Author:
Weng Lu-Chen,Rämö Joel T.,Jurgens Sean J.,Khurshid Shaan,Chaffin Mark,Hall Amelia Weber,Morrill Valerie N.,Nauffal Victor,Sun Yan V.,Beer Dominik,Lee Simon,Nadkarni Girish,Duong ThuyVy,Wang Biqi,Czuba Tomasz,Austin Thomas R.,Yoneda Zachary T.,Friedman Daniel J.,Clayton Anne,Hyman Matthew C.,Judy Renae L.,Skanes Allan C.,Orland Kate M.,Treu Timothy M.,Oetjens Matthew T.,Alonso Alvaro,Soliman Elsayed Z.,Lin Honghuang,Lunetta Kathryn L.,van der Pals Jesper,Issa Tariq Z.,Nafissi Navid A.,May Heidi T.,Leong-Sit Peter,Roselli Carolina,Choi Seung Hoan,Khan Habib R.,Knight Stacey,Linnér Richard K.,Bezzina Connie R.,Ripatti Samuli,Gaziano J. Michael,Loos Ruth,Psaty Bruce M.,Smith J. Gustav,Benjamin Emelia J.,Arking Dan E.,Rader Daniel,Shah Svati H.,Roden Dan M.,Damrauer Scott M.,Eckhardt Lee L.,Roberts Jason D.,Cutler Michael J.,Shoemaker M. Benjamin,Haggerty Christopher M.,Cho Kelly,Palotie Aarno,Wilson Peter W.F.,Ellinor Patrick T.,Lubitz Steven A.,
Abstract
ABSTRACTTo broaden our understanding of bradyarrhythmias and diseases of the cardiac conduction system, we performed cross-sectional multi-ancestry genome-wide association study meta-analyses in up to 1.3 million individuals for sinus node dysfunction (SND), distal conduction disease (DCD), and pacemaker implantation (PM). We evaluated the biological relevance of bradyarrhythmia loci by analyses of transcriptomes, pleiotropy, and partitioned heritability based on cardiac single cell RNA sequencing data. Finally, we performed rare variant burden testing in 460,000 whole exome sequenced individuals from two biobanks. We identified 13, 28, and 21 common variant loci for SND, DCD, and PM, respectively. Four well-known common variant arrhythmia loci (SCN5A/SCN10A,CCDC141, TBX20, andCAMK2D)were shared for SND and DCD, while other loci were more specific for either SND or DCD. Cardiomyocyte-expressed genes were strongly enriched for contributions to DCD heritability, while SND and PM were more heterogeneous. Rare variant analyses implicatedLMNAfor all bradyarrhythmia subtypes;SMAD6andSCN5Afor DCD; andTTN,MYBPC3, andSCN5Afor PM. The genetic architectures of SND and DCD are both overlapping and distinct. Multiple genetic mechanisms involving ion channels, sarcomeric components, cellular homeostasis, and cardiac development may influence the development of bradyarrhythmias.
Publisher
Cold Spring Harbor Laboratory