Refining the Genetic Architecture of Myocardial Infarction Through Integrative Post-GWAS Functional Genomics Analysis

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.