Common Polygenic Variation Significantly Contributes to Migraine in Families

Certain identified variants and genes explain why certain families are more prone to migraine, according to the largest family study of migraine.

Migraines, which affect 12% to 20% of the adult population in developed countries, are known to aggregate in families. While mutations in the ion transporter genes CACNA1A, ATP1A2, and SCN1A are linked to some familial and sporadic cases, these represent only a small fraction of cases and do not represent the more common forms.

“We hypothesize that in addition to some rare, highly penetrant variants, accumulation of common variants with small individual effect sizes contribute to the familial forms of migraine,” wrote the authors of the study.

Researchers conducted an analysis of more than 1500 families, consisting of 8319 individuals, from Finland. Of these, 540 had hemiplegic migraine (HM), 2420 had migraine with aura (MA), 2357 had 2357 with migraine without aura (MO), and 3002 had no migraine.

By previously examining more than 59,000 migraine patients, the researchers had identified 40 significant genetic risk variants that put individuals at risk for migraine. Combining this with evidence of hundreds, maybe thousands, of additional variants that have a smaller effect on migraine risk, the researchers calculated a polygenic risk score (PRS) for each individual.

The score was used to assess the relative polygenic load contributing to both prevalent subtypes of migraine (MA and MO), to the rare subtype (HM), and to other available subtypes. The cohort was also compared against a large sample of 15,000 from the FINRISK cohort.

The researchers found that PRS enrichment in the families was prevalent in both common and rare subtypes of familial migraine compared to both population controls and to population cases of migraine. The PRS explained 3.5% of familial cases—including 2.9% for MO, 5.5% for MA, and 8.2% for HM—compared with just 1.6% of population cases. The polygenic burden was higher among those with MA and HM than those with MO. Results also suggest that a large proportion of migraine risk in HM cases is linked to common polygenic variation, rather than solely linked to highly penetrant, rare variation.

The researchers also noted that, interestingly, migraine cases that started at an earlier age were associated with a higher polygenic burden across all migraine subtypes. According to the researchers, this is consistent with similar findings in other complex disorders.

“Our study supports the hypothesis that migraine subtypes are heterogenous diseases and that regardless of whether they are common or rare subtypes, common polygenic variation significantly contributes to the aggregation of the disease in families,” they concluded.

Reference:

Gormley P, Kurki M, Hiekkala M, et al. Common variant burden contributes to the familial aggregation of migraine in 1589 families. Neuron. doi: https://doi.org/10.1016/j.neuron.2018.04.014.