population structure and correlation among phenotypes by jointly analyzing multiple traits, and further empowers rare variant association analysis by incorporating multiple functional annotations. We applied MultiSTAAR to jointly analyze three lipid traits in 61,838 multi-ethnic samples from the Trans-Omics for Precision Medicine (TOPMed) Program. We discovered and replicated new associations with lipid traits missed by single-trait analysis.
Indexed as
Genetic VariationGenome-Wide Association StudyWhole Genome SequencingGenome, HumanHumansPhenotype
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