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Rare Coding Variants Associated With Electrocardiographic Intervals Identify Monogenic Arrhythmia Susceptibility Genes: A Multi-Ancestry Analysis.
Choi, Seung Hoan; Jurgens, Sean J; Haggerty, Christopher M; Hall, Amelia W; Halford, Jennifer L; Morrill, Valerie N; Weng, Lu-Chen; Lagerman, Braxton; Mirshahi, Tooraj; Pettinger, Mary; Guo, Xiuqing; Lin, Henry J; Alonso, Alvaro; Soliman, Elsayed Z; Kornej, Jelena; Lin, Honghuang; Moscati, Arden; Nadkarni, Girish N; Brody, Jennifer A; Wiggins, Kerri L; Cade, Brian E; Lee, Jiwon; Austin-Tse, Christina; Blackwell, Tom; Chaffin, Mark D; Lee, Christina J-Y; Rehm, Heidi L; Roselli, Carolina; Redline, Susan; Mitchell, Braxton D; Sotoodehnia, Nona; Psaty, Bruce M; Heckbert, Susan R; Loos, Ruth J F; Vasan, Ramachandran S; Benjamin, Emelia J; Correa, Adolfo; Boerwinkle, Eric; Arking, Dan E; Rotter, Jerome I; Rich, Stephen S; Whitsel, Eric A; Perez, Marco; Kooperberg, Charles; Fornwalt, Brandon K; Lunetta, Kathryn L; Ellinor, Patrick T; Lubitz, Steven A.
Afiliação
  • Choi SH; Program 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.).
  • Jurgens SJ; Program 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.).
  • Haggerty CM; Department of Translational Data Science and Informatics (C.M.H., B.K.F.), Geisinger, Danville, PA.
  • Hall AW; Heart Institute (C.M.H., B.K.F.), Geisinger, Danville, PA.
  • Halford JL; Program 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.).
  • Morrill VN; Cardiovascular Research Center (A.W.H., V.N.M., L.-C.W., P.T.E., S.A.L.), Boston, MA.
  • Weng LC; Program 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.).
  • Lagerman B; Harvard Medical School (J.L.H., C.A.-T., H.L.R.), Boston, MA.
  • Mirshahi T; Program 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.).
  • Pettinger M; Cardiovascular Research Center (A.W.H., V.N.M., L.-C.W., P.T.E., S.A.L.), Boston, MA.
  • Guo X; Program 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.).
  • Lin HJ; Cardiovascular Research Center (A.W.H., V.N.M., L.-C.W., P.T.E., S.A.L.), Boston, MA.
  • Alonso A; Phenomic Analytics and Clinical Data Core (B.L.), Geisinger, Danville, PA.
  • Soliman EZ; Department of Molecular and Functional Genomics (T.M.), Geisinger, Danville, PA.
  • Kornej J; Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA (M.P., C.K.).
  • Lin H; The 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.).
  • Moscati A; The 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.).
  • Nadkarni GN; Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA (A.A.).
  • Brody JA; Epidemiological Cardiology Research Center, Wake Forest School of Medicine, Winston Salem, NC (E.Z.S.).
  • Wiggins KL; NHLBI and Boston University's Framingham Heart Study (J.K., E.J.B., R.S.V).
  • Cade BE; Sections of Cardiovascular Medicine and Preventive Medicine, Boston Medical Center (J.K., R.S.V), Boston University School of Medicine, MA.
  • Lee J; Section of Computational Biomedicine, Department of Medicine (H.L.), Boston University School of Medicine, MA.
  • Austin-Tse C; The Charles Bronfman Institute for Personalized Medicine (A.M., G.N., R.J.F.L.), Icahn School of Medicine, Mount Sinai, New York, NY.
  • Blackwell T; The Charles Bronfman Institute for Personalized Medicine (A.M., G.N., R.J.F.L.), Icahn School of Medicine, Mount Sinai, New York, NY.
  • Chaffin MD; Division of Nephrology, Department of Medicine (G.N.), Icahn School of Medicine, Mount Sinai, New York, NY.
  • Lee CJ; Cardiovascular Health Research Unit, Department of Medicine (J.A.B., K.L.W., N.S., B.M.P., S.R.H.), University of Washington, Seattle.
  • Rehm HL; Cardiovascular Health Research Unit, Department of Medicine (J.A.B., K.L.W., N.S., B.M.P., S.R.H.), University of Washington, Seattle.
  • Roselli C; Massachusetts General Hospital. Division of Sleep Medicine, Department of Medicine (B.E.C.), Boston, MA.
  • Redline S; Division of Sleep and Circadian Disorders (J.L.), Harvard Medical School, Brigham and Women's Hospital, Boston.
  • Mitchell BD; Center for Genomic Medicine (C.A.-T., H.L.R.), Boston, MA.
  • Sotoodehnia N; Harvard Medical School (J.L.H., C.A.-T., H.L.R.), Boston, MA.
  • Psaty BM; Laboratory for Molecular Medicine, Partners Healthcare Personalized Medicine, Cambridge, MA (C.A.-T.).
  • Heckbert SR; Department of Biostatistics, University of Michigan, Ann Arbor (T.B.).
  • Loos RJF; Program 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.).
  • Vasan RS; Program 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.).
  • Benjamin EJ; Program 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.).
  • Correa A; Center for Genomic Medicine (C.A.-T., H.L.R.), Boston, MA.
  • Boerwinkle E; Harvard Medical School (J.L.H., C.A.-T., H.L.R.), Boston, MA.
  • Arking DE; Program 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.).
  • Rich SS; Regeneron Genetics Center, Tarrytown, NY. Departments of Medicine, Brigham and Women's Hospital, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA (S.R.).
  • Whitsel EA; University of Maryland School of Medicine (B.D.M.).
  • Perez M; Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, MD (B.D.M.).
  • Kooperberg C; Cardiovascular Health Research Unit, Department of Medicine (J.A.B., K.L.W., N.S., B.M.P., S.R.H.), University of Washington, Seattle.
  • Fornwalt BK; Division of Cardiology, Department of Epidemiology (N.S.), University of Washington, Seattle.
  • Lunetta KL; Cardiovascular Health Research Unit, Department of Medicine (J.A.B., K.L.W., N.S., B.M.P., S.R.H.), University of Washington, Seattle.
  • Ellinor PT; Department of Epidemiology (B.M.P., S.R.H.), University of Washington, Seattle.
  • Lubitz SA; Department of Health Services (B.M.P.), University of Washington, Seattle.
Circ Genom Precis Med ; 14(4): e003300, 2021 08.
Article em En | MEDLINE | ID: mdl-34319147
ABSTRACT

