Abstract 14210: GWAS-driven Pathway Analyses and Functional Validation Reveals GLIS1 Predisposes to Mitral Valve Prolapse
Introduction: Mitral valve prolapse (MVP) is the most common indication for surgical repair of mitral regurgitation. Our genome-wide association study (GWAS) had identified 6 risk loci for MVP.
Hypothesis: Stringent statistical thresholds set in GWAS may exclude genuinely associated loci. Additional genetic predisposition loci and mechanisms for MVP may deserve follow-up among GWAS data.
Methods: We analyzed data from a meta-analysis of two GWAS (1412 MVP cases and 2439 controls) using the gene set enrichment method iGSEA4GWAS. We also investigated 355 suggestively associated SNPs (P<10-6) using the pathway and expression data sets integrative tool DEPICT to prioritize genes and gene-sets. We investigated the protein expression of GLIS1 by immunohistochemistry during valve development (E.13 and E.17) and in adult mice, and assessed atrioventricular (AV) regurgitation in zebrafish after Glis1 knockdown by morpholino oligonucleotides.
Results: We identified 5 enriched gene sets (P<10-4) involved in endothelial cell migration (e.g. GO:0043542), which is highly relevant to valve development. Twenty-six tissue types are enriched (FDR<0.05), including those involved in cardiovascular system. Interestingly, 13 loci were significantly highlighted (P<0.05), including previously described (SMG6, LMCD1 and PBX1) and one new (GLIS1) loci. In the GWAS data, GLIS1 highly associated with MVP risk (rs1879734: OR=1.30, P=7.1х10-6). Follow-up analyses indicate positive replication in 4 case control studies (~1400 cases and ~6400 controls, overall OR=1.23, P=1.2х10-7). iGSEA4GWAS showed GLIS1 is the best ranked gene in 8 enriched gene sets (FDR<0.05) involved in regulation of transcription. We found that Glis1 is expressed during valve morphogenesis in mice and maintained in the adult. Glis1 is detected in nuclei from endothelial and valvular interstitial cells. Knockdown of Glis1 in zebrafish resulted in significant AV valve defect with regurgitation.
Conclusions: Our study identifies GLIS1 is associated with MVP, and provide functional evidence for implicating this transcription factor family in valve development and pathology for the first time. The data also suggest several new candidate genes and pathways that deserve further investigation.
Author Disclosures: M. Yu: None. C. Dina: None. N. Tucker: None. F. Delling: None. S.A. Slaugenhaupt: None. R.A. Levine: None. A.A. Hagège: None. J. Schott: None. X. Jeunemaitre: None. D. Milan: None. R. Norris: None. N. Bouatia-Naji: None.
- © 2016 by American Heart Association, Inc.