ArticlebioRxiv : the preprint server for biology2023
A statistical framework for powerful multi-trait rare variant analysis in large-scale whole-genome sequencing studies.
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69 authors at 20 institutions in 3 countries.
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, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA.
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.ORCID 0000-0003-4256-8705
Hufeng ZhouDepartment of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.ORCID 0000-0001-9382-5674
Yuxuan WangDepartment of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
Ryan SunDepartment of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, TX, USA.ORCID 0000-0003-1176-1561
Zachary R McCawDepartment of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.ORCID 0000-0002-2006-9828
Zhi YuCenter for Genomic Medicine and Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.
Donna K ArnettProvost Office, University of South Carolina, Columbia, SC, USA.ORCID 0000-0003-2219-657X
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, Human Genetics, and Environmental Sciences, 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.ORCID 0000-0003-1424-0673
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, University of Pittsburgh, Pittsburgh, PA, USA.ORCID 0000-0001-5483-0833
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.ORCID 0000-0003-1741-3517
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.ORCID 0000-0002-6898-155X
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, USA.ORCID 0000-0003-0964-0111
Myriam FornageHuman 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, USA.ORCID 0000-0003-0677-8158
Nora FranceschiniDepartment of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.ORCID 0009-0001-8346-3662
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-CostaDepartment of Neurology, Boston University Chobanian & Avedisian School of Medicine, Boston, 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.ORCID 0000-0002-1442-2023
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 KellyDepartment of Medicine, Division of Nephrology, University of Illinois Chicago, Chicago, IL, USA.ORCID 0000-0002-7348-4451
Iain KonigsbergDepartment of Biomedical Informatics, University of Colorado, Aurora, CO, USA.ORCID 0000-0001-7356-100X
Charles KooperbergDivision of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA.ORCID 0000-0002-7986-8560
Brian G KralDepartment of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.ORCID 0000-0001-9493-2084
Changwei LiDepartment of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, USA.ORCID 0000-0002-9203-304X
Ruth J F LoosThe Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.ORCID 0000-0002-8532-5087
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.ORCID 0000-0002-1341-3950
Lisa W MartinGeorge Washington University School of Medicine and Health Sciences, Washington, DC, USA.
Rasika A MathiasDepartment of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.ORCID 0000-0002-2282-9042
Ryan L MinsterDepartment of Human Genetics and Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA, USA.ORCID 0000-0001-7382-6717
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.ORCID 0000-0001-6381-4296
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, USA.
Nicholette D PalmerDepartment of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, NC, USA.ORCID 0000-0002-9717-8459
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.ORCID 0000-0002-7278-2190
Laura M RaffieldDepartment of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.ORCID 0000-0002-7892-193X
Susan RedlineDivision of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA, USA.ORCID 0000-0002-6585-1610
Alexander P ReinerDivision of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA.ORCID 0000-0002-0607-6714
Stephen S RichCenter for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
Colleen M SitlaniCardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.ORCID 0000-0001-7656-7482
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.ORCID 0000-0002-2756-4370
Hemant TiwariDepartment of Biostatistics, School of Public Health, University of Alabama at Birmingham, Birmingham, AL, USA.ORCID 0000-0003-4016-1856
Ramachandran S VasanFramingham Heart Study, Framingham, MA, USA.
Zhe WangThe Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Lisa R YanekDepartment of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.ORCID 0000-0001-7117-1075
Bing YuHuman 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, USA.
NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium
Kenneth M RiceDepartment of Biostatistics, University of Washington, Seattle, WA, USA.ORCID 0000-0002-3071-7278
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.ORCID 0000-0001-7191-1723
Gina M PelosoDepartment of Biostatistics, Boston University School of Public Health, Boston, MA, USA.ORCID 0000-0002-5355-8636
Pradeep NatarajanCenter for Genomic Medicine and Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.ORCID 0000-0001-8402-7435
