Shared Genetic Architecture and Pleiotropy Between Ischemic Stroke and Intracerebral Hemorrhage: An Integrative Genomic Analysis

Background: Epidemiological studies have reported the association between ischemic stroke (IS) and intracerebral hemorrhage (ICH). However, their shared genetic basis remains incompletely characterized. This study quantifies the genetic overlap between them. Methods: We analyzed European-ancestry GWAS summary statistics for IS and ICH. Genetic correlation was estimated using linkage disequilibrium score regression (LDSC), with local correlation assessed by SUPER GeNetic covariance Analyzer (SUPERGNOVA). Partitioned heritability was evaluated across 96 functional categories. Shared loci were identified through cross-trait meta-analysis and evaluated by Bayesian colocalization. Transcriptome-wide association analysis (TWAS) was performed to identify shared gene-expression associations. Bidirectional MR with multiple pleiotropy-robust methods was used to explore causality. Tissue type-specific analysis was performed to investigate shared tissue enrichment. Results: LDSC showed a significant positive genetic correlation between IS and ICH (rg = 0.57, p = 2.13 × 10−8). SUPERGNOVA identified significant local correlations at chromosomes 2q33 and 4q25. Partitioned heritability suggested shared genetic enrichment across five functional domains. Cross-trait analysis identified 25 candidate novel pleiotropic SNPs and strong colocalization at 1q22 (rs2736613 near PMF1). TWAS identified four overlapping genes between stroke subtypes, including FAM117B, ICA1L, NBEAL1, and WDR12, mainly located at 2q33. MR results suggested shared liability rather than direct causality. Tissue-specific analyses identified nominal enrichment signals, although none survived multiple-testing correction. Conclusions: Our findings support substantial shared genetic susceptibility between IS and ICH, likely reflecting pleiotropic mechanisms and shared vascular liability rather than a direct directional causal relationship. Further functional studies are needed to clarify the underlying biological mechanisms.