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Migraine Risk Contributions From Common Variants Supported by New Studies

NEW YORK (GenomeWeb) – A team from the US, Finland, Germany, and Sweden has come up with a polygenic risk score for migraine headaches, made up of common genetic variants that are over-represented in migraine-affected individuals and families.

"The strength of the common variants in these families surprised us," senior author Aarno Palotie, a researcher affiliated with Massachusetts General Hospital, Harvard Medical School, the Broad Institute, and the University of Helsinki, said in a statement, noting that "common variants are very important factors in aggregation of migraines in the family."

He and his colleagues brought together array-based genotyping profiles for more than 8,300 individuals from nearly 1,600 migraine-affected families, demonstrating that a polygenic risk score based on migraine-associated common variants was enhanced in individuals with a range of migraine subtypes. They saw a similar, but less pronounced, common variant enrichment using data for more than 1,100 migraine sufferers participating in the FINRISK population study.

"[O]ur study supports the hypothesis that migraine subtypes are genetically heterogeneous 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," Palotie and his colleagues wrote in a study appearing online today in Neuron.

Past genetic linkage studies have identified a small handful of Mendelian genes involved in familial migraine risk, the team noted, including ion transporter genes such as SCN1A, ATP1A2, and CAC-NA1A, the team explained. Nevertheless, the penetrance of migraine-related mutations in these genes appears to vary, and much of the heritability of migraine risk remains unexplained.

"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," the authors wrote, noting that common variants at dozens of loci have been implicated in migraine risk through genome-wide association studies.

To explore these potential common variant contributions to familial and sporadic migraine risk, the researchers proposed a polygenic risk score based on variants identified in migraine GWAS that Palotie and other members of the team published in Nature Genetics in 2016 involving some 59,000 individuals with migraine and 316,000 without.

When the team applied the risk score to 8,319 genotyped individuals from 1,589 migraine-affected families in Finland, it did see an enrichment for the polygenic risk score variants across the migraine subtypes considered, including migraine with aura, migraine without aura, and a rarer form of the headache called hemiplegic migraine.

When they expanded the analysis to include 13,369 FINRISK study participants, meanwhile, the researchers saw similar ties to migraine, though variant enrichment was less pronounced than it was in the familial cases.

Even so, they did detect some differences in the extent of enrichment depending on the subtype considered. The risky variants were enhanced to a greater extent in individuals who experienced migraine with aura or hemiplegic migraine compared to those who reported migraine without aura.

Across the familial cases, the team estimated that the polygenic risk variants explain roughly 3.5 percent of migraine risk. In that population group, the polygenic risk variant score appeared to explain 1.6 percent of variation associated with the migraine phenotype.

In contrast, the researchers identified rare pathogenic variants in Mendelian migraine genes in individuals from four of 45 sequenced families, but did not detect such rare mutations in more than 200 sequenced individuals with sporadic forms of migraine.

In a related study appearing online today in PLOS Genetics, an independent team led by investigators at the Max Planck Institute for Evolutionary Anthropology and the University College London tracked the distribution of a cold- and/or migraine-related variant called rs10166942 near TRPM8, a cation channel gene implicated in cold perception.

Based on allele frequency data from the 1000 Genomes Project, the researchers found that rs10166942, which is believed to be protective against migraine risk in its ancestral state, is found in a derived state in 88 percent of Finnish individuals, but just 5 percent of individuals from Nigeria.

"[A] likely regulatory genetic variant nearby TRPM8 has several signatures of positive selection raising its frequency in Eurasian populations during the last 25,000 years," senior author Aida Andres, an evolutionary genetics researcher affiliated with Max Planck and UCL, and her co-authors reported, noting that "this same genetic variant has previously been strongly associated with migraine."

From these results, authors of that study proposed that "adaptation to cold has potentially contributed to the variation in migraine prevalence that exists among human groups today."