Sequencing in Over 50,000 Cases Identifies Coding and Structural Variation Underlying Atrial Fibrillation Risk
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 due 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, the genetic link between AF and cardiomyopathies, and expand our understanding of the rare variant architecture for this common arrhythmia Overall design: To characterize the molecular role of KDM5B in cardiomyocytes we knocked the gene out in iPS-derived atrial cardiomyocytes with a lentiviral CRISPR-Cas9-based approach. For this we independently delivered 2 KDM5B targeting sgRNAs that we found to be highly mutagenic After lentiviral delivery and puromycin selection, we then performed transcriptomic analysis using bulk RNA sequencing