The “maternal effect” on epilepsy risk: Analysis of familial epilepsies and reassessment of prior evidence

Abstract

Objective Previous studies have observed that epilepsy risk is higher among offspring of affected women than offspring of affected men. We tested whether this “maternal effect” was present in familial epilepsies, which are enriched for genetic factors that contribute to epilepsy risk. Methods We assessed evidence of a maternal effect in a cohort of families containing ≥3 persons with epilepsy using 3 methods: (1) “downward‐looking” analysis, comparing the rate of epilepsy in offspring of affected women versus men; (2) “upward‐looking” analysis, comparing the rate of epilepsy among mothers versus fathers of affected individuals; and (3) lineage analysis, comparing the proportion of affected individuals with family history of epilepsy on the maternal versus paternal side. Results Downward‐looking analysis revealed no difference in epilepsy rates among offspring of affected mothers versus fathers (prevalence ratio = 1.0, 95% confidence interval [CI] = 0.8–1.2). Upward‐looking analysis revealed more affected mothers than affected fathers; this effect was similar for affected and unaffected sibships (odds ratio = 0.8, 95% CI = 0.5–1.2) and was explained by a combination of differential fertility and participation rates. Lineage analysis revealed no significant difference in the likelihood of maternal versus paternal family history of epilepsy. Interpretation We found no evidence of a maternal effect on epilepsy risk in this familial epilepsy cohort. Confounding sex imbalances can create the appearance of a maternal effect in upward‐looking analyses and may have impacted prior studies. We discuss possible explanations for the lack of evidence, in familial epilepsies, of the maternal effect observed in population‐based studies. ANN NEUROL 2020;87:132–138

Epilepsy risk in offspring of affected parents; a cohort study of the “maternal effect” in epilepsy

“…The findings from this large population‐based study showed a clear maternal effect in epilepsy, thereby confirming the results of previous population‐based studies. This study also provides the first evidence that the maternal effect may extend to familial epilepsies, but the paradox of the absence of a maternal effect in selected high density families 9 remains unexplained.…”

“…In two recent studies of multiplex families, 9,10 there was no evidence of a maternal effect, suggesting that the distribution of causal genetic and non‐genetic factors may differ between sporadic and familial epilepsies. However, these studies were based on highly selected populations.…”

“…Possible explanations for the maternal effect have been discussed extensively over the past few decades, 8,9,24 but none of them fully explains the finding. We found maternal effects in other brain disorders, such as migraine, schizophrenia and cerebral palsy, but in none of these disorders was the effect as pronounced as in epilepsy.…”

“…Previous studies of the maternal effect in epilepsy have commonly applied either a “downward‐looking” or an “upward‐looking” analysis strategy 9 . The downward‐looking analysis examines the risk of epilepsy in offspring of affected mothers compared to offspring of affected fathers, while the upward‐looking analysis examines the risk of having an affected mother compared to having an affected father among affected children.…”

“…In those studies, the risk of unprovoked seizures in the offspring was approximately twofold higher if the affected parent was the mother than if the affected parent was the father 5 . However, two recent studies restricted to familial epilepsies did not replicate the finding 9,10 . In attempts to resolve this apparent inconsistency, we assessed the association between parental and offspring epilepsy in a study of all children born in Denmark over a 35‐year period.…”