Meta-Analysis of Genome-Wide Association Studies Reveals Genetic Mechanisms of Supraventricular Arrhythmias-Reference-Cited by-同舟云学术

Meta-Analysis of Genome-Wide Association Studies Reveals Genetic Mechanisms of Supraventricular Arrhythmias

Published:2024-06 Issue:3 Volume:17 Page:
ISSN:2574-8300
Container-title:Circulation: Genomic and Precision Medicine
language:en
Short-container-title:Circ: Genomic and Precision Medicine

Author:

Weng Lu-Chen¹²³^ORCID,Khurshid Shaan⁴²^ORCID,Hall Amelia Weber⁵^ORCID,Nauffal Victor²³^ORCID,Morrill Valerie N.²,Sun Yan V.⁶⁷,Rämö Joel T.²⁸^ORCID,Beer Dominik⁹,Lee Simon¹⁰^ORCID,Nadkarni Girish¹⁰^ORCID,Johnson Renee¹¹¹²^ORCID,Andreasen Laura¹³¹⁴^ORCID,Clayton Anne¹⁵^ORCID,Pullinger Clive R.¹⁶^ORCID,Yoneda Zachary T.¹⁷^ORCID,Friedman Daniel J.¹⁸^ORCID,Hyman Matthew C.¹⁹^ORCID,Judy Renae L.²⁰^ORCID,Skanes Allan C.²¹^ORCID,Orland Kate M.²²^ORCID,Jordà Paloma²³^ORCID,Treu Timothy M.³,Oetjens Matthew T.²⁴,Subbiah Rajesh¹¹²⁵¹²^ORCID,Hartmann Jacob P.¹³^ORCID,May Heidi T.¹⁵^ORCID,Kane John P.²⁶²⁷^ORCID,Issa Tariq Z.²⁸^ORCID,Nafissi Navid A.¹⁸^ORCID,Leong-Sit Peter²¹,Dubé Marie-Pierre²³²⁹^ORCID,Roselli Carolina²³⁰^ORCID,Choi Seung Hoan²^ORCID, ,Tardif Jean-Claude²³^ORCID,Khan Habib R.²¹^ORCID,Knight Stacey¹⁵³¹^ORCID,Svendsen Jesper H.¹³³²^ORCID,Walker Bruce²⁵¹²,Karlsson Linnér Richard²⁴³³^ORCID,Gaziano J. Michael³³⁴^ORCID,Tadros Rafik²³^ORCID,Fatkin Diane¹¹²⁵¹²^ORCID,Rader Daniel J.³⁵^ORCID,Shah Svati H.¹⁸³⁶^ORCID,Roden Dan M.³⁷,Marcus Gregory M.³⁸^ORCID,Loos Ruth J.F.³⁹^ORCID,Damrauer Scott M.⁴⁰⁴¹^ORCID,Haggerty Christopher M.⁹⁴²^ORCID,Cho Kelly³,Palotie Aarno⁴³⁴⁴⁸^ORCID,Olesen Morten S.¹³¹⁴^ORCID,Eckhardt Lee L.²²^ORCID,Roberts Jason D.²¹^ORCID,Cutler Michael J.¹⁵^ORCID,Shoemaker M. Benjamin¹⁷^ORCID,Wilson Peter W.F.⁴⁵^ORCID,Ellinor Patrick T.⁴²⁷^ORCID,Lubitz Steven A.⁴²^ORCID

Affiliation:

1. Cardiovascular Research Center (L.-C.W.), The Broad Institute of MIT and Harvard, Cambridge.

2. Massachusetts General Hospital, Boston. Cardiovascular Disease Initiative (L.-C.W., S. Khurshid, V.N., V.N.M., J.T.R., C.R., S.H.C., P.T.E., S.A.L.), The Broad Institute of MIT and Harvard, Cambridge.

3. VA Boston Healthcare System (L.-C.W., V.N., T.M.T., J.M.G., K.C.), Brigham and Women’s Hospital, Boston, MA

4. Demoulas Center for Cardiac Arrhythmias (S. Khurshid, P.T.E., S.A.L.), The Broad Institute of MIT and Harvard, Cambridge.

5. Gene Regulation Observatory (A.W.H.), The Broad Institute of MIT and Harvard, Cambridge.

6. Department of Epidemiology, Emory University Rollins School of Public Health, Atlanta, GA (Y.V.S.).

7. VA Atlanta Healthcare System, Decatur, GA (Y.V.S., P.W.F.W.).

8. Institute for Molecular Medicine Finland, Helsinki Institute of Life Science, University of Helsinki, Finland (J.T.R., A.P.).

9. Heart Institute (D.B., C.M.H.), Geisinger, Danville, PA.

10. Icahn School of Medicine at Mount Sinai, New York, NY (S.L., G.N.).

11. Victor Chang Cardiac Research Institute (R.J., R.S., D.F.), Darlinghurst, NSW.

12. School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Kensington, NSW, Australia (R.J., R.S., B.W., D.F.).

13. Department of Cardiology, Laboratory for Molecular Cardiology, Copenhagen University Hospital, Rigshospitalet, Denmark (L.A., J.P.H., J.H.S., M.S.O.).

