Abstract Body (Do not enter title and authors here): Introduction: Mitral valve prolapse (MVP) is the most common cause of primary mitral regurgitation and is estimated to affect between 1-3% of the general population. A subset of individuals with MVP develop malignant arrhythmias, often in the context of myocardial fibrosis. The genetics of MVP, and genetic factors explaining why only some individuals with MVP have adverse outcomes, remains poorly understood.

Methods: We defined MVP using a combination of claims data and echocardiographic diagnosis across 15 cohorts spanning 5 countries and performed a meta-analysis of genome-wide association studies (GWAS) for MVP including 19,487 MVP cases among 2,247,054 individuals. Causal genes were prioritized using a combination of methods including the identification of variants in active promoters/enhancers using mitral valve ATAC-seq data from an external dataset. To determine whether prioritized genes may be differentially expressed in myocardial fibrosis, we compared single-cell RNA sequencing between fibrosed papillary muscles and normal left ventricular among two individuals with severe MVP.

Results: There were 67 unique genome-wide significant (GWS; p<5x10^-8) genomic regions, of which 52 were novel. Of these, 38 GWS regions included either missense variants or variants overlapping a promoter active in valve tissue as suggested by mitral valve ATAC-seq data. Pathway analysis of prioritized genes highlighted etiological roles for extracellular matrix and cardiomyocyte biology. 33 prioritized genes were differentially expressed between fibrotic papillary muscle tissue and normal left ventricle, the majority of which were specific to cardiomyocytes. One of these genes, CAMK2D, was also observed as sub-GWS in a recent GWAS of myocardial interstitial fibrosis and has notable pleiotropy for arrhythmia traits including atrial fibrillation and atrioventricular block.

Conclusions: We performed the largest GWAS of MVP to-date, discovering 52 novel GWS regions, and prioritized genes relevant to myocardial fibrosis, an important risk factor for adverse outcomes among individuals with MVP.