ArticleDiabetes2026
Colocalization of eQTLs With Type 2 Diabetes and Glycemic Traits Using Whole-Genome Sequences in Diverse Populations From the NHLBI Trans-Omics in Precision Medicine (TOPMed) Program.
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95 authors.
Ningyuan WangDepartment of Biostatistics, Boston University School of Public Health, Boston, MA.
Daniel A DiCorpoDepartment of Biostatistics, Boston University School of Public Health, Boston, MA.
Yixin ZhangDepartment of Biostatistics, Boston University School of Public Health, Boston, MA.
Erica KleinbrinkDepartment of Human Genetics, McGill University, Montreal, Quebec, Canada.
Donna K ArnettOffice of the Provost, University of South Carolina, Columbia, SC.
John BarnardDepartment of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH.
John BlangeroDepartment of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX.
Donald W BowdenDepartment of Biochemistry, Wake Forest University of Medicine, Winston-Salem, NC.
April P CarsonDepartment of Medicine, University of Mississippi Medical Center, Jackson, MS.ORCID 0000-0002-7970-6756
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.
Mina K ChungDepartment of Cardiovascular Medicine, Heart, Vascular & Thoracic Institute; Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH.
Joanne E CurranDepartment of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX.
Dawood DarbarCenter for Cardiovascular Research, University of Illinois Chicago, Chicago, IL.
Ravindranath DuggiralaDepartment of Health and Behavioral Sciences, College of Arts and Sciences, Texas A&M University-San Antonio, San Antonio, TX.
Patrick T EllinorCardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, MA.
Diane FatkinCardiology Department, St Vincent's Hospital, Darlinghurst, New South Wales, Australia.
Myriam FornageBrown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science at Houston, Houston, TX.
Nancy Heard-CostaDepartment of Neurology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA.
Jiang HeDepartment of Epidemiology, O'Donnell School of Public Health, University of Texas Southwestern Medical Center, Dallas, TX.
Lifang HouDepartment of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL.ORCID 0000-0003-4877-0031
Sharon L R KardiaDepartment of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI.
Charles KooperbergDivision of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA.
Ruth J F LoosThe Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY.
David D McManusUMass Chan Medical School, Worcester, MA.
Braxton D MitchellDepartment of Medicine, University of Maryland School of Medicine, Baltimore, MD.ORCID 0000-0003-4920-4744
Ryan L MinsterDepartment of Human Genetics, University of Pittsburgh, Pittsburgh, PA.
Kari E NorthDepartment of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC.
Bruce M PsatyCardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA.
Laura M RaffieldDepartment of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC.
Susan RedlineDivision of Sleep and Circadian Disorders, Departments of Neurology and Medicine, Brigham and Women's Hospital, Boston, MA.
Stephen S RichCenter for Public Health Genomics, Department of Public Health Sciences, University of Virginia, Charlottesville, VA.ORCID 0000-0003-3872-7793
Dan RodenDepartment of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN.
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.
Moore B ShoemakerDivision of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN.
Jonathan D SmithCleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH.
David R Van WagonerDepartment of Cardiovascular Medicine, Heart, Vascular & Thoracic Institute; Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH.
Francois AguetBroad Institute of MIT and Harvard, Cambridge, MA.
Kristin ArdlieBroad Institute of MIT and Harvard, Cambridge, MA.
Joshua C BisCardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA.
Jennifer A BrodyCardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA.
Brian E CadeDivision of Sleep and Circadian Disorders, Departments of Neurology and Medicine, Brigham and Women's Hospital, Boston, MA.
Clary B ClishBroad Institute of MIT and Harvard, Cambridge, MA.ORCID 0000-0001-8259-9245
Paul S de VriesHuman Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX.
James S FloydCardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA.ORCID 0000-0002-0365-9041
Barry I FreedmanDepartment of Internal Medicine, Section on Nephrology, Wake Forest University of Medicine, Winston-Salem, NC.
Stacey GabrielProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA.
Robert E GerzstenDivision of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.ORCID 0000-0002-6767-7687
Mark O GoodarziDepartment of Medicine, Division of Endocrinology Diabetes and Metabolism, Cedars-Sinai Medical Center, Los Angeles, CA.ORCID 0000-0001-6364-5103
Charles GuCenter for Biostatistics and Data Science, Institute for Informatics, Data Science, and Biostatistics, School of Medicine, Washington University in St. Louis, St. Louis, MO.
