Exploring the association between familial hemiplegic migraine genes (, and ) with migraine and epilepsy: A UK Biobank exome-wide association study.

Background: Familial hemiplegic migraine (FHM) types 1-3 are associated with protein-altering genetic variants in , and , respectively. These genes have also been linked to epilepsy. Previous studies primarily focused on phenotypes, examining genetic variants in individuals with characteristic FHM symptoms. This study aimed to investigate the association of FHM genetic variation with migraine and epilepsy, utilizing a genotype-first approach.

Methods: Whole-exome sequence data from 454,706 individuals from the UK Biobank were examined for self-reported and inpatient-diagnosed migraine and epilepsy. Carriers were compared with non-carriers in a burden analysis using logistic regression while accounting for age, biological sex and UK Biobank assessment center. A machine learning-based approach was employed to predict whether variants resulted in gain-of-function (GoF), loss-of-function (LoF) or neutral effects.

Results: Heterozygous carriers of GoF variants, LoF variants or neutral variants were at increased risk of migraine. Homozygous carriers of neutral variants were also associated with migraine but these carriers showed a reduced disease risk of epilepsy.

Conclusions: Heterozygous genotypes in all three FHM genes were associated with migraine but not epilepsy in this genotype-focused study. Homozygous genotypes also showed increased disease risk of migraine, yet these carriers were protected against epilepsy.