ArticleCirculation2022
Monogenic and Polygenic Contributions to QTc Prolongation in the Population.
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Article in Circulation, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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33 citing papers in PubMed, 47 citations in OpenAlex.
- Genetic Investigation of Corrected QT Interval Sensitivity to Oral Bepridil Hydrochloride Hydrate in Patients With Atrial Fibrillation.Journal of the American Heart Association · 2026Article
- Prioritizing Discovery and Advancements in Arrhythmia Therapies: NIH/NHLBI Workshop.JACC. Clinical electrophysiology · 2026Review
- Clinical use of polygenic risk scores: current status, barriers and future directions.Nature reviews. Genetics · 2026Review
- Empowering genetic discoveries and cardiovascular risk assessment by predicting electrocardiograms from genotype.NPJ digital medicine · 2026Article
- Kv11.1 (hERG) Protein Interaction Networks Connect Endocytic Trafficking to Polygenic Influences on Cardiac Repolarization.bioRxiv : the preprint server for biology · 2026Article
- Chamber-specific chromatin architecture guides functional interpretation of disease-associated Cis-regulatory elements in human cardiomyocytes.Nature communications · 2026Article
- Polygenic risk modulates myocardial repolarization and T-wave geometry in congenital long-QT syndrome type 1: evidence from digital ECG phenotyping.Frontiers in cardiovascular medicine · 2026Article
- Genetic and Genomic Testing in Cardiovascular Disease: A Policy Statement From the American Heart Association.Circulation · 2025Review
- The Utility of Genome-Wide Association Studies in Inherited Arrhythmias and Cardiomyopathies.Genes · 2025Review
- N-palmitoyl glycine differentially modulates TRPM4 and TRPC5 and is causally linked to Brugada syndrome.Communications biology · 2025Article
- Loperamide-Induced Ventricular Arrhythmia and Seizures.JACC. Case reports · 2025Article
- A combined genomic arrhythmia propensity score delineates cumulative risk.Cell reports. Medicine · 2025Article
- Phenotypic expression of rare progressive cardiac conduction disease variants in the general population.Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology · 2025Article
- Cardiac arrhythmias and genetics - current stage.Medizinische Genetik : Mitteilungsblatt des Berufsverbandes Medizinische Genetik e.V · 2025Article
- Inhibition of Putative Ibrutinib Targets Promotes Atrial Fibrillation, Conduction Blocks, and Proarrhythmic Electrocardiogram Indices: A Mendelian Randomization Analysis.Cancer innovation · 2025Article
- Dissecting the causal effects of smoking, alcohol consumption, and related DNA methylation markers on electrocardiographic indices.Clinical epigenetics · 2025Article
- Genome-Wide Association Study for Resting Electrocardiogram in the Qatari Population Identifies 6 Novel Genes and Validates Novel Polygenic Risk Scores.Journal of the American Heart Association · 2025Article
- Genetic QT score as a predictor of sudden cardiac death in participants with sleep-disordered breathing in the UK Biobank.Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine · 2025Article
- Does COVID-19 impact the QT interval prolongation? Answers from genetic causal inference.Bioscience reports · 2025Article
- Polygenic risk score for drug-induced long QT syndrome: independent validation in a real-world patient cohort.Pharmacogenetics and genomics · 2025Article
Corrections and comments
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Authors and funding
40 authors at 19 institutions in 6 countries.
Victor Nauffal *Division of Cardiovascular Medicine (V.N.), Brigham and Women's Hospital, Boston, MA.
Valerie N Morrill *Cardiovascular Disease Initiative (V.N., V.N.M., S.J.J., S.H.C., L.-C.W., J.L.H., P.T.E., S.A.L.), Broad Institute, Cambridge, MA.ORCID 0000-0003-3245-304X
Sean J JurgensCardiovascular Disease Initiative (V.N., V.N.M., S.J.J., S.H.C., L.-C.W., J.L.H., P.T.E., S.A.L.), Broad Institute, Cambridge, MA.ORCID 0000-0002-1605-9782
Seung Hoan ChoiCardiovascular Disease Initiative (V.N., V.N.M., S.J.J., S.H.C., L.-C.W., J.L.H., P.T.E., S.A.L.), Broad Institute, Cambridge, MA.
