ArticleAmerican journal of human genetics2019
Impact of Rare and Common Genetic Variants on Diabetes Diagnosis by Hemoglobin A1c in Multi-Ancestry Cohorts: The Trans-Omics for Precision Medicine Program.
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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 37 papers, 4 of them syntheses that pooled it.
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37citing papers in PubMed, 4 pooled it
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Who cites it
37 citing papers in PubMed, 4 syntheses or guidelines pooled it, 64 citations in OpenAlex.
- Pan-UK Biobank genome-wide association analyses enhance discovery and resolution of ancestry-enriched effects.Nature genetics · 2025Pooled it
- Clonal Hematopoiesis of Indeterminate Potential (CHIP) and Incident Type 2 Diabetes Risk.Diabetes care · 2023Pooled it
- The contribution of common and rare genetic variants to variation in metabolic traits in 288,137 East Asians.Nature communications · 2022Pooled it
- Association Between Hemoglobin Glycation Index and Risk of Cardiovascular Disease and All Cause Mortality in Type 2 Diabetic Patients: A Meta-Analysis.Frontiers in cardiovascular medicine · 2021Pooled it
- Racial differences in measures of glycemia in the Vitamin D and Type 2 Diabetes (D2d) Study: a secondary analysis of a randomized trial.BMJ open diabetes research & care · 2024Trial
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- Large-scale admixture mapping in the All of Us Research Program improves the characterization of cross-population phenotypic differences.Nature communications · 2026Article
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- Association between hemoglobin glycation index and delirium after gastric surgery: Based upon the MIMIC-IV.Medicine · 2026Article
- Insights into the genetic aetiology of diabetes in Africa.EBioMedicine · 2026Review
- Case Report: Abnormally low hemoglobin A1c in a diabetic patient withFrontiers in endocrinology · 2026Article
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- X chromosome inactivation across primary human tissues is mostly complete, with significant implications for genetic and clinical studies.BMC genomics · 2025Article
- Impact of polymorphisms on gene expression and splicing in response to exercise and diet-induced weight loss in human skeletal muscle tissues.Cell genomics · 2025Article
- Evidence of a novel gene locusPhysiological genomics · 2025Article
- Valid inference for machine learning-assisted genome-wide association studies.Nature genetics · 2024Article
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- A Novel GenebioRxiv : the preprint server for biology · 2024Article
- Racial and ethnic differences in circulating N-terminal pro-brain-type natriuretic peptide (NT-proBNP) in US adults.American journal of preventive cardiology · 2023Article
- The Type 2 Diabetes Knowledge Portal: An open access genetic resource dedicated to type 2 diabetes and related traits.Cell metabolism · 2023Article
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Authors and funding
46 authors at 20 institutions in 1 country.
Chloé SarnowskiDepartment of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA. Electronic address: chloesar@bu.edu.
Aaron LeongDivision of General Internal Medicine, Massachusetts General Hospital, Boston 02114, MA USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Programs in Metabolism and Medical & Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: ASLEONG@partners.org.
Laura M RaffieldDepartment of Genetics, University of North Carolina, Chapel Hill, NC 27514, USA.
Peitao WuDepartment of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA.
Paul S de VriesHuman Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
Daniel DiCorpoDepartment of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA.
Xiuqing GuoInstitute for Translational Genomics and Population Sciences, LABioMed and Department of Pediatrics at Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
Huichun XuDivision of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Yongmei LiuDepartment of Epidemiology & Prevention, Wake Forest School of Medicine, Winston-Salem, NC 27101, USA.
Xiuwen ZhengDepartment of Biostatistics, University of Washington, Seattle, WA 98195, USA.
Yao HuDivision of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98108, USA.
Jennifer A BrodyCardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 98195, USA.
Mark O GoodarziDivision of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
Bertha A HidalgoUniversity of Alabama at Birmingham, Department of Epidemiology, Birmingham, AL 35294, USA.
Heather M HighlandDepartment of Epidemiology, UNC Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Deepti JainDepartment of Biostatistics, University of Washington, Seattle, WA 98195, USA.
Ching-Ti LiuDepartment of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA.
Rakhi P NaikDivision of Hematology, Department of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
Jeffrey R O'ConnellUniversity of Maryland School of Medicine, Baltimore, MD 21201, USA.
James A PerryUniversity of Maryland School of Medicine, Baltimore, MD 21201, USA.
Bianca C PornealaDivision of General Internal Medicine, Massachusetts General Hospital, Boston 02114, MA USA.
Elizabeth SelvinDepartment of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.
