Meta-Analysis

. 2024 Jun;17(3):e004320.

doi: 10.1161/CIRCGEN.123.004320. Epub 2024 May 28.

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

Lu-Chen Weng^#^{1

2

3}, Shaan Khurshid^#^{4

2}, Amelia Weber Hall^#⁵, Victor Nauffal^{2

3}, Valerie N Morrill², Yan V Sun^{6

7}, Joel T Rämö^{2

8}, Dominik Beer⁹, Simon Lee¹⁰, Girish Nadkarni¹⁰, Renee Johnson^{11

12}, Laura Andreasen^{13

14}, Anne Clayton¹⁵, Clive R Pullinger¹⁶, Zachary T Yoneda¹⁷, Daniel J Friedman¹⁸, Matthew C Hyman¹⁹, Renae L Judy²⁰, Allan C Skanes²¹, Kate M Orland²², Paloma Jordà²³, Timothy M Treu³, Matthew T Oetjens²⁴, Rajesh Subbiah^{11

25

12}, Jacob P Hartmann¹³, Heidi T May¹⁵, John P Kane^{26

27}, Tariq Z Issa²⁸, Navid A Nafissi¹⁸, Peter Leong-Sit²¹, Marie-Pierre Dubé^{23

29}, Carolina Roselli^{2

30}, Seung Hoan Choi²; FinnGen, Million Veteran Program, Regeneron Genetics Center; Jean-Claude Tardif²³, Habib R Khan²¹, Stacey Knight^{15

31}, Jesper H Svendsen^{13

32}, Bruce Walker^{25

12}, Richard Karlsson Linnér^{24

33}, J Michael Gaziano^{3

34}, Rafik Tadros²³, Diane Fatkin^{11

25

12}, Daniel J Rader³⁵, Svati H Shah^{18

36}, Dan M Roden³⁷, Gregory M Marcus³⁸, Ruth J F Loos³⁹, Scott M Damrauer^{40

41}, Christopher M Haggerty^{9

42}, Kelly Cho³, Aarno Palotie^{43

44

8}, Morten S Olesen^{13

14}, Lee L Eckhardt²², Jason D Roberts²¹, Michael J Cutler¹⁵, M Benjamin Shoemaker¹⁷, Peter W F Wilson⁴⁵, Patrick T Ellinor^{4

2

7}, Steven A Lubitz^{4

2}

Affiliations

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.).

^# Contributed equally.

PMID: 38804128
PMCID: PMC11187659
DOI: 10.1161/CIRCGEN.123.004320

Meta-Analysis

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

Lu-Chen Weng et al. Circ Genom Precis Med. 2024 Jun.

. 2024 Jun;17(3):e004320.

doi: 10.1161/CIRCGEN.123.004320. Epub 2024 May 28.

Authors

Affiliations

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.).

^# Contributed equally.

PMID: 38804128
PMCID: PMC11187659
DOI: 10.1161/CIRCGEN.123.004320

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.

Keywords: atrial fibrillation; genome-wide association study; heart rate; heart ventricles; tachycardia, supraventricular.

PubMed Disclaimer

Conflict of interest statement

Disclosures Dr Lubitz is a full-time employee of Novartis as of July 2022. Previously, Dr Lubitz received research support from Bristol Myers Squibb/Pfizer, Bayer AG, Boehringer Ingelheim, Fitbit, IBM, Medtronic, and Premier, Inc, and consulted for Bristol Myers Squibb/Pfizer, Bayer AG, Blackstone Life Sciences, and Invitae. Dr Ellinor receives research support from Bayer AG, IBM, and Bristol Myers Squibb/Pfizer and has consulted for Novartis, MyoKardia, and Bayer AG. Dr Damrauer receives research support for RenalytixAI and has consulted for Calico Labs. Dr Svendsen is a member of Medtronic advisory boards and has received speaker honoraria and research grants from Medtronic outside this work. Dr Cutler has consulted for Janssen Scientific. Dr Roselli is supported by a grant from Bayer AG to the Broad Institute focused on the development of therapeutics for cardiovascular disease. The other authors report no conflicts.

Figures

**Figure 1.**
Study design. Chart summarizes study design. We performed a meta-analysis of genome-wide association studies (GWAS), with 7 datasets contributing to analysis of Atrioventricular Accessory Pathways or Atrioventricular Reciprocating Tachycardia (AVAP/AVRT, n=2,811 cases), and 4 contributing to Atrioventricular Nodal Reentrant Tachycardia (AVNRT, n=2,384 cases). We prioritized candidate genes using expression quantitative trait loci (eQTL) in atrial appendage and left ventricle tissue, transcriptome analysis in atrial appendage and left ventricle tissue and assessment of identified variants in prior cardiovascular GWAS.

**Figure 2.**
Manhattan plot for AVNRT. Manhattan plot for the AVNRT meta-analysis. P-value is presented in −log10 scale for each association test between variant and AVNRT from fixed-effects meta-analysis of 106,489 multi-ancestry individuals (2,384 cases). The red line indicates genome-wide significance (p=5×10⁻⁸), and the blue line indicates suggestive significance (p=1×10⁻⁶). Candidate genes are labeled in black (genome-wide significance) or gray (suggestive significance).

**Figure 3.**
Manhattan plot for AVAP/AVRT. Manhattan plot for AVAP/AVRT meta-analysis. P-value is presented in −log10 scale for each association test between SNP and AVAP/AVRT from fixed-effects meta-analysis of 1,483,093 multi-ancestry individuals (2,384 cases). The red line indicates genome-wide significance (p=5×10⁻⁸), and the blue line indicates suggestive significance (p=1×10⁻⁶). Candidate genes are labeled in black (genome-wide significance) or gray (suggestive significance).

**Figure 4.**
Summary of results. Depicted is a summary of candidate genes and their functions. Genome-wide significant associations are depicted in black and underlined with larger font, while suggestive associations are depicted in black with smaller font. Associations seen in conditional analysis are starred. Additional associations seen in European ancestry-only analyses are double-starred.

See this image and copyright information in PMC

References

1. Khurshid S, Choi SH, Weng LC, Wang EY, Trinquart L, Benjamin EJ, Ellinor PT and Lubitz SA. Frequency of Cardiac Rhythm Abnormalities in a Half Million Adults. Circ Arrhythm Electrophysiol. 2018;11:e006273. - PMC - PubMed
1. Murman DH, McDonald AJ, Pelletier AJ and Camargo CA Jr. U.S. emergency department visits for supraventricular tachycardia, 1993–2003. Acad Emerg Med. 2007;14:578–581. - PubMed
1. Wellens HJJ. Electrical Stimulation of the Heart in the Treatment of Tachycardias Dordrecht: Springer; 1971.
1. Michowitz Y, Anis-Heusler A, Reinstein E, Tovia-Brodie O, Glick A and Belhassen B. Familial Occurrence of Atrioventricular Nodal Reentrant Tachycardia. Circ Arrhythm Electrophysiol. 2017;10:e004680. - PubMed
1. Gollob MH, Green MS, Tang AS, Gollob T, Karibe A, Ali Hassan AS, Ahmad F, Lozado R, Shah G, Fananapazir L, et al. Identification of a gene responsible for familial Wolff-Parkinson-White syndrome. N Engl J Med. 2001;344:1823–1831. - PubMed

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

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

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