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

Weng LC, Khurshid S, Hall AW, Nauffal V, Morrill VN, Sun YV, Rämö JT, Beer D, Lee S, Nadkarni G, Johnson R, Andreasen L, Clayton A, Pullinger CR, Yoneda ZT, Friedman DJ, Hyman MC, Judy RL, Skanes AC, Orland KM, Jordà P, Treu TM, Oetjens MT, Subbiah R, Hartmann JP, May HT, Kane JP, Issa TZ, Nafissi NA, Leong-Sit P, Dubé MP, Roselli C, Choi SH, FinnGen, Million Veteran Program, Regeneron Genetics Center, Tardif JC, Khan HR, Knight S, Svendsen JH, Walker B, Karlsson Linnér R, Gaziano JM, Tadros R, Fatkin D, Rader DJ, Shah SH, Roden DM, Marcus GM, Loos RJF, Damrauer SM, Haggerty CM, Cho K, Palotie A, Olesen MS, Eckhardt LL, Roberts JD, Cutler MJ, Shoemaker MB, Wilson PWF, Ellinor PT, Lubitz SA. Meta-Analysis of Genome-Wide Association Studies Reveals Genetic Mechanisms of Supraventricular Arrhythmias. Circulation. Genomic and precision medicine. 2024 Jun 1; 17(3):e004320.

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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 and as disease susceptibility genes. A transcriptome-wide association analysis supported an association between reduced predicted cardiac expression of and AVNRT. We identified 3 significant loci for AVAP/AVRT, which implicate , , and . 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.