Amelia W HallGene Regulation Observatory (A.W.H.), Broad Institute, Cambridge, MA.
Lu-Chen WengCardiovascular Disease Initiative (V.N., V.N.M., S.J.J., S.H.C., L.-C.W., J.L.H., P.T.E., S.A.L.), Broad Institute, Cambridge, MA.
Jennifer L HalfordCardiovascular Disease Initiative (V.N., V.N.M., S.J.J., S.H.C., L.-C.W., J.L.H., P.T.E., S.A.L.), Broad Institute, Cambridge, MA.ORCID 0000-0002-1454-3650
Christina Austin-TseCenter for Genomic Medicine (C.A.-T., H.L.R.), Massachusetts General Hospital, Boston.ORCID 0000-0001-6492-6716
Christopher M HaggertyDepartment of Translational Data Science and Informatics, Geisinger, Danville, PA (C.M.H., B.K.F.).ORCID 0000-0002-3227-4490
Stephanie L HarrisCardiovascular Genetics Program (S.L.H., E.K.W.), Massachusetts General Hospital, Boston.
Eugene K WongCardiovascular Genetics Program (S.L.H., E.K.W.), Massachusetts General Hospital, Boston.ORCID 0000-0001-7866-733X
Alvaro AlonsoDepartment of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA (A.A.).ORCID 0000-0002-2225-8323
Dan E ArkingMcKusick-Nathans Institute, Department of Genetic Medicine (D.E.A.), Johns Hopkins University School of Medicine, Baltimore, MD.ORCID 0000-0001-8980-8695
Emelia J BenjaminBoston University School of Public Health, MA (E.J.B., K.L.L.).ORCID 0000-0003-4076-2336
Eric BoerwinkleHuman Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, University of Texas Health Science Center at Houston (E.B., A.C.M.).ORCID 0000-0001-8813-0544
Yuan-I MinDepartment of Medicine, University of Mississippi Medical Center, Jackson (Y.-I.M., A.C.).
Adolfo CorreaDepartment of Medicine, University of Mississippi Medical Center, Jackson (Y.-I.M., A.C.).ORCID 0000-0002-9501-600X
Brandon K FornwaltDepartment of Translational Data Science and Informatics, Geisinger, Danville, PA (C.M.H., B.K.F.).ORCID 0000-0002-6231-9442
Susan R HeckbertCardiovascular Health Research Unit and Department of Epidemiology (S.R.H.).ORCID 0000-0002-7100-512X
National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine (TOPMed) Consortium
Charles KooperbergDivision of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA (C.K.).ORCID 0000-0002-7986-8560
Henry J LinInstitute for Translational Genomics and Population Sciences, Department of Pediatrics, Lundquist Institute for Biomedical Innovation at Harbor-University of California-Los Angeles Medical Center, Torrance (H.J.L., J.I.R.).ORCID 0000-0001-6771-0486
Ruth J F LoosCharles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York (R.J.F.L.).ORCID 0000-0002-8532-5087
Kenneth M RiceDepartment of Biostatistics (K.M.R.).
Namrata GuptaProgram in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge (N.G., S.J.J., S.H.C., L.C.W., J.L.H., C.A.T., H.L.R., P.T.E., S.A.L.).ORCID 0000-0001-6786-4995
Thomas W BlackwellDepartment of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor (T.W.B.).
