Meta-Analysis of Genome-Wide Association Studies Reveals Genetic Mechanisms of Supraventricular Arrhythmias.
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Weng Lu-Chen, Khurshid Shaan, Hall Amelia Weber, Nauffal Victor, Morrill Valerie N, Sun Yan V, Rämö Joel T, Beer Dominik, Lee Simon, Nadkarni Girish, Johnson Renee, Andreasen Laura, Clayton Anne, Pullinger Clive R, Yoneda Zachary T, Friedman Daniel J, Hyman Matthew C, Judy Renae L, Skanes Allan C, Orland Kate M, Jordà Paloma, Treu Timothy M, Oetjens Matthew T, Subbiah Rajesh, Hartmann Jacob P, May Heidi T, Kane John P, Issa Tariq Z, Nafissi Navid A, Leong-Sit Peter, Dubé Marie-Pierre, Roselli Carolina, Choi Seung Hoan, FinnGen, Million Veteran Program, Regeneron Genetics Center, Tardif Jean-Claude, Khan Habib R, Knight Stacey, Svendsen Jesper H, Walker Bruce, Karlsson Linnér Richard, Gaziano J Michael, Tadros Rafik, Fatkin Diane, Rader Daniel J, Shah Svati H, Roden Dan M, Marcus Gregory M, Loos Ruth J F, Damrauer Scott M, Haggerty Christopher M, Cho Kelly, Palotie Aarno, Olesen Morten S, Eckhardt Lee L, Roberts Jason D, Cutler Michael J, Shoemaker M Benjamin, Wilson Peter W F, Ellinor Patrick T, Lubitz Steven A
Аннотация
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.