Causal relationship between hypertension and epilepsy mediated by diabetic retinopathy

Epilepsy is a brain condition with recurring seizures impacting millions globally. Accumulating evidences show that hypertension is one causative factor of epilepsy. This study uses Mendelian randomization (MR) to investigate the causal link between hypertension and epilepsy, and explore diabetic retinopathy’s mediating role in epilepsy pathogenesis. Based on Genome-wide association studies (GWAS) data of hypertension, epilepsy and diabetic retinopathy, we performed a two-step MR analysis to investigate the association between hypertension and epilepsy, as well as the role of diabetic retinopathy traits as mediators. The primary approach utilized for causal analysis is inverse variance weighting (IVW), with the addition of multiple sensitivity analyses to assess the reliability of MR outcomes. Subsequently, the causal relationship between hypertension and epilepsy was further corroborated through the analysis of an additional epilepsy GWAS database. This correlation was further supported by clinical data derived from patients with epilepsy in local hospitals. IVW analysis indicated hypertension is an etiological factor for epilepsy, raising its incidence (OR_IVW = 1.14, 95% CI = 1.06 - 1.22, P = 0.0003), with diabetic retinopathy mediating 11.5% of the genetic prediction. Validation analysis further confirmed the association (OR_IVW = 1.12, 95% CI = 1.04 - 1.20, P = 0.0027). Local hospital data showed 32.3% of patients with epilepsy had hypertension. Our MR analysis first reveals the causal effect between hypertension and epilepsy, with diabetic retinopathy acting as a key mediator. This enhances epilepsy etiology understanding and offers clues for better epilepsy intervention. • Utilizing mendelian randomization analysis, we revealed a causal effect between hypertension and epilepsy, indicating a positive association. • Our results further suggested that diabetic retinopathy may mediate this causal relationship. • Mechanistically, hypertension leaded to aberrant neuronal discharge through pathological alterations associated with diabetic retinopathy, such as the formation of inflammasomes, upregulation of cytokines, microvessel damage, and activation of the RAS, ultimately resulting in the onset of seizures.