BACKGROUND: The causal relationship between brain structures and epilepsy remains unclear. This study integrates genomic and neuroimaging data to bridge the gap between epilepsy genetics and brain imaging, supporting advances in precision medicine. METHODS: We employed a comprehensive pipeline-including Mendelian randomization (MR), linkage disequilibrium score regression (LDSC), co-localization, and multi-gene enrichment analysis-to investigate the causal effects of brain regions and fiber tracts across ten epilepsy subtypes. RESULTS: Our analysis identified 93 structural phenotypes with evidence of causal effects on epilepsy. Among these, 15 demonstrated robust support for co-localization, highlighting five key SNPs: rs2471738 (MAPT), rs6719550 (CALCRL), rs8044158 (HAS3), rs10276111 (CPED1), and rs11944081 (RAPGEF2). Specifically, increased isthmus cingulate volume was associated with a 24% lower risk of childhood absence epilepsy, while HAS3-linked olfactory cortical thickness was associated with higher juvenile myoclonic epilepsy risk. Findings regarding the cingulate gyrus suggest its role in the cognitive and emotional integration deficits observed in patients. CONCLUSIONS: This study establishes an epilepsy neuroimaging genetic map, providing a framework for predicting epilepsy risk through functional brain phenotypes. Our results highlight inflammation-related gene loci as potential therapeutic targets and offer new insights into the causal links between brain microstructure and epilepsy.
Peng et al. (Fri,) studied this question.