BACKGROUND:

Alterations 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.

METHODS:

Using 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).

RESULTS:

We found that rare variants associated with population-based electrocardiographic intervals identify established monogenic SCD genes (KCNQ1, KCNH2, and SCN5A), a controversial monogenic SCD gene (KCNE1), and novel genes (PAM and MFGE8) involved in cardiac conduction. Loss-of-function and pathogenic SCN5A variants, carried by 0.1% of individuals, were associated with a nearly 6-fold increased odds of the first-degree atrioventricular block (P=8.4×10-5). Similar variants in KCNQ1 and KCNH2 (0.2% of individuals) were associated with a 23-fold increased odds of marked corrected QT interval prolongation (P=4×10-25), a marker of SCD risk. Incomplete penetrance of such deleterious variation was common as over 70% of carriers had normal electrocardiographic intervals.

CONCLUSIONS:

Our 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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Variação Genética / Síndrome do QT Longo / Morte Súbita Cardíaca / Predisposição Genética para Doença / Eletrocardiografia / Heterozigoto Tipo de estudo: Prognostic_studies / Risk_factors_studies Limite: Female / Humans / Male Idioma: En Revista: Circ Genom Precis Med Ano de publicação: 2021 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Variação Genética / Síndrome do QT Longo / Morte Súbita Cardíaca / Predisposição Genética para Doença / Eletrocardiografia / Heterozigoto Tipo de estudo: Prognostic_studies / Risk_factors_studies Limite: Female / Humans / Male Idioma: En Revista: Circ Genom Precis Med Ano de publicação: 2021 Tipo de documento: Article