Risk of Epilepsy and Autism in Full- and Half-Siblings: A Population-Based Cohort Study

Background: Epilepsy and autism spectrum disorder (ASD) frequently co-occur in the same individual and they may share common etiological factors. The sibling recurrence risk in both ASD and epilepsy is higher than expected which suggests that genes or environmental factors shared by family members play an important causal role in each disorder. However, no studies have previously evaluated the cross-disorder sibling risk for ASD and epilepsy.

Objectives: In a large population-based study, estimate the cross-disorder sibling risk for epilepsy and ASD in full and half-siblings of children with these conditions.

Methods: The study population comprised all Danish births, 1 January 1980 through 31 December 2006, and followed through 2012 (N=1,663,302) for reported ASD (N=17,145), epilepsy (N=22,531), death or immigration. All births were linked to parents and full and half siblings born in the birth cohort. The oldest child in a sibling set defined the exposure for all younger siblings. We used Cox regression to calculate the adjusted hazard ratio (aHR; risk for ASD or epilepsy in younger sibling given older sibling diagnosis) and the Kaplan-Meier method to calculate the cumulative incidence. Cox models adjusted for child’s sex, parental age, and parental psychiatric or epilepsy history. Sensitivity analyses included analyses by birth year group, childhood autism specifically, epilepsy subtype, and considering intellectual disability in the younger sibling.

Results:  The aHR of epilepsy in younger siblings increased by 70% (aHR = 1.70 (95% CI: 1.34-2.16%)) if the older sibling had ASD (64 events) compared with siblings where the older sibling did not; the aHR was 4.56 if the older sibling had both disorders. The cumulative incidence of epilepsy at 20 years of age was 2.54% (95% CI: 1.97-2.32%) if the older sibling had ASD and 1.63% (95% CI: 1.60-1.66%) if the older sibling did not. The aHR of ASD in younger siblings increased by 54% if the older sibling had epilepsy (159 events; aHR = 1.54 (95% CI: 1.32-1.80)) compared with siblings where the older sibling did not; the aHR was 4.44 if the older sibling had both disorders. The cumulative incidence of ASD at 20 years of age was 2.06% (95% CI: 1.84-2.32%) if the older sibling had epilepsy and 1.27% (95% CI: 1.25-1.29%) if the older sibling did not. Cross-disorder risks were increased in both full and half siblings. Similar results were found considering cross-disorder risk between epilepsy and autistic disorder; after excluding younger siblings with intellectual disability; and by birth year group of older sibling. ASD risks in the younger sibling by epilepsy subtype in the older sibling were similar to overall results. Risks for epilepsy subtype in the younger sibling from an older sibling with ASD were somewhat lower than overall results and not statistically significant.

Conclusions: The cross-disorder sibling risks of epilepsy and ASD suggest that genes or environmental factors shared by family members may play a causal role in the co-occurrence of ASD and epilepsy. The results may also inform developmental follow-up practices for healthcare professionals and parents.