Causal cues and mediating pathways of potential genetic mechanisms of subarachnoid hemorrhage and intracerebral hemorrhage

Subarachnoid hemorrhage (SAH) and intracerebral hemorrhage (ICH) are the primary subtypes of hemorrhagic stroke. Obesity and dietary factors may play significant roles in their pathogenesis, yet the genetic causal relationships and potential mediating pathways remain unclear. This study utilized publicly available genome-wide association study databases and applied Mendelian randomization (MR) methods to systematically evaluate the causal associations between obesity, nutritional intake (fats, proteins, and carbohydrates), alcohol intake, and both SAH and ICH. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were conducted on the genes associated with significant risk factors to explore potential biological pathways and mediating factors. Independent validation was performed using data from East Asian populations. MR analysis revealed positive causal relationships between obesity, alcohol intake, and nutritional intake with both SAH and ICH. Fat intake was identified as a significant risk factor for ICH, while protein intake was significantly associated with SAH. Validation results in East Asian populations were consistent with the primary analyses. Reverse MR analysis did not detect any reverse causal associations. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses indicated that genes associated with fat intake were enriched in the thiamin metabolism pathway, while those related to protein intake were enriched in immune and inflammatory pathways. Thiamine may mediate the relationship between fat intake and ICH, whereas uric acid may act as a mediator between protein intake and SAH. This study elucidated the potential genetic causal relationships between obesity, diet, alcohol consumption, and hemorrhagic stroke, highlighting thiamin and uric acid as potential key mediating factors. These findings provide a genetic basis and potential intervention targets for stroke prevention.