Victor Nauffal1,2, Valerie N Morrill2, Patrick T Ellinor2,3,4, Steven A Lubitz2,3,4, Sean J Jurgens2,5,4, Seung Hoan Choi2,4, Amelia W Hall6, Lu-Chen Weng2,4, Jennifer L Halford2,4, Christina Austin-Tse7,4, Christopher M Haggerty8, Stephanie L Harris9, Eugene K Wong9, Alvaro Alonso10, Dan E Arking11, Emelia J Benjamin12,13, Eric Boerwinkle14, Yuan-I Min15, Adolfo Correa15, Brandon K Fornwalt8, Susan R Heckbert16, Charles Kooperberg17, Henry J Lin18, Ruth J F Loos19, Kenneth M Rice20, Namrata Gupta4, Thomas W Blackwell21, Braxton D Mitchell22, Alanna C Morrison14, Bruce M Psaty23, Wendy S Post24, Susan Redline25, Heidi L Rehm7,4, Stephen S Rich26, Jerome I Rotter18, Elsayed Z Soliman27, Nona Sotoodehnia28, Kathryn L Lunetta12. 1. Division of Cardiovascular Medicine (V.N.), Brigham and Women's Hospital, Boston, MA. 2. 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. 3. Cardiac Arrhythmia Service and Cardiovascular Research Center (P.T.E., S.A.L.), Massachusetts General Hospital, Boston. 4. Program 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.). 5. Department of Experimental Cardiology, Amsterdam University Medical Centers, The Netherlands (S.J.J.). 6. Gene Regulation Observatory (A.W.H.), Broad Institute, Cambridge, MA. 7. Center for Genomic Medicine (C.A.-T., H.L.R.), Massachusetts General Hospital, Boston. 8. Department of Translational Data Science and Informatics, Geisinger, Danville, PA (C.M.H., B.K.F.). 9. Cardiovascular Genetics Program (S.L.H., E.K.W.), Massachusetts General Hospital, Boston. 10. Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA (A.A.). 11. McKusick-Nathans Institute, Department of Genetic Medicine (D.E.A.), Johns Hopkins University School of Medicine, Baltimore, MD. 12. Boston University School of Public Health, MA (E.J.B., K.L.L.). 13. Boston University School of Medicine, MA (E.J.B.). 14. Human 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.). 15. Department of Medicine, University of Mississippi Medical Center, Jackson (Y.-I.M., A.C.). 16. Cardiovascular Health Research Unit and Department of Epidemiology (S.R.H.). 17. Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA (C.K.). 18. Institute 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.). 19. Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York (R.J.F.L.). 20. Department of Biostatistics (K.M.R.). 21. Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor (T.W.B.). 22. Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore (B.D.M.). 23. Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology and Health Systems and Population Health, University of Washington, Seattle, WA (B.M.P.). 24. Division of Cardiology, Department of Medicine (W.S.P.), Johns Hopkins University School of Medicine, Baltimore, MD. 25. Harvard Medical School (S.R.), Brigham and Women's Hospital, Boston, MA. 26. Center for Public Health Genomics and Department of Public Health Sciences, University of Virginia, Charlottesville (S.S.R.). 27. Epidemiological Cardiology Research Center, Wake Forest School of Medicine, Winston-Salem, NC (E.Z.S.). 28. Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, Cardiology, University of Washington, Seattle, WA (N.S.).
Abstract
BACKGROUND: Rare 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. METHODS: We 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. RESULTS: Fifty-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/decile of PRS=1.4 ms [95% CI, 1.3 to 1.5]; P=1.1×10-196). Carriers of putative pathogenic rare variants had longer QTc than noncarriers (ΔQTc=10.9 ms [95% CI, 7.4 to 14.4]). Of individuals with QTc>480 ms, 23.7% carried either a monogenic rare variant or had a PRS in the top decile (3.4% monogenic, 21% top decile of PRS). CONCLUSIONS: QTc 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.
BACKGROUND: Rare 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. METHODS: We 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. RESULTS: Fifty-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/decile of PRS=1.4 ms [95% CI, 1.3 to 1.5]; P=1.1×10-196). Carriers of putative pathogenic rare variants had longer QTc than noncarriers (ΔQTc=10.9 ms [95% CI, 7.4 to 14.4]). Of individuals with QTc>480 ms, 23.7% carried either a monogenic rare variant or had a PRS in the top decile (3.4% monogenic, 21% top decile of PRS). CONCLUSIONS: QTc 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.
Entities:
Keywords:
QT interval; long QT syndrome; monogenic; polygenic; sudden cardiac death
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