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Circ Genom Precis Med. 2019 May;12(5):e002497. doi: 10.1161/CIRCGEN.119.002497.

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

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INSERM, UMR970, Paris Cardiovascular Research Center, France (M.Y., A.G., S.K., A.A.H., X.J., N.B.-N.).
Faculty of Medicine, University Paris Descartes, Sorbonne Paris Cité, France (M.Y., A.G., S.K., A.A.H., X.J., N.B.-N.M.Y., A.G., S.K., A.A.H., X.J., N.B.-N.).
Cardiology Division, Cardiovascular Research Center (N.R.T., P.T.E., D.J.M.), Massachusetts General Hospital, Harvard Medical School, Boston.
Precision Cardiology Laboratory, The Broad Institute, Cambridge, MA (N.R.T., P.T.E.).
Cardiovascular Developmental Biology Center, Department of Regenerative Medicine and Cell Biology, College of Medicine, Children's Research Institute, Medical University of South Carolina, Charleston (K.T.).
Inserm U1087, institut du thorax, University Hospital Nantes, France (J.-J.S., C.D.).
CNRS, UMR 6291, Université de Nantes, France (J.-J.S., C.D.).
Université de Nantes, France (J.-J.S., C.D.).
Department of Medicine, Division of Cardiology, University of California, San Francisco (F.N.D.).
HM Hospitales-Centro Integral de Enfermedades Cardiovasculares HM-CIEC, Madrid, Spain (L.F.-F., J.S.).
Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain (L.F.-F., J.S.).
Cardiac Ultrasound Laboratory, Cardiology Division (R.A.L.), Massachusetts General Hospital, Harvard Medical School, Boston.
Center for Human Genetic Research, Massachusetts General Hospital and Department of Neurology, Harvard Medical School, Boston (S.A.S.).
Department of Cardiology (A.A.H.), Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, France.
Department of Genetics (X.J.), Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, France.


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.


heart valve disease; mitral valve; mitral valve prolapse; morpholinos; zebrafish

[Available on 2020-05-01]

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