Genetic link between metabolic syndrome and coronary artery disease: Insights from genome-wide cross-trait analysis

Metabolic syndromes (MeS), marked by central obesity, high blood pressure, abnormal cholesterol and blood sugar, are key cardiovascular disease (especially coronary artery disease, CAD) risk factors. Genetic studies show MeS-CAD genetic overlap, indicating shared biological pathways. We used Summary-data-based Mendelian Randomization (SMR), Bayesian colocalization (with large GWAS summary stats for MeS/CAD and cis-eQTL data from 3 tissues) and Transcriptome-Wide Association Study (TWAS). We also investigated the effects of gene knockout on mouse phenotypes. SMR found 886/737/192 shared genes in blood/brain cortex/liver; colocalization identified 11/13/5 shared causal genes in these tissues and 46 shared loci (e.g., CAMK1D, OR=1.11; AGPAT1, OR=1.13; FDR<0.05). Moreover, knocking out these genes in mice affected metabolism, adipose tissue, cardiovascular function, glucose homeostasis, and the fat/muscle balance. This study identified common regulatory genes between MeS and CAD, suggesting that targeted therapies or interventions could potentially address both conditions simultaneously, offering prospects for more integrated treatment strategies.