Genetic Risk Factors for Intracerebral Hemorrhage in Populations of East Asian Ancestry

Spontaneous intracerebral hemorrhage (ICH) is a devastating neurologic emergency with high mortality. The distribution of ICH subtypes differs by ancestry, with lobar ICH more prevalent in individuals of European ancestry and deep ICH more common in populations of East Asian ancestry, potentially reflecting distinct genetic predispositions. However, the genetic basis of ICH in populations of East Asian ancestry remains underexplored, partly due to the limited availability of large, ancestry-specific cohorts with adequate genomic data.

We conducted a genome-wide association study meta-analysis including 3,375 ICH cases and 334,926 controls of East Asian ancestry, integrating cohorts from Taiwan and Biobank Japan. Owing to the lack of imaging data, ICH case identification relied on validated International Classification of Diseases coding algorithms. To prioritize genetic signals, we used functional annotation, transcriptome-wide association (TWAS), and gene-based methods.

We identified 2 novel ICH-associated loci with a genome-wide significance (p < 5 × 10^-8) at 4q21.1 and 12q24.13 genomic regions. Gene prioritization and functional annotation highlight fibroblast growth factor 5 (FGF5) at 4q21.1 and HECTD4 at 12q24.13, both previously implicated in blood pressure regulation, a key risk factor for ICH. Furthermore, the TWAS revealed an ICH-associated FGF5 gene expressions in the kidney cortex, suggesting potential vascular pathways in disease risk. These key findings remained robust in sensitivity analyses adjusting for population structure and clinical covariates. We also identified associations of PRDM8, BMP3, and ABO with ICH, although the evidence for their contribution to risk was less compelling.

Our findings highlight novel genetic risk loci for ICH in populations of East Asian ancestry and suggest shared vascular mechanisms, including hypertension-related pathways. While imaging-based subtyping was not feasible in this data set, these results lay the groundwork for future studies integrating neuroimaging, replication cohorts, and functional validation.