High-Risk Genes for Familial Hemiplegic Migraine Do Not Elevate Epilepsy Risk, Study Shows

Christian Staehr, MD, PhD

A large-scale whole-exome sequencing study of nearly 500,000 individuals showed that missense and protein-truncating variants in familial hemiplegic migraine (FHM)-associated genes were associated with increased risk of migraine but not epilepsy. Notably, homozygous carriers of neutral SCN1A variants were also associated with migraine but these carriers showed a reduced disease risk of epilepsy, suggesting a potential role for SCN1A in more common types of migraine.¹

Coming into the study, it had been known that FHM types 1-3 were associated with protein-altering genetic variants in CACNA1A, ATP1A2, and SCN1A, respectively. Using data from the UK Biobank, the study included 454,706 individuals who had whole exome sequence data available, 6065 of whom had at least 1 epilepsy ICD-10 code and, among them, 2691 had reported they had epilepsy in the questionnaire. Overall, there were many more patients who self-reported migraine (n = 16,621) than had an inpatient ICD-10 code of any migraine diagnosis (n = 6492).

Led by Christian Staehr, MD, PhD, a medical doctor in the Department of Biomedicine at Aarhus University, carriers were compared with non-carriers in a burden analysis using logistic regression while accounting for age, biological sex, and UK Biobank assessment center. For each FHM gene, 3 different genetic scenarios were defined: (1) all missense and protein-truncating variants subdivided according to their predicted gain-of-function (GoF), loss-of-function (LoF) or neurtral effects based on LoGoFunc, a machine learning approach developed to explicitly predict pathogenicity; (2) missense or LoF variants that have been associated with FHM in ClinVar; and (3) FHM-associated variants that were reported in ClinVar as pathogenic, likely pathogenic or pathogenic/likely pathogenic using the American College of Medical Genetics and Genomics (ACMG) classification.

Analysis of the CACNA1A gene identified 4128 sequence variants, including 1423 missense and 125 protein-truncating variants. Heterozygous GoF variants were associated with an increased risk of self-reported migraine, while LoF and neutral variants showed no such association. Carrier frequencies varied significantly, with 0.2% of the cohort carrying GoF variants and higher frequencies for LoF and neutral variants (43.3% and 26.5%, respectively). No homozygous GoF carriers were detected, and homozygous LoF and neutral carriers were present in small numbers, with no significant link to migraine with aura after corrections.

Additionally, 22 CACNA1A variants linked to FHM were identified, but most showed no association with migraine or epilepsy. However, five pathogenic or likely pathogenic FHM-associated variants were linked to an increased risk of diagnosed migraine with aura and unspecified migraine, highlighting the need for further study of rare pathogenic variants in migraine risk.

READ MORE: Combination of Zavegepant and Sumatriptan Considered a Safe Combination With Stable Pharmacokinetics

An analysis of the ATP1A2 gene, associated with FHM type 2, identified 2221 sequence variants, including 424 missense and 50 protein-truncating variants. Among the cohort, 1.8% were heterozygous carriers of at least one variant, with most classified as LoF or neutral, and only 3 as GoF. LoF variant carriers showed an increased risk of self-reported migraine, while GoF and neutral variants had no association. Homozygous carriers of neutral or LoF variants were rare and showed no link to migraine or epilepsy.

Of 135 ATP1A2 variants previously reported in ClinVar as associated with FHM, no significant association with migraine or epilepsy was found. However, when focusing on 13 pathogenic/likely pathogenic variants, an increased risk of self-reported migraine was observed, though no association with epilepsy was detected. These findings suggest that while ATP1A2 variants may contribute to migraine risk, the effect is primarily associated with pathogenic or LoF variants.

The analysis of the SCN1A gene identified 1,999 variants, including 796 missense and 18 protein-truncating variants, with most classified as neutral or GoF and only 3 as LoF. Neutral variants were the primary drivers of associations with migraine, as heterozygous carriers had an increased risk of self-reported migraine, while homozygous carriers showed an increased risk of diagnosed unspecified migraine. GoF variants were not associated with increased migraine risk, and no homozygous LoF carriers were identified.

Homozygous carriers of SCN1A variants also showed a reduced risk of diagnosed unspecified epilepsy, driven by neutral variants, with no link to generalized idiopathic epilepsy. Among 31 ClinVar-reported variants, heterozygous carriers had an increased risk of self-reported migraine, and homozygous carriers were linked to a higher risk of diagnosed unspecified migraine but a lower risk of unspecified epilepsy. Only one variant was classified as pathogenic, with no observed associations with migraine or epilepsy.

"The findings provide valuable insights into the genetic component of migraine, highlighting the potential role of FHM-related genes in broader migraine phenotypes," the study authors wrote. "By identifying associations between specific genetic variants and migraine, this research enhances our understanding of the genetic underpinnings of the disorder. These insights have the potential to inform future diagnostic tools and treatment strategies. Understanding mutation-related alterations in protein function can catalyze research into novel treatment paradigms, driving innovation in migraine medicine."

Staehr et al added, "The future development of this research will require a more detailed categorization of diagnoses that may be linked to the FHM-related mutations. It is crucial to establish clear connections between specific genetic changes and their functional impacts on the pathogenicity of migraine and related disorders. Although these initial mechanistic insights may be derived from experimental models, it is essential to consider these findings in the context of multicellular organisms and validate them in future studies within a polygenic environment similar to that of our current study."

REFERENCE
1. Staehr C, Nyegaard M, Matchkov VV, et al. Exploring the association between familial hemiplegic migraine genes (CACNA1A, ATP1A2 and SCN1A) with migraine and epilepsy: A UK Biobank exome-wide association study. Cephalalgia. Published online January 9, 2025. doi:10.1177/03331024241306103