Monogenic and Polygenic Contributions to QTc Prolongation in the Population-Reference-Cited by-同舟云学术

Monogenic and Polygenic Contributions to QTc Prolongation in the Population

Published:2022-05-17 Issue:20 Volume:145 Page:1524-1533
ISSN:0009-7322
Container-title:Circulation
language:en
Short-container-title:Circulation

Author:

Nauffal Victor¹²,Morrill Valerie N.²^ORCID,Jurgens Sean J.²³⁴^ORCID,Choi Seung Hoan²⁴,Hall Amelia W.⁵,Weng Lu-Chen²⁴,Halford Jennifer L.²⁴^ORCID,Austin-Tse Christina⁶⁴^ORCID,Haggerty Christopher M.⁷^ORCID,Harris Stephanie L.⁸,Wong Eugene K.⁸^ORCID,Alonso Alvaro⁹^ORCID,Arking Dan E.¹⁰^ORCID,Benjamin Emelia J.¹¹¹²^ORCID,Boerwinkle Eric¹³^ORCID,Min Yuan-I¹⁴,Correa Adolfo¹⁴^ORCID,Fornwalt Brandon K.⁷^ORCID,Heckbert Susan R.¹⁵^ORCID,Kooperberg Charles¹⁶^ORCID,Lin Henry J.¹⁷^ORCID,J.F. Loos Ruth¹⁸^ORCID,Rice Kenneth M.¹⁹,Gupta Namrata⁴^ORCID,Blackwell Thomas W.²⁰,Mitchell Braxton D.²¹^ORCID,Morrison Alanna C.¹³^ORCID,Psaty Bruce M.²²^ORCID,Post Wendy S.²³^ORCID,Redline Susan²⁴^ORCID,Rehm Heidi L.⁶⁴^ORCID,Rich Stephen S.²⁵^ORCID,Rotter Jerome I.¹⁷^ORCID,Soliman Elsayed Z.²⁶^ORCID,Sotoodehnia Nona²⁷,Lunetta Kathryn L.¹¹^ORCID,Ellinor Patrick T.²²⁸⁴^ORCID,Lubitz Steven A.²²⁸⁴^ORCID, ,

Affiliation:

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. Department of Experimental Cardiology, Amsterdam University Medical Centers, The Netherlands (S.J.J.).

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. Gene Regulation Observatory (A.W.H.), Broad Institute, Cambridge, MA.

6. Center for Genomic Medicine (C.A.-T., H.L.R.), Massachusetts General Hospital, Boston.

7. Department of Translational Data Science and Informatics, Geisinger, Danville, PA (C.M.H., B.K.F.).

8. Cardiovascular Genetics Program (S.L.H., E.K.W.), Massachusetts General Hospital, Boston.

9. Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA (A.A.).

10. McKusick-Nathans Institute, Department of Genetic Medicine (D.E.A.), Johns Hopkins University School of Medicine, Baltimore, MD.

11. Boston University School of Public Health, MA (E.J.B., K.L.L.).

12. Boston University School of Medicine, MA (E.J.B.).

13. 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.).

14. Department of Medicine, University of Mississippi Medical Center, Jackson (Y.-I.M., A.C.).

15. Cardiovascular Health Research Unit and Department of Epidemiology (S.R.H.)

16. Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA (C.K.).

17. 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.).

18. Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York (R.J.F.L.).

19. Department of Biostatistics (K.M.R.)

20. Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor (T.W.B.).

21. Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore (B.D.M.).

22. Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology and Health Systems and Population Health, University of Washington, Seattle, WA (B.M.P.).

23. Division of Cardiology, Department of Medicine (W.S.P.), Johns Hopkins University School of Medicine, Baltimore, MD.

24. Harvard Medical School (S.R.), Brigham and Women’s Hospital, Boston, MA.

25. Center for Public Health Genomics and Department of Public Health Sciences, University of Virginia, Charlottesville (S.S.R.).

26. Epidemiological Cardiology Research Center, Wake Forest School of Medicine, Winston-Salem, NC (E.Z.S.).

27. Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, Cardiology, University of Washington, Seattle, WA (N.S.).

28. Cardiac Arrhythmia Service and Cardiovascular Research Center (P.T.E., S.A.L.), Massachusetts General Hospital, Boston.

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.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Physiology (medical),Cardiology and Cardiovascular Medicine

Reference29 articles.

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