Mengyao Yu1, Sergiy Kyryachenko1, Stephanie Debette2,3, Philippe Amouyel4, Jean-Jacques Schott5, Thierry Le Tourneau5, Christian Dina5, Russell A Norris6,7, Albert A Hagège8, Xavier Jeunemaitre1, Nabila Bouatia-Naji1. 1. PARCC, Inserm, Université de Paris, F-75015, Paris, France (M.Y., S.K., X.J., N.B.-N.). 2. Bordeaux Population Health Research Center, Inserm Center U1219, University of Bordeaux, France (S.D.). 3. Department of Neurology, Bordeaux University Hospital, Inserm U1219, France (S.D.). 4. University of Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1167 - RID-AGE - Labex DISTALZ - Risk Factors and Molecular Determinants of Aging-Related Disease, Lille, France (P.A.). 5. Université de Nantes, INSERM, CNRS, CHU Nantes, l'institut du thorax, F-44000, France (J.-J.S., T.L.T., C.D.). 6. Department of Regenerative Medicine and Cell Biology (R.A.N.), Medical University of South Carolina, Charleston, SC. 7. Department of Medicine (R.A.N.), Medical University of South Carolina, Charleston, SC. 8. Assistance Publique - Hôpitaux de Paris, Department of Cardiology, Hôpital Européen Georges Pompidou, France (A.A.H.).
Abstract
BACKGROUND: Mitral valve prolapse (MVP) is a common cardiac valve disease, which affects 1 in 40 in the general population. Previous genome-wide association study has identified 6 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 data set from the UK Biobank. METHODS: We also incorporated 434 MVP cases and 4527 controls from the UK Biobank for discovery analyses. Genetic association was conducted using SNPTEST and meta-analyses using METAL. We used Functional Mapping and Annotation of Genome-Wide Association Studies for post-genome-wide association study annotations and Multi-marker Analysis of GenoMic Annotation for gene-based and gene-set analyses. RESULTS: We found Trans-Omics for Precision Medicine imputation to perform better in terms of accuracy in the lower ranges of minor allele frequency below 0.1. Our updated meta-analysis included UK Biobank study for ≈8 million common single-nucleotide polymorphisms (minor allele frequency >0.01) and replicated the association on Chr2 as the top association signal near TNS1. We identified an additional risk locus on Chr1 (SYT2) and 2 suggestive risk loci on chr8 (MSRA) and chr19 (FBXO46), all driven by common variants. Gene-based association using Multi-marker Analysis of GenoMic Annotation revealed 6 risk genes for MVP with pronounced expression levels in cardiovascular tissues, especially the heart and globally part of enriched GO terms related to cardiac development. CONCLUSIONS: We report an updated meta-analysis genome-wide association study 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.
BACKGROUND: Mitral valve prolapse (MVP) is a common cardiac valve disease, which affects 1 in 40 in the general population. Previous genome-wide association study has identified 6 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 data set from the UK Biobank. METHODS: We also incorporated 434 MVP cases and 4527 controls from the UK Biobank for discovery analyses. Genetic association was conducted using SNPTEST and meta-analyses using METAL. We used Functional Mapping and Annotation of Genome-Wide Association Studies for post-genome-wide association study annotations and Multi-marker Analysis of GenoMic Annotation for gene-based and gene-set analyses. RESULTS: We found Trans-Omics for Precision Medicine imputation to perform better in terms of accuracy in the lower ranges of minor allele frequency below 0.1. Our updated meta-analysis included UK Biobank study for ≈8 million common single-nucleotide polymorphisms (minor allele frequency >0.01) and replicated the association on Chr2 as the top association signal near TNS1. We identified an additional risk locus on Chr1 (SYT2) and 2 suggestive risk loci on chr8 (MSRA) and chr19 (FBXO46), all driven by common variants. Gene-based association using Multi-marker Analysis of GenoMic Annotation revealed 6 risk genes for MVP with pronounced expression levels in cardiovascular tissues, especially the heart and globally part of enriched GO terms related to cardiac development. CONCLUSIONS: We report an updated meta-analysis genome-wide association study 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.
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