Sequencing in over 50,000 cases identifies coding and structural variation underlying atrial fibrillation risk.
Choi SH., Jurgens SJ., Xiao L., Hill MC., Haggerty CM., Sveinbjörnsson G., Morrill VN., Marston NA., Weng L-C., Pirruccello JP., Arnar DO., Gudbjartsson DF., Mantineo H., von Falkenhausen AS., Natale A., Tveit A., Geelhoed B., Roselli C., Van Wagoner DR., Darbar D., Haase D., Soliman EZ., Davogustto GE., Jun G., Calkins H., Anderson JL., Brody JA., Halford JL., Barnard J., Hokanson JE., Smith JD., Bis JC., Young K., Johnson LSB., Risch L., Gula LJ., Kwee LC., Chaffin MD., Kühne M., Preuss M., Gupta N., Nafissi NA., Smith NL., Nilsson PM., van der Harst P., Wells QS., Judy RL., Schnabel RB., Johnson R., Smit RAJ., Gabriel S., Knight S., Furukawa T., Blackwell TW., Nauffal V., Wang X., Min Y-I., Yoneda ZT., Laksman ZWM., Bezzina CR., Alonso A., Psaty BM., Albert CM., Arking DE., Roden DM., Chasman DI., Rader DJ., Conen D., McManus DD., Fatkin D., Benjamin EJ., Boerwinkle E., Marcus GM., Christophersen IE., Smith JG., Roberts JD., Raffield LM., Shoemaker MB., Cho MH., Cutler MJ., Rienstra M., Chung MK., S Olesen M., Sinner MF., Sotoodehnia N., Kirchhof P., Loos RJF., Nazarian S., Mohanty S., Damrauer SM., Kaab S., Heckbert SR., Redline S., Shah SH., Tanaka T., Ebana Y., Regeneron Genetics Center None., NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium None., Holm H., Stefansson K., Ruff CT., Sabatine MS., Lunetta KL., Lubitz SA., Ellinor PT.
Atrial fibrillation (AF) is a prevalent and morbid abnormality of the heart rhythm with a strong genetic component. Here, we meta-analyzed genome and exome sequencing data from 36 studies that included 52,416 AF cases and 277,762 controls. In burden tests of rare coding variation, we identified novel associations between AF and the genes MYBPC3, LMNA, PKP2, FAM189A2 and KDM5B. We further identified associations between AF and rare structural variants owing to deletions in CTNNA3 and duplications of GATA4. We broadly replicated our findings in independent samples from MyCode, deCODE and UK Biobank. Finally, we found that CRISPR knockout of KDM5B in stem-cell-derived atrial cardiomyocytes led to a shortening of the action potential duration and widespread transcriptomic dysregulation of genes relevant to atrial homeostasis and conduction. Our results highlight the contribution of rare coding and structural variants to AF, including genetic links between AF and cardiomyopathies, and expand our understanding of the rare variant architecture for this common arrhythmia.