Genome-Wide Association Meta-Analysis Supports Genes Involved in Valve and Cardiac Development to Associate With Mitral Valve Prolapse.
Genome-Wide Association Meta-Analysis Supports Genes Involved in Valve and Cardiac Development to Associate With Mitral Valve Prolapse.
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DOI：
10.1161/circgen.120.003148
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发表时间：
2021-10
期刊：
影响因子：
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通讯作者：
Bouatia-Naji N
中科院分区：
文献类型：
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作者：
Yu M;Kyryachenko S;Debette S;Amouyel P;Schott JJ;Le Tourneau T;Dina C;Norris RA;Hagège AA;Jeunemaitre X;Bouatia-Naji N
二尖瓣脱垂 (MVP) 是一种常见的心脏瓣膜疾病，影响普通人群中四分之一的人。之前的 GWAS 已经确定了 MVP 的 6 个风险位点。但这些位点只能部分解释 MVP 的遗传风险。我们的目标是通过添加 UKBiobank 的数据集来确定 MVP 的其他风险位点。我们使用 HRC 和 TOPMed 小组重新分析了 MVP-France 研究中的 1007 个病例和 1469 个对照，以及 MVP-Nantes 研究中的 479 个病例和 862 个对照，进行基因型重新估算。我们还纳入了 UKBiobank 的 434 个 MVP 病例和 4,527 个对照进行发现分析。使用 SNPTEST 进行遗传关联并使用 METAL 进行荟萃分析。我们使用 FUMA 进行 GWAS 注释，使用 MAGMA 进行基于基因和基因集的分析。我们发现 TOPMed 插补在次要等位基因频率 (MAF) 低于 0.1 的较低范围内的准确性方面表现更好。我们更新的荟萃分析包括 UKBiobank 对约 800 万个常见 SNP (MAF>0.01) 的研究，并将 Chr2 上的关联复制为 TNS1 附近的顶级关联信号。我们在 Chr1 (SYT2) 上确定了一个额外的风险位点，在 Chr8 (MSRA) 和 chr19 (FBXO46) 上确定了两个提示性风险位点，所有这些都由常见变异驱动。使用 MAGMA 进行的基于基因的关联揭示了 MVP 的 6 个风险基因，它们在心血管组织（尤其是心脏）以及与心脏发育相关的丰富 GO 术语的整体部分中具有显着的表达水平。我们使用密集插补覆盖和改进的病例对照样本报告了更新的 MVP 荟萃分析 GWAS。我们描述了几个具有 MVP 的位点和基因，跨越了与 MVP 高度相关的生物机制，特别是在瓣膜和心脏发育期间。
Mitral valve prolapse (MVP) is a common cardiac valve disease, which affects 1 in 40 in the general population. Previous GWAS have identified six 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 dataset from the UKBiobank. We reanalyzed 1007 cases and 1469 controls from the MVP-France study and 479 cases and 862 controls from the MVP-Nantes study for genotype reimputation using HRC and TOPMed panels. We also incorporated 434 MVP cases and 4,527 controls from the UKBiobank for discovery analyses. Genetic association was conducted using SNPTEST and meta-analyses using METAL. We used FUMA for post-GWAS annotations and MAGMA for gene-based and gene-set analyses. We found TOPMed imputation to perform better in terms of accuracy in the lower ranges of minor allele frequency (MAF) below 0.1. Our updated meta-analysis included UKBiobank study for ~8 million common SNPs (MAF>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 two suggestive risk loci on chr8 (MSRA), and chr19 (FBXO46), all driven by common variants. Gene-based association using MAGMA revealed 6 risk genes for MVP with pronounced expression levels in cardiovascular tissues, especially heart and globally part of enriched GO terms related to cardiac development. We report an updated meta-analysis GWAS 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.