Investigating the shared genetic architecture between type 2 diabetes and stroke

Abstract

Individuals with type 2 diabetes (T2D) have an approximately two-fold higher risk of stroke compared to those without diabetes. However, the genetic relationships and biological mechanisms underlying T2D and stroke remain incompletely understood. This study aims to explore the shared genetic architecture and causal relationships of T2D and stroke using large-scale genome-wide association study (GWAS) datasets. We observed a significant causal genetic overlap ([~]900 variants) and global genetic correlation between T2D and stroke (rG = 0.35, P = 3.5 x 10-24). We identified a significant genetic causal association of T2D, independent from its confounders such as coronary artery disease, BMI, and educational attainment, on the stroke risk. This causal association was not affected by reverse causations. A cross-trait meta-analysis and functional annotation revealed 76 independent SNPs, of which 19 were lead SNPs with genome-wide significance (P-value 0.01) where seven genes were found overlapping between T2D and stroke; of which SREBF1, LTBP3, FAM234A, PABPC4, and RMC1 were novel for stroke. Pathway-based functional enrichment analyses identified critical pathways, including regulation of autophagy, negative regulation of insulin secretion, and positive regulation of cholesterol biosynthetic process, as shared molecular targets. Overall, the findings of this study provide novel risk loci, causal genes, and pathways shared between T2D and stroke, suggesting molecular targets for these co-occurring diseases.