ArticleCirculation. Genomic and precision medicine2021
Rare Coding Variants Associated With Electrocardiographic Intervals Identify Monogenic Arrhythmia Susceptibility Genes: A Multi-Ancestry Analysis.
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Article in Circulation. Genomic and precision medicine, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers, 1 of them a synthesis that pooled it.
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10citing papers in PubMed, 1 pooled it
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Who cites it
10 citing papers in PubMed, 1 synthesis or guideline pooled it, 18 citations in OpenAlex.
- Meta-Analysis of Genome-Wide Association Studies Reveals Genetic Mechanisms of Supraventricular Arrhythmias.Circulation. Genomic and precision medicine · 2024Pooled it
- Aging-Induced QT Prolongation as a Potential Contributor to Longevity.Journal of cardiovascular development and disease · 2026Review
- predicTox: an integrated database of clinical risk frequencies and human gene expression signatures for cardiotoxic drugs.Database : the journal of biological databases and curation · 2026Article
- Functional Profiling ofCirculation. Genomic and precision medicine · 2025Article
- Cardiac arrhythmias and genetics - current stage.Medizinische Genetik : Mitteilungsblatt des Berufsverbandes Medizinische Genetik e.V · 2025Article
- The impact of common and rare genetic variants on bradyarrhythmia development.Nature genetics · 2025Article
- High-throughput functional mapping of variants in an arrhythmia gene, KCNE1, reveals novel biology.Genome medicine · 2024Article
- A human FLII gene variant alters sarcomeric actin thin filament length and predisposes to cardiomyopathy.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Endophenotype effect sizes support variant pathogenicity in monogenic disease susceptibility genes.Nature communications · 2022Article
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Authors and funding
50 authors at 20 institutions in 3 countries.
Seung Hoan ChoiProgram in Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA (S.H.C., S.J.J., A.W.H., J.L.H., V.N.M., L.-C.W., M.D.C., C.J.-Y.L., H.L.R., C.R., P.T.E., S.A.L.).
Sean J JurgensProgram in Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA (S.H.C., S.J.J., A.W.H., J.L.H., V.N.M., L.-C.W., M.D.C., C.J.-Y.L., H.L.R., C.R., P.T.E., S.A.L.).
Christopher M HaggertyDepartment of Translational Data Science and Informatics (C.M.H., B.K.F.), Geisinger, Danville, PA.
Amelia W HallProgram in Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA (S.H.C., S.J.J., A.W.H., J.L.H., V.N.M., L.-C.W., M.D.C., C.J.-Y.L., H.L.R., C.R., P.T.E., S.A.L.).
Jennifer L HalfordProgram in Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA (S.H.C., S.J.J., A.W.H., J.L.H., V.N.M., L.-C.W., M.D.C., C.J.-Y.L., H.L.R., C.R., P.T.E., S.A.L.).
Valerie N MorrillProgram in Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA (S.H.C., S.J.J., A.W.H., J.L.H., V.N.M., L.-C.W., M.D.C., C.J.-Y.L., H.L.R., C.R., P.T.E., S.A.L.).
Lu-Chen WengProgram in Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA (S.H.C., S.J.J., A.W.H., J.L.H., V.N.M., L.-C.W., M.D.C., C.J.-Y.L., H.L.R., C.R., P.T.E., S.A.L.).
Braxton LagermanPhenomic Analytics and Clinical Data Core (B.L.), Geisinger, Danville, PA.
Tooraj MirshahiDepartment of Molecular and Functional Genomics (T.M.), Geisinger, Danville, PA.
Mary PettingerDivision of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA (M.P., C.K.).
Xiuqing GuoThe Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Insti for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA (X.G., H.J.L., J.I.R.).
Henry J LinThe Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Insti for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA (X.G., H.J.L., J.I.R.).
Alvaro AlonsoDepartment of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA (A.A.).
Elsayed Z SolimanEpidemiological Cardiology Research Center, Wake Forest School of Medicine, Winston Salem, NC (E.Z.S.).
Jelena KornejNHLBI and Boston University's Framingham Heart Study (J.K., E.J.B., R.S.V).
Honghuang LinSection of Computational Biomedicine, Department of Medicine (H.L.), Boston University School of Medicine, MA.
Arden MoscatiThe Charles Bronfman Institute for Personalized Medicine (A.M., G.N., R.J.F.L.), Icahn School of Medicine, Mount Sinai, New York, NY.
Girish N NadkarniThe Charles Bronfman Institute for Personalized Medicine (A.M., G.N., R.J.F.L.), Icahn School of Medicine, Mount Sinai, New York, NY.
