As humans migrated from the warm climate of Africa to colder locales in Asia, Europe, and elsewhere, a genetic variant implicated in migraine may have proliferated to adapt them to the cold, and may explain variation in migraine prevalence among human groups today, according to research published in PLOS Genetics.
Australian researchers discovered human local adaptation of the TRPM8 cold receptor. The TRPM8 gene encodes for a cation channel that mediates an endogenous response to moderate cold. It is expressed in pain and temperature-sensitive neurons of the dorsal root ganglia.
“We show that 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. While the genetic variant was, and is, rare in Africa, it is now common outside of Africa, with frequencies that strongly correlate with latitude and are highest in northern European populations,” they wrote. “Interestingly, this same genetic variant has previously been strongly associated with migraine. This suggests that adaptation to cold has potentially contributed to the variation in migraine prevalence that exists among human groups today.”
To investigate the recent evolutionary history of TRPM8, the researchers targeted the rs10166942 single nucleotide polymorphism (SNP). This SNP is strongly associated with migraine in Europeans. The ancestral C allele had been shown previously to be associated with a reduced risk of migraine in different populations.
The frequency of TRPM8-rs10166942 increased with higher latitude, and reached up to 88% in the northern European Finnish. By comparison, the frequency in Nigerians was only 5%. Latitude alone or combined with temperature was a better predictor of rs10166942 T allele frequency than shared ancestry. Researchers confirmed this correlation with latitude using 110 populations of the Simons Genome Diversity Project (SGDP) dataset, which provides a dense worldwide population sample.
Using FST, a measure of population differentiation to the equatorial Nigerian population, the authors explored signatures of local positive selection. A high FST signature was found to extend for approximately 65 kb in the upstream half of TRPM8. Although some SNPs show comparable signatures, only rs10166942 has been associated with a migraine phenotype. FST sharply declines beyond the 65kb upstream portion of TRPM8, they noted.
The selection of the rs10166942 variant in non-African populations started about 26,000 years ago, and was moderate in Asians and stronger in Europeans. Cold temperatures in northern latitudes were likely to be the driver of positive selection.
According to the investigators, “While the precise functional effect of rs10166942 remains unknown, in large part due to the difficulties associated with studying TRPM8 expression, the SNP falls 1kb upstream of the gene and has been predicted to have a regulatory role. It is thus possible that variation in rs10166942 affects expression levels of TRPM8, which in turn affects cold sensation.”
The investigators concluded, “while the putative influence of rs10166942 in migraine risk is moderate, and additional factors are likely at play, local adaptation in TRPM8 may have contributed to modify, by yet unknown molecular mechanisms, pain-related phenotypes in human populations.”