Potential circadian rhythm-related pathogenic genes in coronary artery disease: a Mendelian randomization study

PURPOSE: Coronary artery disease (CAD) is a leading cause of cardiovascular morbidity and mortality worldwide. Recent studies suggest disruptions in circadian rhythms may contribute to CAD, but the underlying mechanisms remain unclear. This study employs summary-data-based Mendelian randomization to explore the roles of circadian rhythm genes in CAD and their clinical implications. METHODS: We retrieved circadian rhythm-related genes from the GeneCards database and utilized genome-wide association study summary data for CAD from the IEU database, further validated with FinnGen and UK Biobank datasets. We integrated expression quantitative trait loci (eQTL), methylation quantitative trait loci (mQTL), and protein abundance quantitative trait loci (pQTL) data to assess causal associations with CAD. Colocalization analysis confirmed that the signals originated from the same genetic variants. RESULTS: Our analyses identified 49 mQTLs, 11 eQTLs, and one pQTL causally associated with CAD. Integration of mQTL and eQTL data revealed 13 methylation sites and eight key genes, particularly RASD1 (OR = 0.777, 95% CI: 0.672-0.898) and SREBF1 (OR = 0.893, 95% CI: 0.844-0.946). The DNA methylation level at site cg20122488 was negatively correlated with RASD1 expression, while eQTL data for SREBF1 indicated a regulatory relationship with CAD risk. CONCLUSIONS: This study emphasizes the significant roles of circadian rhythm genes RASD1 and SREBF1 in CAD pathogenesis. Findings suggest therapeutic potential for these genes, warranting further research to validate their functions and inform preventive and treatment strategies. Key messages What is already known Coronary artery disease (CAD) is a leading global cause of cardiovascular mortality, with circadian rhythm disruptions increasingly implicated in its pathogenesis, though causal genetic mechanisms remain unclear. What this study adds This Mendelian randomization study identifies 13 methylation sites and eight key circadian-related genes (e.g. RASD1, SREBF1) with causal links to CAD, revealing specific epigenetic and transcriptional regulatory effects on disease risk. How this study might affect research, practice, or policy The findings highlight circadian rhythm genes as potential therapeutic targets, offering novel insights for CAD prevention strategies and guiding future research into circadian-based interventions.