Jennifer A BrodyCardiovascular Health Research Unit, Department of Medicine (J.A.B., K.L.W., N.S., B.M.P., S.R.H.), University of Washington, Seattle.
Kerri L WigginsCardiovascular Health Research Unit, Department of Medicine (J.A.B., K.L.W., N.S., B.M.P., S.R.H.), University of Washington, Seattle.
Brian E CadeMassachusetts General Hospital. Division of Sleep Medicine, Department of Medicine (B.E.C.), Boston, MA.
Jiwon LeeDivision of Sleep and Circadian Disorders (J.L.), Harvard Medical School, Brigham and Women's Hospital, Boston.
Christina Austin-TseCenter for Genomic Medicine (C.A.-T., H.L.R.), Boston, MA.
Tom BlackwellDepartment of Biostatistics, University of Michigan, Ann Arbor (T.B.).
Mark D ChaffinProgram in Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA (S.H.C., S.J.J., A.W.H., J.L.H., V.N.M., L.-C.W., M.D.C., C.J.-Y.L., H.L.R., C.R., P.T.E., S.A.L.).
Christina J-Y LeeProgram in Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA (S.H.C., S.J.J., A.W.H., J.L.H., V.N.M., L.-C.W., M.D.C., C.J.-Y.L., H.L.R., C.R., P.T.E., S.A.L.).
Heidi L RehmProgram in Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA (S.H.C., S.J.J., A.W.H., J.L.H., V.N.M., L.-C.W., M.D.C., C.J.-Y.L., H.L.R., C.R., P.T.E., S.A.L.).
Carolina RoselliProgram in Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA (S.H.C., S.J.J., A.W.H., J.L.H., V.N.M., L.-C.W., M.D.C., C.J.-Y.L., H.L.R., C.R., P.T.E., S.A.L.).
Regeneron Genetics Center
Susan RedlineRegeneron Genetics Center, Tarrytown, NY. Departments of Medicine, Brigham and Women's Hospital, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA (S.R.).
Braxton D MitchellUniversity of Maryland School of Medicine (B.D.M.).
Nona SotoodehniaCardiovascular Health Research Unit, Department of Medicine (J.A.B., K.L.W., N.S., B.M.P., S.R.H.), University of Washington, Seattle.
Bruce M PsatyCardiovascular Health Research Unit, Department of Medicine (J.A.B., K.L.W., N.S., B.M.P., S.R.H.), University of Washington, Seattle.
Susan R HeckbertCardiovascular Health Research Unit, Department of Medicine (J.A.B., K.L.W., N.S., B.M.P., S.R.H.), University of Washington, Seattle.
Ruth J F LoosThe Charles Bronfman Institute for Personalized Medicine (A.M., G.N., R.J.F.L.), Icahn School of Medicine, Mount Sinai, New York, NY.
Ramachandran S VasanNHLBI and Boston University's Framingham Heart Study (J.K., E.J.B., R.S.V).
Emelia J BenjaminNHLBI and Boston University's Framingham Heart Study (J.K., E.J.B., R.S.V).
Adolfo CorreaDepartments of Medicine, Pediatrics, and Population Health Science, University of Mississippi Medical Center, Jackson (A.C.).
Eric BoerwinkleHuman Genetics Center, University of Texas Health Science Center, Houston (E.B.).
Dan E ArkingMcKusick-Nathans Institute, Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD (D.E.A.).
Jerome I RotterThe Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Insti for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA (X.G., H.J.L., J.I.R.).
Stephen S RichCenter for Public Health Genomics, University of Virginia School of Medicine, Charlottesville (S.S.R.).
Eric A WhitselDepartment of Epidemiology, Gillings School of Global Public Health (E.A.W.), School of Medicine, University of North Carolina, Chapel Hill.
Marco PerezDivision of Cardiovascular Medicine, Stanford University, CA (M.P.). Dr Sotoodehnia is supported by NIH grant R01HL141989, by AHA grant 19SFRN34830063, and by the Laughlin Family.
Charles KooperbergDivision of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA (M.P., C.K.).
Brandon K FornwaltDepartment of Translational Data Science and Informatics (C.M.H., B.K.F.), Geisinger, Danville, PA.
Kathryn L LunettaDepartment of Biostatistics (K.L.L.), Boston University School of Public Health, MA.
Patrick T EllinorProgram in Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA (S.H.C., S.J.J., A.W.H., J.L.H., V.N.M., L.-C.W., M.D.C., C.J.-Y.L., H.L.R., C.R., P.T.E., S.A.L.).
Steven A LubitzProgram in Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA (S.H.C., S.J.J., A.W.H., J.L.H., V.N.M., L.-C.W., M.D.C., C.J.-Y.L., H.L.R., C.R., P.T.E., S.A.L.).
NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium
Broad Institute · USUniversity of Washington · USGeisinger Medical Center · USUCLA Medical Center · USBoston University · USBrigham and Women's Hospital · USCape Town HVTN Immunology Laboratory / Hutchinson Centre Research Institute of South Africa · ZAChild Health and Development Institute · USBeth Israel Deaconess Medical Center · USBoston Medical Center · USEmory University · USGrant Medical Center · USHarvard University · USIcahn School of Medicine at Mount Sinai · USJohns Hopkins University · USThe University of Texas Health Science Center at Houston · USUniversity of Maryland, Baltimore · USUniversity of Michigan · USUniversity of Mississippi Medical Center · USUniversity of North Carolina at Chapel Hill · 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
$20.6MPhenotypic and Molecular Signatures for Sleep Apnea and Related MorbiditiesR35HL135818 · NHLBI · BRIGHAM AND WOMEN'S HOSPITAL · PI REDLINE, SUSAN S. · 2017 to 2023
$7.2MFAMILIAL AGGREGATION OF OBSTRUCTIVE SLEEP APNEAR01HL046380 · NHLBI · UNIVERSITY HOSPITALS OF CLEVELAND · PI REDLINE, SUSAN S · 1990 to 2005
$3.5MGenomics of Cardiac ArrhythmiasR01HL139731 · NHLBI · MASSACHUSETTS GENERAL HOSPITAL · PI ELLINOR, PATRICK THOMAS · 2018 to 2022
$3.3MA Precision Medicine Approach to Arrhythmogenic CardiomyopathyR01HL141901 · NHLBI · GEISINGER CLINIC · PI CARRUTH, ERIC DAVID · 2019 to 2023
$3.1MMentoring in Arrhythmia ResearchK24HL105780 · NHLBI · MASSACHUSETTS GENERAL HOSPITAL · PI ELLINOR, PATRICK THOMAS · 2011 to 2020
$1.2MSystems Biology Analysis of Cardiac Electrical Activity and Arrhythmias.R01HL141989 · NHLBI · UNIVERSITY OF WASHINGTON · PI ARKING, DAN E, SHOJAIE, ALI · 2019 to 2020
$968kWhole Genomic Characterization of Sleep Apnea Traits and Comorbid DisordersK01HL135405 · NHLBI · BRIGHAM AND WOMEN'S HOSPITAL · PI CADE, BRIAN EDMAND · 2017 to 2020
$695kMentoring in patient-oriented atrial fibrillation and cardiovascular researchK24HL148521 · NHLBI · EMORY UNIVERSITY · PI ALONSO, ALVARO · 2019 to 2023
$593kAmerican Heart Association-American Stroke Association 18SFRN34250007British Heart Foundation CH/1996001/9454Medical Research Council MC_PC_17228Medical Research Council MC_QA137853NHLBI NIH HHS K01 HL135405NHLBI NIH HHS K24 HL105780NHLBI NIH HHS K24 HL148521NHLBI NIH HHS R01 HL046380NHLBI NIH HHS R01 HL092577NHLBI NIH HHS R01 HL139731NHLBI NIH HHS R01 HL141901NHLBI NIH HHS R01 HL141989NHLBI NIH HHS R35 HL135818
Abstract
backgroundAlterations in electrocardiographic (ECG) intervals are well-known markers for arrhythmia and sudden cardiac death (SCD) risk. While the genetics of arrhythmia syndromes have been studied, relations between electrocardiographic intervals and rare genetic variation at a population level are poorly understood.
methodsUsing a discovery sample of 29 000 individuals with whole-genome sequencing from Trans-Omics in Precision Medicine and replication in nearly 100 000 with whole-exome sequencing from the UK Biobank and MyCode, we examined associations between low-frequency and rare coding variants with 5 routinely measured electrocardiographic traits (RR, P-wave, PR, and QRS intervals and corrected QT interval).
resultsWe found that rare variants associated with population-based electrocardiographic intervals identify established monogenic SCD genes (
conclusionsOur findings indicate that large-scale high-depth sequence data and electrocardiographic analysis identifies monogenic arrhythmia susceptibility genes and rare variants with large effects. Known pathogenic variation in conventional arrhythmia and SCD genes exhibited incomplete penetrance and accounted for only a small fraction of marked electrocardiographic interval prolongation.
Indexed as
ElectrocardiographyGenetic Predisposition to DiseaseGenetic VariationHeterozygoteLong QT SyndromeDeath, Sudden, CardiacExome SequencingFemaleHumansMaledeath, sudden, cardiacepidemiologygeneticsgenomepopulation
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