Xiuqing GuoThe Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA.
Namrata GuptaProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA.
Susan R HeckbertCardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA.
Sarah HsuBroad Institute of MIT and Harvard, Cambridge, MA.
Yi-Jen HungDivision of Endocrine and Metabolism, Tri-Service General Hospital Songshan Branch, Taipei, Taiwan.
Rita R KalyaniDepartment of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.ORCID 0000-0002-1530-6884
Tanika N KellyDepartment of Medicine, University of Illinois Chicago, Chicago, IL.
Gregory L KinneyColorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, CO.
Changwei LiDepartment of Epidemiology, O'Donnell School of Public Health, University of Texas Southwestern Medical Center, Dallas, TX.
Simin LiuCenter for Global Cardiometabolic Health, Brown University, Providence, MA.ORCID 0000-0003-2098-3844
Yongmei LiuDepartment of Medicine, Division of Cardiology, Duke University School of Medicine, Durham, NC.ORCID 0000-0002-6562-1858
Donald M Lloyd-JonesDepartment of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL.ORCID 0000-0003-0847-6110
JoAnn E MansonDepartment of Medicine, Division of Preventive Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
Rasika A MathiasDepartment of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.
Josep M MercaderProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA.ORCID 0000-0001-8494-3660
Alanna C MorrisonDepartment of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX.
Take NaseriNaseri & Associates Public Health Consultancy Firm and Family Health Clinic, Apia, Samoa.
Suna OnengutCenter for Public Health Genomics, Department of Public Health Sciences, University of Virginia, Charlottesville, VA.ORCID 0000-0002-6563-8334
Nicholette D PalmerDepartment of Biochemistry, Wake Forest University of Medicine, Winston-Salem, NC.ORCID 0000-0001-8883-2511
Patricia A PeyserDepartment of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI.
Qibin QiDepartment of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY.
Sridharan RaghavanSection of Academic Primary Care, VA Eastern Colorado Health Care System, Aurora, CO.
Alex P ReinerDepartment of Epidemiology, University of Washington, Seattle, WA.
Mary R RooneyDepartment of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD.ORCID 0000-0002-5607-4848
Magdalena Sevilla-GonzalezProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA.ORCID 0000-0001-6135-9998
Chloe SarnowskiDepartment of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX.ORCID 0000-0002-6090-7099
Joshua D SmithNorthwest Genomic Center, University of Washington, Seattle, WA.
Jennifer A SmithDepartment of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI.
Nicole L SpartanoBoston University Chobanian & Avedisian School of Medicine, Boston, MA.ORCID 0000-0002-0724-8629
Usman TahirDivision of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
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.
Deirdre K TobiasDepartment of Medicine, Division of Preventive Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.ORCID 0000-0003-0020-9552
Russel P TracyDepartment of Pathology and Laboratory Medicine, University of Vermont Larner College of Medicine, Burlington, VT.
Satupa'itea VialiSchool of Medicine, National University of Samoa, Apia, Samoa.
Heming WangDivision of Sleep and Circadian Disorders, Departments of Neurology and Medicine, Brigham and Women's Hospital, Boston, MA.
Alexis C WoodUSDA/ARS Children's Nutrition Research Center, Baylor College of Medicine and U.S. Department of Agriculture, Houston, TX.
Lisa R YanekDepartment of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.
Wei ZhaoDepartment of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI.
Yinan ZhengDepartment of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL.
Josée DupuisDepartment of Biostatistics, Boston University School of Public Health, Boston, MA.
Ching-Ti LiuDepartment of Biostatistics, Boston University School of Public Health, Boston, MA.ORCID 0000-0002-0703-0742
Robert SladekDepartment of Human Genetics, McGill University, Montreal, Quebec, Canada.
Jennifer WesselDepartment of Medicine, Indiana University School of Medicine, Indianpolis, IN.