Braxton D MitchellDivision of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore (B.D.M.).ORCID 0000-0003-4920-4744
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 (E.B., A.C.M.).ORCID 0000-0001-6381-4296
Bruce M PsatyCardiovascular Health Research Unit, Departments of Medicine, Epidemiology and Health Systems and Population Health, University of Washington, Seattle, WA (B.M.P.).ORCID 0000-0002-7278-2190
Wendy S PostDivision of Cardiology, Department of Medicine (W.S.P.), Johns Hopkins University School of Medicine, Baltimore, MD.ORCID 0000-0002-8655-5204
Susan RedlineHarvard Medical School (S.R.), Brigham and Women's Hospital, Boston, MA.ORCID 0000-0002-6585-1610
Heidi L RehmCenter for Genomic Medicine (C.A.-T., H.L.R.), Massachusetts General Hospital, Boston.ORCID 0000-0002-6025-0015
Stephen S RichCenter for Public Health Genomics and Department of Public Health Sciences, University of Virginia, Charlottesville (S.S.R.).ORCID 0000-0003-3872-7793
Jerome I RotterInstitute for Translational Genomics and Population Sciences, Department of Pediatrics, Lundquist Institute for Biomedical Innovation at Harbor-University of California-Los Angeles Medical Center, Torrance (H.J.L., J.I.R.).ORCID 0000-0001-7191-1723
Elsayed Z SolimanEpidemiological Cardiology Research Center, Wake Forest School of Medicine, Winston-Salem, NC (E.Z.S.).ORCID 0000-0001-5632-8150
Nona SotoodehniaCardiovascular Health Research Unit, Departments of Medicine, Epidemiology, Cardiology, University of Washington, Seattle, WA (N.S.).
Kathryn L LunettaBoston University School of Public Health, MA (E.J.B., K.L.L.).ORCID 0000-0002-9268-810X
Patrick T Ellinor *Cardiovascular Disease Initiative (V.N., V.N.M., S.J.J., S.H.C., L.-C.W., J.L.H., P.T.E., S.A.L.), Broad Institute, Cambridge, MA.ORCID 0000-0002-2067-0533
Steven A Lubitz *Cardiovascular Disease Initiative (V.N., V.N.M., S.J.J., S.H.C., L.-C.W., J.L.H., P.T.E., S.A.L.), Broad Institute, Cambridge, MA.ORCID 0000-0002-9599-4866
TOPMed Investigators
Broad Institute · USBoston University · USBrigham and Women's Hospital · USCenter for Human Genetics · USGeisinger Medical Center · USJohns Hopkins University · USLos Angeles Biomedical Research Institute · USMassachusetts General Hospital · USUniversity of Mississippi Medical Center · USAnna Needs Neuroblastoma Answers · USCape Town HVTN Immunology Laboratory / Hutchinson Centre Research Institute of South Africa · ZAChild Health and Development Institute · USDepartment of Health · TWEmory University · USOffice of Public Health Genomics · USStatistical Service · CYUniversity of Maryland, Baltimore · USUniversity of Washington · USWake Forest University · US
Funding
IDENTIFICATION OF COMMON GENETIC VARIANTS FOR ATRIAL FIBRILLATION AND PR INTERVALR01HL092577 · NHLBI · MASSACHUSETTS GENERAL HOSPITAL · PI BENJAMIN, EMELIA J., ELLINOR, PATRICK THOMAS · 2009 to 2025
$20.6MTRAINING PROGRAM IN CARDIOVASCULAR RESEARCHT32HL007604 · NHLBI · BRIGHAM AND WOMEN'S HOSPITAL · PI MARK W FEINBERG · 1985 to 2026
$19.0MCell Interactions in the Inflamed Intestinal MucosaR01DK075787 · NIDDK · BOSTON CHILDREN'S HOSPITAL · PI JOEL N HIRSCHHORN · 2007 to 2026
$13.1MPolygenic Risk Scores for Diverse Populations - Bridging Research and Clinical CareR01HL151152 · NHLBI · FRED HUTCHINSON CANCER RESEARCH CENTER · PI Christy Leigh Avery, Jennifer Below · 2020 to 2026
$12.3MStudies of Rare Genetic Variation in the Isolated Population of SardiniaR01HL117626 · NHLBI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI ABECASIS, GONCALO · 2013 to 2016
