整合 post-GWAS 功能基因组学分析细化心肌梗死遗传结构
Refining the Genetic Architecture of Myocardial Infarction Through Integrative Post-GWAS Functional Genomics Analysis
一项整合 post-GWAS 功能基因组学证据的分析细化了心肌梗死的遗传结构，在 Million Veteran Program 与 UK Biobank 的荟萃分析（62,129 例病例、828,364 例对照）中识别出 135 个全基因组显著风险位点，其中 5 个可能为新位点。基于基因的分析得到 333 个显著基因，fine-mapping 优先排序出 613 个高置信度变异，贝叶斯共定位在 25 个合格位点上识别出 39 个显著基因–组织信号。
来源：Bioinformatics Advances · doi.org
Motivation
Myocardial infarction is a leading cause of death worldwide and has a strong genetic component. Genome-wide association studies have identified many associated loci, but the genes and variants through which most of them act remain unclear. We aimed to refine the genetic architecture of myocardial infarction by integrating complementary post-association evidence.
Results
A meta-analysis of the Million Veteran Program and UK Biobank (62,129 cases and 828,364 controls) identified 135 genome-wide significant risk loci, five of them potentially novel. Gene-based analysis yielded 333 significant genes, fine-mapping prioritized 613 high-confidence variants, and Bayesian colocalization identified 39 significant gene–tissue signals across 25 eligible loci. Combining all evidence highlighted ten high-confidence candidate genes, including PHACTR1 and SLC22A3, with enrichment for lipid metabolism, mitogen-activated protein kinase signaling, angiogenesis and chromatin remodeling. Repeating the pipeline with a stricter allele frequency threshold retained 129 loci and full support for eight of the ten genes.
Availability and implementation
Input summary statistics are publicly available from the European Bioinformatics Institute genome-wide association study catalog (accessions GCST90475932 and GCST90473536); derived results are provided in the supplementary data.