Bidirectional Mendelian randomisation reveals genetic associations between cancer and epilepsy subtypes

Observational studies indicate a bidirectional association between epilepsy and cancer, yet causal insight remains limited. This study employed bidirectional Mendelian randomisation (MR) to investigate their potential complex genetic connections. Genome-wide association study (GWAS) summary data for epilepsies (all-type [AE], generalized [GE], focal [FE]) and 15 cancers were sourced from IEU Open GWAS. Single-nucleotide polymorphisms (SNPs) at genome-wide significance (P < 5e-8 or 5e-6) served as instruments. Expression quantitative trait locus (eQTL) analyses explored mediating pathways. Sensitivity analyses included Cochran’s Q and MR-PRESSO. Forward MR linked esophageal adenocarcinoma and neuroblastoma to AE; breast, lung, and invasive mucinous ovarian cancers to GE; esophageal adenocarcinoma, neuroblastoma, and mucinous ovarian cancer to FE. Reverse MR suggested that genetic liability to all three epilepsy subtypes was significantly associated with a higher risk of lung cancer. eQTL analysis implicated iroquois homeobox 3 (IRX3), colony-stimulating factor 1 receptor (CSF1R), and Fibrillin-2 (FBN2) as shared genetic mechanisms, suggesting roles in metabolic reprogramming, inflammation, and extracellular matrix remodeling. This study supports a bidirectional genetic association between specific cancers and epilepsy subtypes, which is likely driven by shared genetic mechanisms.