Migraine fueled by a host of common genetic variants

The conflation of a myriad of common genetic risk variants underlies familial trends in migraine, according to new research published in Neuron.

“Both rare, high-impact and common genetic variants with smaller impact could contribute to the familial aggregation of migraine,” stated study author Maija Wessman, PhD, Institute of Genetics, Folkhälsan Research Center, Helsinki. “In this study, we wanted to find out which one is more important and whether the genetic load is higher in certain types of migraine.”

Experts have long observed that chronic disease aggregates in families, however, the basis for such aggregation has yet to be elucidated. To date, linkage studies have been somewhat successful in spotting highly penetrant disease variants; nevertheless, genetic loci determined by genome-wide association studies (GWAS) overlap infrequently with linkage peaks. Moreover, whole-exome sequencing (WES) and whole-genome sequencing (WGS) studies have been too low power to explain this observation.

Migraines are an example of a type of chronic disease that clumps in families, and because migraines are very common—affecting between 15% and 20% of adults in developed countries—this condition is ripe picking for familial aggregation studies leveraging large sample sizes.

An international consortium of researchers analyzed the medical histories and genetic data from 8,319 Finns representing 1,589 families. In addition to calculating migraine polygenic risk scores (PRSs) for these 8,319 subjects, the team also calculated PRSs for a control cohort comprising 14,470 individuals including 1,101 with migraine (ie, the FINRISK population cohort). Importantly, the team originally developed the PRS measure based on data from a previous GWAS, which involved hundreds—or even thousands—of genetic loci.

“We then used the migraine PRS to assess the relative polygenic load contributing to both prevalent subtypes of migraine (migraine without aura and migraine with typical aura), to the rare subtype [hemiplegic migraine] (HM), and to other available subtypes,” the researchers wrote.

Dr. Wessman and co-investigators also looked at the influence of three Mendelian migraine-linked genes involved in ion transport (CACNA1A, ATP1A2, and SCN1A). More specifically, these genes are tied to HM, a severe type of migraine resulting in stroke-like symptoms.

The investigators employed a logistic mixed model—which they adjusted for sex, age, and genetic relatedness—to determine an association between PRS (the continuous variable) and different migraine subtypes. They found that when compared with the control cohort “the burden of common migraine-associated variation, measured via the PRS, was enriched across all of the migraine subtypes in the family collection, including rare forms of the disease.”

“The polygenic burden was higher for MA compared to those individuals that do not suffer any migraine aura symptoms,” the authors wrote. Furthermore, the investigators found that if a subject’s migraines commenced at an earlier age or were more severe, the greater the likelihood that polygenic variants were to blame.

The accumulation of polygenic common variants mediated migraine far more than the three migraine-related Mendelian genes examined. Specifically, in only 4 of 45 families displaying HM, Mendelian genes were at work, with more HM families instead influenced by common polygenic variants.

“Our study supports the hypothesis that migraine subtypes are genetically heterogeneous diseases, and that common polygenic variation significantly contributes to the aggregation of the disease in families, both for common and rare migraine subtypes,” said corresponding author, Aarno Palotie, MD, PhD, Massachusetts General Hospital, Boston, MA.

"This really shows, in a very big sample set, that common variants are very important factors in aggregation of migraines in the family," added Dr. Palotie. Finally, the researchers suggest that findings from the current study could advance precision medicine and aid with the development of drugs that target specific pathways.

"This is of special interest for drug development," concluded Dr. Palotie.

“Unique cohort provides unique results. It is evident that a targeted, personalized treatment approach based on individual properties of the patients will be safer, more efficient, and more cost effective than selecting the medication based on trial and error approach. This study brings us one step closer to the goal,” agreed co-author Dr. Mikko Kallela, Department of Neurology, Helsinki University Central Hospital, Finland.