James B MeigsProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA.ORCID 0000-0002-2439-2657
Alisa K ManningProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA.ORCID 0000-0003-0247-902X
NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium*
Funding
Large Scale Sequencing and Analysis of GenomesU54HG003067 · NHGRI · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · PI GABRIEL, STACEY, LANDER, ERIC S · 2004 to 2015
$568.6MThe Human Genome Sequencing CenterU54HG003273 · NHGRI · BAYLOR COLLEGE OF MEDICINE · PI GIBBS, RICHARD A · 2004 to 2015
$341.3MUCLA Clinical Translational Science InstituteUL1TR001881 · NCATS · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI ARLEEN F. BROWN, ARASH NAEIM · 2016 to 2026
$118.1MGenomic Architecture of Common Disease in Diverse Populations: WGS of Ongoing Hemorrhagic Stroke Study SupplementUM1HG008898 · NHGRI · BAYLOR COLLEGE OF MEDICINE · PI GIBBS, RICHARD A · 2016 to 2020
$77.0MInstitute for Clinical and Translational ResearchUL1TR001079 · NCATS · JOHNS HOPKINS UNIVERSITY · PI FORD, DANIEL ERNEST · 2013 to 2017
$60.1MGenetic Epidemiology of COPDU01HL089897 · NHLBI · NATIONAL JEWISH HEALTH · PI CRAPO, JAMES D · 2007 to 2021
$56.9MCTSA INFRASTRUCTURE FOR PEDIATRIC RESEARCHUL1RR024989 · NCRR · CASE WESTERN RESERVE UNIVERSITY · PI DAVIS, PAMELA B · 2007 to 2011
$53.7MWOMEN'S HEALTH INITIATIVE - CLINICAL COORDINATING CENTER: TASK AREA B - LONG LIFE STUDY VISIT 2 LIMITED HOME VISIT75N92021D00001 · NHLBI · FRED HUTCHINSON CANCER RESEARCH CENTER · PI ANDERSON, GARNET L. · 2021 to 2025
$52.0MTransgenic & 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
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Abstract
Large-scale multiancestry genome-wide association studies have identified hundreds of loci associated with type 2 diabetes (T2D) and glycemic traits, yet imputed genotyping arrays limit the detection of low-frequency and rare variants. Whole-genome sequencing (WGS) offers a more complete view of genetic variation, especially across diverse populations. We analyzed high-coverage (38×) WGS data from 21,913 T2D case subjects, 61,036 control subjects, and up to 50,011 individuals with no diabetes with fasting glucose, fasting insulin, and HbA1c from the National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine Program. We performed single-variant association testing, conditional analysis, fine-mapping, and Bayesian colocalization to identify genetic signals and assess regulatory relevance in diabetes-related tissues. We identified 76 distinct association signals across 34 loci, including novel variants at DUSP9 for T2D, and ROBO1, NDN, and MYT1 for HbA1c. Fine-mapping narrowed credible sets and improved causal variant resolution. Colocalization highlighted 80 expression signals in diabetes-related tissues, linking genetic associations to functional regulatory mechanisms. Our findings demonstrate the utility of WGS to uncover novel variants in diverse populations, enhance locus resolution, and link regulatory variation to disease-relevant tissues. This work refines the genetic architecture of T2D and glycemic traits and supports precision medicine efforts targeting diverse populations. ARTICLE HIGHLIGHTS: We aimed to improve understanding of the genetic architecture of type 2 diabetes and glycemic traits by leveraging whole-genome sequencing in diverse populations. Our goal was to identify novel variants, refine known loci, and link genetic signals to regulatory mechanisms through colocalization with expression quantitative trait loci. We discovered novel variants, significantly improved fine-mapping resolution, and identified 80 regulatory colocalization signals in diabetes-relevant tissues. These findings support precision medicine approaches by connecting genetic variation to functional biology in type 2 diabetes.
Indexed as
Blood GlucoseDiabetes Mellitus, Type 2Quantitative Trait LociFemaleGenome-Wide Association StudyGlycated HemoglobinHumansMaleMiddle AgedNational Heart, Lung, and Blood Institute (U.S.)Polymorphism, Single NucleotidePrecision MedicineUnited StatesWhole Genome SequencingBlood GlucoseGlycated Hemoglobin
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