Zilin LiDepartment of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.ORCID 0000-0003-1521-8945
Zhonghua LiuDepartment of Biostatistics, Mailman School of Public Health, Columbia University, New York, NY, USA.ORCID 0000-0003-3048-9823
Xihong LinProgram in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA.ORCID 0000-0001-7067-7752
University of Washington · USBroad Institute · USThe University of Texas Health Science Center at Houston · USUniversity of North Carolina at Chapel Hill · USBoston University · USHarvard University · USJohns Hopkins University · USThe University of Texas Rio Grande Valley · USUCLA Medical Center · USUniversity of Michigan · USWake Forest University · USIcahn School of Medicine at Mount Sinai · USTulane University · USUniversity of Alabama at Birmingham · USUniversity of Maryland, Baltimore · USUniversity of Pittsburgh · USAlbert Einstein College of Medicine · USBaylor College of Medicine · USBrigham and Women's Hospital · USBrown Foundation · US
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
$40.4MZINC 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
$32.3MFRAMINGHAM 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, Rayjean J. Hung · 2017 to 2026
$23.7MIDENTIFICATION OF COMMON GENETIC VARIANTS FOR ATRIAL FIBRILLATION AND PR INTERVALR01HL092577 · NHLBI · MASSACHUSETTS GENERAL HOSPITAL · PI BENJAMIN, EMELIA J., ELLINOR, PATRICK THOMAS · 2009 to 2025
$20.6MHYPERGEN: GENETICS OF LEFT VENTRICULAR HYPERTROPHYR01HL055673 · NHLBI · UNIVERSITY OF MINNESOTA TWIN CITIES · PI ARNETT, DONNA K · 1996 to 2016
$18.1MNCATS NIH HHS UL1 TR000040NCATS NIH HHS UL1 TR001079NCATS NIH HHS UL1 TR001420NCATS NIH HHS UL1 TR001881NCI NIH HHS R35 CA197449NCI NIH HHS U19 CA203654NCRR NIH HHS M01 RR000052NCRR NIH HHS M01 RR007122NCRR NIH HHS UL1 RR033176NHGRI NIH HHS U01 HG009088NHGRI NIH HHS U01 HG012064NHLBI NIH HHS 75N92019D00031NHLBI NIH HHS 75N92020D00001NHLBI NIH HHS 75N92020D00002NHLBI NIH HHS 75N92020D00003NHLBI NIH HHS 75N92020D00004NHLBI NIH HHS 75N92020D00005NHLBI NIH HHS 75N92020D00006NHLBI NIH HHS 75N92020D00007NHLBI NIH HHS F32 HL085989NHLBI NIH HHS HHSN268201500001CNHLBI NIH HHS HHSN268201500001INHLBI NIH HHS HHSN268201500003CNHLBI NIH HHS HHSN268201500003INHLBI NIH HHS HHSN268201600001CNHLBI NIH HHS HHSN268201600002CNHLBI NIH HHS HHSN268201600003CNHLBI NIH HHS HHSN268201600004CNHLBI NIH HHS HHSN268201600018CNHLBI NIH HHS HHSN268201700001CNHLBI NIH HHS HHSN268201700001INHLBI NIH HHS HHSN268201700002CNHLBI NIH HHS HHSN268201700002INHLBI NIH HHS HHSN268201700003CNHLBI NIH HHS HHSN268201700003INHLBI NIH HHS HHSN268201700004CNHLBI NIH HHS HHSN268201700004INHLBI NIH HHS HHSN268201700005CNHLBI NIH HHS HHSN268201700005INHLBI NIH HHS HHSN268201800001CNHLBI NIH HHS HHSN268201800010INHLBI NIH HHS HHSN268201800011CNHLBI NIH HHS HHSN268201800011INHLBI NIH HHS HHSN268201800012CNHLBI NIH HHS HHSN268201800012INHLBI NIH HHS HHSN268201800014CNHLBI NIH HHS HHSN268201800014INHLBI NIH HHS HHSN268201800015INHLBI NIH HHS N01 HC025195NHLBI NIH HHS N01 HC095159NHLBI NIH HHS N01 HC095160NHLBI NIH HHS N01 HC095161NHLBI NIH HHS N01 HC095162NHLBI NIH HHS N01 HC095163NHLBI NIH HHS N01 HC095164NHLBI NIH HHS N01 HC095165NHLBI NIH HHS N01 HC095166NHLBI NIH HHS N01 HC095167NHLBI NIH HHS N01 HC095168NHLBI NIH HHS N01 HC095169NHLBI NIH HHS P01 HL045522NHLBI NIH HHS R01 HL049762NHLBI NIH HHS R01 HL055673NHLBI NIH HHS R01 HL059684NHLBI NIH HHS R01 HL067348NHLBI NIH HHS R01 HL071025NHLBI NIH HHS R01 HL071051NHLBI NIH HHS R01 HL071205NHLBI NIH HHS R01 HL071250NHLBI NIH HHS R01 HL071251NHLBI NIH HHS R01 HL071258NHLBI NIH HHS R01 HL071259NHLBI NIH HHS R01 HL087660NHLBI NIH HHS R01 HL087698NHLBI NIH HHS R01 HL092301NHLBI NIH HHS R01 HL092577NHLBI NIH HHS R01 HL104135NHLBI NIH HHS R01 HL105756NHLBI NIH HHS R01 HL112064NHLBI NIH HHS R01 HL113323NHLBI NIH HHS R01 HL113338NHLBI NIH HHS R01 HL117626NHLBI NIH HHS R01 HL119443NHLBI NIH HHS R01 HL120393NHLBI NIH HHS R01 HL127564NHLBI NIH HHS R01 HL142711NHLBI NIH HHS R01 HL153805NHLBI NIH HHS R01 HL163560NHLBI NIH HHS R03 HL154284NHLBI NIH HHS R35 HL135818NHLBI NIH HHS U01 HL054457NHLBI NIH HHS U01 HL054464NHLBI NIH HHS U01 HL054472NHLBI NIH HHS U01 HL054473NHLBI NIH HHS U01 HL054481NHLBI NIH HHS U01 HL054495NHLBI NIH HHS U01 HL054509NHLBI NIH HHS U01 HL072518NHLBI NIH HHS U01 HL072524NHLBI NIH HHS U01 HL120393NHLBI NIH HHS U01 HL137162NIAMS NIH HHS R01 AR048797NIA NIH HHS R01 AG058921NIDDK NIH HHS K26 DK138425NIDDK NIH HHS P30 DK063491NIDDK NIH HHS R01 DK071891NIDDK NIH HHS R01 DK117445NIDDK NIH HHS U01 DK085524NIMHD NIH HHS HHSN268201800013INIMHD NIH HHS R01 MD012765NIMH NIH HHS R01 MH078111NIMH NIH HHS R01 MH078143NIMH NIH HHS R01 MH083824NINDS NIH HHS R01 NS058700
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 (low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides) in 61,861 multi-ethnic samples from the Trans-Omics for Precision Medicine (TOPMed) Program. We discovered new associations with lipid traits missed by single-trait analysis, including rare variants within an enhancer of
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