14. Department of Biomedical Sciences (L.A., M.S.O.), University of Copenhagen, Denmark.

15. Intermountain Heart Institute, Intermountain Medical Center, Murray, UT (A.C., H.T.M., S. Knight, M.J.C.).

16. Cardiovascular Research Institute and Department of Physiological Nursing (C.R.P.), University of California, San Francisco.

17. Department of Medicine, Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN (Z.T.Y., M.B.S.).

18. Division of Cardiology, Department of Medicine (D.J.F., N.A.N., S.H.S.), Duke University School of Medicine, Durham, NC.

19. Division of Cardiac Electrophysiology, Hospital of the University of Pennsylvania, Philadelphia (M.C.H.).

20. Department of Surgery (R.L.J.), University of Pennsylvania, Philadelphia.

21. Division of Cardiology, Department of Medicine, Section of Cardiac Electrophysiology, Western University, London, ON, Canada (A.C.S., P.L.-S., H.R.K., J.D.R.).

22. Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin–Madison, WI (K.M.O., L.L.E.).

23. Montreal Heart Institute Research Center and Faculty of Medicine, Université de Montréal, QC, Canada (P.J., M.-P.D., J.-C.T., R.T.).

24. Autism and Developmental Medicine Institute, Geisinger, Lewisburg, PA (M.T.O., R.K.L.).

25. St Vincent’s Hospital (R.S., B.W., D.F.), Darlinghurst, NSW.

26. Cardiovascular Research Institute (J.P.K.), University of California, San Francisco.

27. Department of Medicine, Department of Biochemistry and Biophysics (J.P.K.), University of California, San Francisco.

28. Feinberg School of Medicine, Northwestern University, Chicago, IL (T.Z.I.).

29. Beaulieu-Saucier Pharmacogenomics Center, Montreal, QC, Canada (M.-P.D.).

30. Department of Cardiology, University of Groningen, University Medical Center Groningen, the Netherlands (C.R.).

31. Department of Medicine, University of Utah, Salt Lake City (S. Knight).

32. Department of Clinical Medicine (J.H.S.), University of Copenhagen, Denmark.

33. Department of Economics, Leiden Law School, Leiden University, the Netherlands (R.K.L.).

34. Harvard Medical School, Boston, MA (J.M.G.).

35. Division of Cardiovascular Medicine, Department of Medicine (D.J.R.), University of Pennsylvania, Philadelphia.

36. Duke Molecular Physiology Institute (S.H.S.), Duke University School of Medicine, Durham, NC.

37. Vanderbilt University Medical Center, Nashville, TN (D.M.R.).

38. Division of Cardiology (G.M.M.), University of California, San Francisco.

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

40. Department of Surgery and Department of Genetics, Perelman School of Medicine (S.M.D.), University of Pennsylvania, Philadelphia.

41. Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA (S.M.D.).

42. Department of Translational Data Science and Informatics (C.M.H.), Geisinger, Danville, PA.

43. Analytic and Translational Genetics Unit, Department of Medicine, Department of Neurology, Department of Psychiatry (A.P.), The Broad Institute of MIT and Harvard, Cambridge.

44. The Stanley Center for Psychiatric Research & Program in Medical & Population Genetics (A.P.), The Broad Institute of MIT and Harvard, Cambridge.

45. Department of Medicine, Emory University School of Medicine, Atlanta, GA (P.W.F.W.).

Abstract

BACKGROUND: Substantial data support a heritable basis for supraventricular tachycardias, but the genetic determinants and molecular mechanisms of these arrhythmias are poorly understood. We sought to identify genetic loci associated with atrioventricular nodal reentrant tachycardia (AVNRT) and atrioventricular accessory pathways or atrioventricular reciprocating tachycardia (AVAPs/AVRT). METHODS: We performed multiancestry meta-analyses of genome-wide association studies to identify genetic loci for AVNRT (4 studies) and AVAP/AVRT (7 studies). We assessed evidence supporting the potential causal effects of candidate genes by analyzing relations between associated variants and cardiac gene expression, performing transcriptome-wide analyses, and examining prior genome-wide association studies. RESULTS: Analyses comprised 2384 AVNRT cases and 106 489 referents, and 2811 AVAP/AVRT cases and 1,483 093 referents. We identified 2 significant loci for AVNRT, which implicate NKX2-5 and TTN as disease susceptibility genes. A transcriptome-wide association analysis supported an association between reduced predicted cardiac expression of NKX2-5 and AVNRT. We identified 3 significant loci for AVAP/AVRT, which implicate SCN5A , SCN10A , and TTN/CCDC141 . Variant associations at several loci have been previously reported for cardiac phenotypes, including atrial fibrillation, stroke, Brugada syndrome, and electrocardiographic intervals. CONCLUSIONS: Our findings highlight gene regions associated with ion channel function (AVAP/AVRT), as well as cardiac development and the sarcomere (AVAP/AVRT and AVNRT) as important potential effectors of supraventricular tachycardia susceptibility.

Publisher

Ovid Technologies (Wolters Kluwer Health)

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