Familial Liability to Epilepsy and Attention-Deficit/Hyperactivity Disorder: A Nationwide Cohort Study

Abstract

Background: Epilepsy and attention-deficit/hyperactivity disorder (ADHD) are strongly associated; however, the underlying factors contributing to their co-occurrence remain unclear. A shared genetic liability has been proposed as one possible mechanism. Therefore, our goal in this study was to investigate the familial coaggregation of epilepsy and ADHD and to estimate the contribution of genetic and environmental risk factors to their co-occurrence.

Methods: We identified 1,899,654 individuals born between 1987 and 2006 via national Swedish registers and linked each individual to his or her biological relatives. We used logistic regression to estimate the association between epilepsy and ADHD within individual and across relatives. Quantitative genetic modeling was used to decompose the cross-disorder covariance into genetic and environmental factors.

Results: Individuals with epilepsy had a statistically significant increased risk of ADHD (odds ratio [OR] = 3.47, 95% confidence interval [CI] = 3.33-3.62). This risk increase extended to children whose mothers had epilepsy (OR = 1.85, 95% CI = 1.75-1.96), children whose fathers had epilepsy (OR = 1.64, 95% CI = 1.54-1.74), full siblings (OR = 1.56, 95% CI = 1.46-1.67), maternal half siblings (OR = 1.28, 95% CI = 1.14-1.43), paternal half siblings (OR = 1.10, 95% CI = 0.96-1.25), and cousins (OR = 1.15, 95% CI = 1.10-1.20). The genetic correlation was 0.21 (95% CI = 0.02-0.40) and explained 40% of the phenotypic correlation between epilepsy and ADHD, with the remaining variance largely explained by nonshared environmental factors (49%, nonshared environmental correlation = 0.36, 95% CI = 0.23-0.49). The contribution of shared environmental factors to the cross-disorder overlap was not statistically significant (11%, shared environmental correlation = 0.32, 95% CI = -0.16-0.79).

Conclusions: This study demonstrates a strong and etiologically complex association between epilepsy and ADHD, with shared familial factors and risk factors unique to the individual contributing to co-occurrence of the disorders. Our findings suggest that epilepsy and ADHD may share less genetic risk as compared with other neurodevelopmental disorders.

Keywords: ADHD; Comorbidity; Epilepsy; Genetics; Neurodevelopment; Risk factors.

Figure 1

Within-individual and family level co-aggregation of ADHD and epilepsy. Odds ratios (OR) represent the association between ADHD and epilepsy, within-individual, and across different types of relatives. ORs are adjusted for birth year and sex and presented together with 95% confidence intervals.

Figure 2

Path estimates for the bivariate ACE model presented for one sibling only Rectangles represent the liability for ADHD and epilepsy and are fixed at a variance of 1. Circles represent latent additive genetic (A), shared environmental (C) and non-shared environmental (E) factors. Each latent variable has a variance of 1. Values within the square root sign are the squared path estimates and represent the percentage of variance accounted for by the A, C and E parameter for each trait. Curved double-headed arrows refer to the correlations between A (rG), C (rC) and E (rE) across ADHD and epilepsy. 95% confidence intervals are presented in parentheses.