Genome-Wide Association Study-Driven Gene-Set Analyses, Genetic, and Functional Follow-Up Suggest GLIS1 as a Susceptibility Gene for Mitral Valve Prolapse.

Background Mitral valve prolapse (MVP) is a common heart valve disease, the most frequent indication for valve repair or replacement. MVP is characterized by excess extracellular matrix secretion and cellular disorganization, which leads to bulky valves that are unable to coapt correctly during ventricular systole resulting in mitral regurgitation, and it is associated with sudden cardiac death. Here we aim to characterize globally the biological mechanisms underlying genetic susceptibility to MVP to better characterize its triggering mechanisms. Methods We applied i-GSEA4GWAS and DEPICT, two pathway enrichment tools to MVP genome-wide association studies. We followed-up the association with MVP in an independent dataset of cases and controls. This research was conducted using the UK Biobank Resource. Immunohistochemistry staining for Glis1 (GLIS family zinc finger 1) was conducted in developing heart of mice. Knockdown of Glis1 using morpholinos was performed in zebrafish animals 72 hours postfertilization. Results We show that genes at risk loci are involved in biological functions relevant to actin filament organization, cytoskeleton biology, and cardiac development. The enrichment for positive regulation of transcription, cell proliferation, and migration motivated the follow-up of GLIS1, a transcription factor from the Krüppel-like zinc finger family. In combination with previously available data, we now report a genome-wide significant association with MVP (odds ratio, 1.20; P=4.36×10