Shared Genetic Basis and Causality Between Epilepsy and Psychiatric Disorders: Evidence From a Comprehensive Genetic...

Growing evidence suggests that epilepsy and psychiatric disorders may share common genetic underpinnings, yet the precise etiological relationship remains unclear. Psychiatric comorbidities affect approximately 30% of individuals with epilepsy, a rate markedly higher than in the general population, with depression (∼23%) and anxiety (∼20%) being the most prevalent. This high comorbidity burden not only worsens prognosis but also complicates management, underscoring the need for genetic insights into their relationship. To address this gap, we aimed to systematically evaluate the genetic correlation, pleiotropy, and potential causal associations between epilepsy and 14 major psychiatric disorders.

We analyzed N million single-nucleotide polymorphisms (SNPs) from genome-wide association study (GWAS) summary statistics of epilepsy and 14 psychiatric disorders. These GWAS data were obtained from large international consortia, primarily comprising individuals of European ancestry. First, we assessed the genetic correlation between epilepsy and 14 psychiatric disorders using Linkage Disequilibrium Score Regression (LDSC). Second, we used Pleiotropic Analysis under the Composite Null Hypothesis (PLACO) to identify pleiotropic loci at the SNP level. Summary genotype-phenotype association statistics were used, excluding SNPs with extreme Z² values (>80), and testing for pleiotropy with the Inverse-Variance Weighted (IVW) method. For gene-level pleiotropy, we conducted genome annotation multi-marker analysis (MAGMA v.1.07b). This analysis aggregated SNP-level associations into gene-level signals, focusing on 18,563 protein-coding genes on autosomes. Gene positions were obtained from the Ensembl build (GRCh37) and 1000G EUR data. Functional mapping and annotation of pleiotropic loci were performed using Functional Mapping and Annotation (FUMA). Finally, the bidirectional Mendelian randomization (MR) method was used to investigate causal correlations between epilepsy and 14 psychiatric disorders.

We identified a significant genetic link between epilepsy and attention deficit and hyperactivity disorder (ADHD) (r_g = 0.252, P < 0.001), between epilepsy and schizophrenia (SCZ) (r_g = -0.060, p = 0.003), and between epilepsy and major depressive disorder (MDD) (r_g = 0.167, p = 0.014). The genetic correlation between epilepsy and ADHD, epilepsy, and SCZ passed the Bonferroni correction (0.05/14 = 0.0035). Nine shared genetic loci and six pleiotropic genes, including SCN1A, PGBD1, ZKSCAN3, ZKSCAN4, VRK2, and ZSCAN23, have been identified between epilepsy and psychiatric disorders. Furthermore, these loci and genes mainly involve the MAPK signaling pathway. MR analysis showed ADHD (OR = 1.097, 95% CI: 1.019-1.180, p = 0.014) and MDD (OR = 1.277, 95% CI 1.114-1.463, p = 0.000) are the risk factors for epilepsy. BIP is the protecting factor against epilepsy (OR = 0.930, 95% CI: 0.878-0.986, p = 0.014). The causality between MDD and epilepsy passed the Bonferroni correction (0.05/14 = 0.0035).

SCZ, ADHD, MDD and epilepsy may share a common etiology, respectively. These etiologies may be related to precise molecular mechanisms, leading to overlapping pathological physiology and clinical features. These findings may offer insights into treatment trials.