$10.5MCHARGE Consortium: Omics Discovery for CVD and Aging PhenotypesR01HL105756 · NHLBI · UNIVERSITY OF WASHINGTON · PI Bruce M Psaty, NICHOLAS L SMITH · 2011 to 2026
$9.5MRare variants and NHLBI traits in deeply phenotyped cohortsR01HL120393 · NHLBI · UNIVERSITY OF WASHINGTON · PI PSATY, BRUCE M, RICE, KENNETH M. · 2014 to 2016
$8.9MPAGE III: Population Architecture using Genomics and EpidemiologyR01HG010297 · NHGRI · RUTGERS, THE STATE UNIV OF N.J. · PI GIGNOUX, CHRISTOPHER R, MATISE, TARA C. · 2019 to 2022
$6.5MHispanic Latino Lipid ConsortiumR01HL142302 · NHLBI · VANDERBILT UNIVERSITY MEDICAL CENTER · PI Jennifer Below, JOSEPH MCCORMICK · 2018 to 2026
$5.8MRare variants and NHLBI traits in deeply phenotyped cohortsU01HL120393 · NHLBI · UNIVERSITY OF WASHINGTON · PI PSATY, BRUCE M, RICE, KENNETH M. · 2017 to 2018
$5.6MGenomics of Cardiac ArrhythmiasR01HL139731 · NHLBI · MASSACHUSETTS GENERAL HOSPITAL · PI ELLINOR, PATRICK THOMAS · 2018 to 2022
$3.3MAFGen Consortium: Atrial Fibrillation Genomics to Functional AnalysesR01HL128914 · NHLBI · BOSTON UNIVERSITY MEDICAL CAMPUS · PI BENJAMIN, EMELIA J., ELLINOR, PATRICK THOMAS · 2015 to 2018
$3.1MMedical Research Council MC_PC_17228Medical Research Council MC_QA137853NHGRI NIH HHS R01 HG010297NHLBI NIH HHS HHSN268201800001CNHLBI NIH HHS K24 HL105780NHLBI NIH HHS K24 HL148521NHLBI NIH HHS R01 HL092577NHLBI NIH HHS R01 HL105756NHLBI NIH HHS R01 HL116747NHLBI NIH HHS R01 HL117626NHLBI NIH HHS R01 HL120393NHLBI NIH HHS R01 HL128914NHLBI NIH HHS R01 HL139731NHLBI NIH HHS R01 HL141989NHLBI NIH HHS R01 HL142302NHLBI NIH HHS R01 HL151152NHLBI NIH HHS R01 HL157635NHLBI NIH HHS T32 HL007604NHLBI NIH HHS U01 HL120393NIDDK NIH HHS R01 DK075787NIDDK NIH HHS R01 DK107786NIDDK NIH HHS R01 DK110113NIDDK NIH HHS R01 DK124097
Abstract
backgroundRare sequence variation in genes underlying cardiac repolarization and common polygenic variation influence QT interval duration. However, current clinical genetic testing of individuals with unexplained QT prolongation is restricted to examination of monogenic rare variants. The recent emergence of large-scale biorepositories with sequence data enables examination of the joint contribution of rare and common variations to the QT interval in the population.
methodsWe performed a genome-wide association study of the QTc in 84 630 UK Biobank participants and created a polygenic risk score (PRS). Among 26 976 participants with whole-genome sequencing and ECG data in the TOPMed (Trans-Omics for Precision Medicine) program, we identified 160 carriers of putative pathogenic rare variants in 10 genes known to be associated with the QT interval. We examined QTc associations with the PRS and with rare variants in TOPMed.
resultsFifty-four independent loci were identified by genome-wide association study in the UK Biobank. Twenty-one loci were novel, of which 12 were replicated in TOPMed. The PRS composed of 1 110 494 common variants was significantly associated with the QTc in TOPMed (ΔQTc
conclusionsQTc duration in the population is influenced by both rare variants in genes underlying cardiac repolarization and polygenic risk, with a sizeable contribution from polygenic risk. Comprehensive assessment of the genetic determinants of QTc prolongation includes incorporation of both polygenic and monogenic risk.
Indexed as
Genome-Wide Association StudyLong QT SyndromeElectrocardiographyHeterozygoteHumansMultifactorial InheritanceWhole Genome Sequencinglong QT syndromemonogenicpolygenicQT intervalsudden cardiac death
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