A Genome-wide Association Study of Nonsyndromic Mitral Valve Prolapse and Functional Studies of Risk Loci Provide Insight Into Underlying Biological Mechanisms

Background: Nonsyndromic mitral valve prolapse (MVP) is a common, progressively degenerative valvulopathy. MVP is the most frequent indication for surgical repair of mitral regurgitation, and causes heart failure, arrhythmia and sudden death. However, the genetic basis and physiopathology of MVP remain elusive. The genetic heterogeneity and high prevalence (2-5%) of MVP support the utility of a genome-wide association study in large populations to identify risk loci, which may uncover novel pathogenic mechanisms. Methods: We tested 4.8 million common genotyped/imputed variants in 1412 sporadic MVP cases and 2439 controls. Replication for 23 loci was performed in 4 case control studies from USA, France, Spain and Canada, all of European ancestry (Ncases=1442, NControls=6779). High profile candidate genes were investigated for protein expression by immunohistochemistry on mitral valves in embryonic and adult mice and morpholino knockdown (KD) assessed cardiac function in zebrafish. Results: Six susceptibility loci were identified after replication (P Conclusions: In this multidisciplinary study we discovered 6 loci with effect sizes (OR range: 1.22-1.33) compatible with a complex genetic pattern of inheritance, and identified new actors in valve development and biology. We provide genetic and functional evidence implicating LMCD1 and TNS1 in valve development and function. This study reveals new pathways that can potentially be modified to improve the natural history of MVP.