Genome-wide association meta-analysis supports genes involved in valve and cardiac development to associate with mitral valve prolapse

Objective Mitral valve prolapse (MVP) is a common cardiac valve disease, which affects 1 in 40 in the general population. Previous GWAS have identified six risk loci for MVP. But these loci explained only partially the genetic risk for MVP. We aim to identify additional risk loci for MVP by adding a dataset from the UK Biobank. Approaches and Results We re-analyzed 1,007/1,469 cases and 479/862 controls from the MVP-France study and the MVP-Nantes study, respectively. We re-imputed genotypes using HRC and TOPMed, and found this latter to perform better in terms of accuracy in the lower ranges of minor allele frequency (MAF) below 0.1. We then incorporated 434 MVP cases and 4,527 controls from the UKBiobank and conducted a meta-analysis GWAS including ∼2000 MVP cases and over 6,800 controls for ∼8 million genotyped or imputed common SNPs (MAF>0.01). We replicated the association on chr2 and now provide a finer association map near TNS1 . We identified three suggestive risk loci, all driven by common variants on Chr1 ( SYT2 ), Chr8 ( MSRA ), and Chr19 ( FBXO46 ). Gene-based association using MAGMA revealed 15 risk genes for MVP including GLIS1, TGFB2, ID2, TBX5, MSRA , and DMPK . Extensive functional annotation showed that genes associated with MVP are highly expressed in cardiovascular tissues, especially heart, and are involved in cardiac development and potentially aging. Conclusions We report an updated meta-analysis GWAS for MVP using dense imputation coverage and an improved case-control sample. We describe several loci and genes with MVP spanning biological mechanisms highly relevant to MVP, especially during valve and heart development. TOC category - basic and population studies TOC subcategory - Arteriosclerosis, Thrombosis, and Vascular Biology Highlights Provide high coverage meta-analysis of GWAS based on TOPMed imputation involving ∼8 million common variants in ∼2000 MVP patients and ∼6800 controls. Low frequency variant contributed little to the association of the genes mentioned, where the associations were driven by common variants Several association loci involve genes related to cardiac development and potentially aging.