Jennifer WesselDepartment of Epidemiology, Indiana University Fairbanks School of Public Health, Indianapolis, IN 46202, USA; Department of Medicine and Diabetes Translational Research Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Bruce M PsatyCardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 98195, USA; Kaiser Permanente Washington Health Research Institute, Seattle, WA 98101, USA; Departments of Epidemiology and Health Services, University of Washington, Seattle, WA 98195, USA.
Joanne E CurranDepartment of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX 78520, USA.
Juan M PeraltaDepartment of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX 78520, USA.
John BlangeroDepartment of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX 78520, USA.
Charles KooperbergDivision of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98108, USA.
Rasika MathiasDepartment of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA; GeneSTAR Research Program, Department of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
Andrew D JohnsonNational Heart, Lung, and Blood Institute and Boston University's Framingham Heart Study, Framingham MA 01702, USA; Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20814, USA.
Alexander P ReinerDivision of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98108, USA; Department of Epidemiology, University of Washington, Seattle, WA 98195, USA.
Braxton D MitchellDivision of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA; Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, Baltimore, MD 21201, USA.
L Adrienne CupplesDepartment of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA; National Heart, Lung, and Blood Institute and Boston University's Framingham Heart Study, Framingham MA 01702, USA.
Ramachandran S VasanNational Heart, Lung, and Blood Institute and Boston University's Framingham Heart Study, Framingham MA 01702, USA; Section of Preventive Medicine and Epidemiology, Evans Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA; Whitaker Cardiovascular Institute and Cardiology Section, Evans Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA.
Adolfo CorreaDepartments of Medicine, Pediatrics, and Population Health Science, University of Mississippi Medical Center, Jackson, MS 39216, USA; The Jackson Heart Study, Jackson, MS 39213, USA.
Alanna C MorrisonHuman Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
Eric BoerwinkleHuman Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
Jerome I RotterInstitute for Translational Genomics and Population Sciences, LABioMed and Department of Pediatrics at Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
Stephen S RichCenter for Public Health Genomics, University of Virginia, Charlottesville, VA 22908, USA.
Alisa K ManningDivision of General Internal Medicine, Massachusetts General Hospital, Boston 02114, MA USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Programs in Metabolism and Medical & Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Josée DupuisDepartment of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA; National Heart, Lung, and Blood Institute and Boston University's Framingham Heart Study, Framingham MA 01702, USA.
James B MeigsDivision of General Internal Medicine, Massachusetts General Hospital, Boston 02114, MA USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Programs in Metabolism and Medical & Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
TOPMed Diabetes Working Group
TOPMed Hematology Working Group
TOPMed Hemostasis Working Group
National Heart, Lung, and Blood Institute TOPMed Consortium
Boston University · USUniversity of Maryland, Baltimore · USUniversity of Washington · USFred Hutch Cancer Center · USJohns Hopkins University · USThe University of Texas Rio Grande Valley · USBroad Institute · USFramingham Heart Study · USHarbor–UCLA Medical Center · USNational Heart Lung and Blood Institute · USThe University of Texas Health Science Center at Houston · USUniversity of North Carolina at Chapel Hill · USBaylor College of Medicine · USCedars-Sinai Medical Center · USHarvard University · USIndiana University – Purdue University Indianapolis · USMassachusetts General Hospital · USUniversity of Alabama at Birmingham · USUniversity of Mississippi Medical Center · USUniversity of Virginia · US
Funding
University of Alabama at Birmingham's Diabetes Research CenterP30DK079626 · NIDDK · UNIVERSITY OF ALABAMA AT BIRMINGHAM · PI BARBARA A GOWER · 2013 to 2026
