PUBLICATION

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

Authors

Yu, M., Georges, A., Tucker, N.R., Kyryachenko, S., Toomer, K., Schott, J.J., Delling, F.N., Fernandez-Friera, L., Solis, J., Ellinor, P.T., Levine, R.A., Slaugenhaupt, S.A., Hagège, A.A., Dina, C., Jeunemaitre, X., Milan, D.J., Norris, R.A., Bouatia-Naji, N.

ID

ZDB-PUB-190522-6

Date

2019

Source

Circulation. Genomic and precision medicine 12: e002497 (Journal)

Registered Authors

Ellinor, Patrick, Milan, David J.

Keywords

heart valve disease, mitral valve, mitral valve prolapse, morpholinos, zebrafish

MeSH Terms

Animals
DNA-Binding Proteins/genetics*
DNA-Binding Proteins/metabolism
Female
Follow-Up Studies
Genetic Predisposition to Disease
Genome-Wide Association Study
Heart/growth & development
Heart Valves/growth & development
Heart Valves/metabolism
Humans
Male
Mice
Mitral Valve Insufficiency/etiology
Mitral Valve Insufficiency/metabolism
Mitral Valve Prolapse/complications
Mitral Valve Prolapse/embryology
Mitral Valve Prolapse/genetics*
Mitral Valve Prolapse/metabolism
Polymorphism, Single Nucleotide
Transcription Factors/genetics*
Transcription Factors/metabolism
United Kingdom
Zebrafish

PubMed

31112420 Full text @ Circ Genom Precis Med

Abstract

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^-10), indicating that Glis1 is expressed during embryonic development predominantly in nuclei of endothelial and interstitial cells of mitral valves in mouse. We also show that Glis1 knockdown causes atrioventricular regurgitation in developing hearts in zebrafish. Conclusions Our findings define globally molecular and cellular mechanisms underlying common genetic susceptibility to MVP and implicate established and unprecedented mechanisms. Through the GLIS1 association and function, we point at regulatory functions during cardiac development as common mechanisms to mitral valve degeneration.

Genes / Markers

Figures

Show all Figures

Expression

Phenotype

Mutations / Transgenics

Human Disease / Model

Sequence Targeting Reagents

Fish

Antibodies

Orthology

Engineered Foreign Genes

Mapping

Yu et al., 2019 ZDB-PUB-190522-6 PMID:31112420

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

Yu et al., 2019

ZDB-PUB-190522-6
PMID:31112420