Shared genetics and causality underlying epilepsy and attention-deficit hyperactivity disorder

The prevalence of attention deficit hyperactivity disorder (ADHD) in patients with epilepsy was much higher than prevalence in general population, and vice versa. The mechanisms underlying comorbid ADHD and epilepsy remained largely unknown. Here, we systematically analyzed the genetic correlation, causality, shared genetics and specific trait related tissues by using linkage disequilibrium score regression (LDSC), two sample Mendelian randomization (TwoSampleMR), bivariate causal mixture model (MiXeR), conjunctional false discovery rate (conjFDR) and LDSC applied to specifically expressed genes based on genome wide association studies (GWASs) data of ADHD and epilepsy. We found that ADHD had significant positive genetic association with epilepsy. Two-sample Mendelian randomization analysis with genome wide significant single nucleotide polymorphisms (SNPs) as instrument variables suggested a positively causal effect of ADHD on epilepsy. Using MiXeR, which estimates the total amount of shared variants, we observed 1 K causal variants overlapped between ADHD and epilepsy. At conjFDR <0.05, ADHD shared 2 distinct genomic loci with Epilepsy. Further disease-relevant tissues analysis showed that cortex, substantia nigra, amygdala and hippocampus were both associated with ADHD and epilepsy. Our results suggested that ADHD was genetically correlated with epilepsy, which might be due to the fact that they shared common pathogenic sites and tissues origin.