Bidirectional causal relationships between epilepsy subtypes and psychiatric disorders: A two-sample mendelian...

Epilepsy is frequently accompanied by psychiatric disorders in observational studies, but the causal direction and subtype-specific associations remain unclear.

To examine causal relationships between 10 epilepsy subtypes and 17 psychiatric disorders using a bidirectional two-sample Mendelian randomization (MR) analysis.

Genetic instruments were derived from large-scale genome-wide association studies (GWAS) of epilepsy and psychiatric traits. The inverse variance weighted (IVW) method was the primary approach, complemented by sensitivity analyses including maximum likelihood, MR-Egger regression, weighted median, weighted mode, and IVW under a fixed effect.

Epilepsy subtypes exerted heterogeneous effects on psychiatric risk. Focal epilepsy increased the risk of anorexia nervosa, major depressive disorder, and obsessive-compulsive disorder, whereas juvenile absence epilepsy reduced the risk of schizophrenia and other phobias. In contrast, focal epilepsy with hippocampal sclerosis increased risk of attention deficit hyperactivity disorder (ADHD) but reduced risk of suicide attempt. Conversely, psychiatric traits also influenced epilepsy risk. ADHD increased susceptibility to overall epilepsy, generalized epilepsy, and juvenile absence epilepsy, while obsessive-compulsive disorder reduced risk of childhood absence epilepsy but increased risk of juvenile myoclonic epilepsy. Most findings were consistent across sensitivity analyses without evidence of pleiotropy.

This comprehensive bidirectional MR analysis demonstrates that epilepsy and psychiatric disorders are linked by complex and subtype-specific causal pathways, highlighting shared neurobiological mechanisms and underscoring the need for integrated neuropsychiatric care. Identifying these causal relationships provides a foundation for precision medicine approaches in the prevention and management of comorbid epilepsy and psychiatric disorders.