Abstract
BACKGROUND: Blood lipid levels are linked to stroke risk, but the genetic correlation between blood lipids and stroke is not well understood. We investigated the shared genetic architecture between blood lipids and stroke, including its subtypes, identifying common risk loci, genes, and underlying genetic mechanisms. METHODS: Utilizing large-scale genome-wide association study (GWAS) summary data, we identified genetic overlap between blood lipid levels and stroke. Cross-trait pleiotropic analysis was conducted to detect shared pleiotropic loci and genes. The statistical methods employed encompassed linkage disequilibrium score regression (LDSC), stratified-LDSC (s-LDSC), heritability estimation from summary statistics (rho-HESS), pleiotropic analysis under composite null hypothesis (PLACO), cross-trait meta-analyses, colocalization analysis, multi-marker analysis of genomic annotation (MAGMA), tissue-specific enrichment analysis (TSEA), and transcriptome-wide association studies (TWASs). Bidirectional Mendelian randomization (MR) analysis was employed to explore causal associations. RESULTS: Our research highlights the shared genetic mechanisms between stroke and blood lipid levels. We identified 147 pleiotropic loci at a genome-wide significance level (P < 5 × 10(–8)). Further gene-level analysis identified 10 unique pleiotropic genes shared by stroke and lipid traits, including CUX2, SH2B3, and ICA1L. Cross-trait meta-analysis identified 28 loci, with colocalization analysis revealing two unique pleiotropic genes, PPTPN11 and SH2B3, significantly enriched in adipose, musculoskeletal, and brain tissues. Two-sample MR analysis indicated that higher HDL-C levels were associated with reduced risks of stroke and IS, while elevated TG levels increased IS risk. In a transcriptome-wide association study, we identified one previously unreported pleiotropic gene (ALDH2). CONCLUSIONS: Our research revealed a common genetic architecture between stroke and blood lipid levels, highlighting potential genetic pathways involved in both conditions. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40246-025-00789-8.