$19.5MProposal for the AMP T2D-GENES Data Coordination Center and Web PortalU01DK105554 · NIDDK · BROAD INSTITUTE, INC. · PI FLOREZ, JOSE CARLOS · 2015 to 2019
$16.8MStudies of Rare Genetic Variation in the Isolated Population of SardiniaR01HL117626 · NHLBI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI ABECASIS, GONCALO · 2013 to 2016
$10.5MCardiovascular Epidemiology Training GrantT32HL007055 · NHLBI · UNIV OF NORTH CAROLINA CHAPEL HILL · PI Wayne D. Rosamond · 1986 to 2026
$10.0MRare variants and NHLBI traits in deeply phenotyped cohortsR01HL120393 · NHLBI · UNIVERSITY OF WASHINGTON · PI PSATY, BRUCE M, RICE, KENNETH M. · 2014 to 2016
$8.9MCHS research resources for the cardiovascular health of older adultsU01HL130114 · NHLBI · UNIVERSITY OF WASHINGTON · PI BURKE, GREGORY L, KRONMAL, RICHARD A · 2016 to 2019
$6.6MEpigenetics of Successful AgingR01HL131136 · NHLBI · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · PI BOERWINKLE, ERIC A. · 2017 to 2020
$4.0MThe Genetic Epidemiology of Heart, Lung, and Blood TraitsTraining Grant (GenHLB)T32HL129982 · NHLBI · UNIV OF NORTH CAROLINA CHAPEL HILL · PI Christy Leigh Avery, KAREN L. MOHLKE · 2016 to 2026
$3.8MTOPMed Omics of Type 2 Diabetes and Quantitative TraitsUM1DK078616 · NIDDK · MASSACHUSETTS GENERAL HOSPITAL · PI MANNING, ALISA KNODLE · 2021 to 2025
$3.8MRare Sequence Variation and Diabetes Quantitative TraitsU01DK078616 · NIDDK · MASSACHUSETTS GENERAL HOSPITAL · PI MEIGS, JAMES B · 2015 to 2019
$3.6MEpidemiology of Precursors to Type 2 DiabetesK24DK080140 · NIDDK · MASSACHUSETTS GENERAL HOSPITAL · PI MEIGS, JAMES B · 2007 to 2016
$1.9MHigh-performance mixed model toolset for integrative omics analysis of big dataU01HL137181 · NHLBI · UNIVERSITY OF MARYLAND BALTIMORE · PI O'CONNELL, JEFFREY R · 2017 to 2019
$1.8MMedical Research Council MC_PC_17228Medical Research Council MC_QA137853NHGRI NIH HHS L30 HG009840NHLBI NIH HHS R01 HL117626NHLBI NIH HHS R01 HL120393NHLBI NIH HHS R01 HL131136NHLBI NIH HHS T32 HL007055NHLBI NIH HHS T32 HL129982NHLBI NIH HHS U01 HL130114NHLBI NIH HHS U01 HL137181NIDDK NIH HHS K01 DK107836NIDDK NIH HHS K24 DK080140NIDDK NIH HHS P30 DK079626NIDDK NIH HHS R03 DK118305NIDDK NIH HHS U01 DK078616NIDDK NIH HHS U01 DK105554NIDDK NIH HHS UM1 DK078616
Abstract
Hemoglobin A1c (HbA1c) is widely used to diagnose diabetes and assess glycemic control in individuals with diabetes. However, nonglycemic determinants, including genetic variation, may influence how accurately HbA1c reflects underlying glycemia. Analyzing the NHLBI Trans-Omics for Precision Medicine (TOPMed) sequence data in 10,338 individuals from five studies and four ancestries (6,158 Europeans, 3,123 African-Americans, 650 Hispanics, and 407 East Asians), we confirmed five regions associated with HbA1c (GCK in Europeans and African-Americans, HK1 in Europeans and Hispanics, FN3K and/or FN3KRP in Europeans, and G6PD in African-Americans and Hispanics) and we identified an African-ancestry-specific low-frequency variant (rs1039215 in HBG2 and HBE1, minor allele frequency (MAF) = 0.03). The most associated G6PD variant (rs1050828-T, p.Val98Met, MAF = 12% in African-Americans, MAF = 2% in Hispanics) lowered HbA1c (-0.88% in hemizygous males, -0.34% in heterozygous females) and explained 23% of HbA1c variance in African-Americans and 4% in Hispanics. Additionally, we identified a rare distinct G6PD coding variant (rs76723693, p.Leu353Pro, MAF = 0.5%; -0.98% in hemizygous males, -0.46% in heterozygous females) and detected significant association with HbA1c when aggregating rare missense variants in G6PD. We observed similar magnitude and direction of effects for rs1039215 (HBG2) and rs76723693 (G6PD) in the two largest TOPMed African American cohorts, and we replicated the rs76723693 association in the UK Biobank African-ancestry participants. These variants in G6PD and HBG2 were monomorphic in the European and Asian samples. African or Hispanic ancestry individuals carrying G6PD variants may be underdiagnosed for diabetes when screened with HbA1c. Thus, assessment of these variants should be considered for incorporation into precision medicine approaches for diabetes diagnosis.
Indexed as
Genetic VariationPrecision MedicineCohort StudiesDiabetes MellitusFemaleGlycated HemoglobinHumansMalePolymorphism, Single NucleotidePopulation GroupsGlycated Hemoglobinhemoglobin A1c protein, humanhemoglobin A1cmulti-ancestry sampleThe Trans-Omics for Precision Medicine (TOPMed) programwhole-genome sequence association analyses
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