Reduced TRPM8 expression underpins reduced migraine risk and attenuated cold pain sensation in humans.

Multiple genome-wide association studies have identified non-coding single-nucleotide variants (SNVs) near (e.g., rs10166942[C]) or within (rs17862920[T]) the TRPM8 gene that encodes a cold thermosensor is associated with reduced migraine risk. Furthermore, rs10166942[C]) and rs10166942[T]) are more prevalent in populations that reside in hotter and colder climates, respectively. Here we assessed whether these alleles affect TRPM8 expression in humans and human physiologic responses to cold challenge. Here we show that TRPM8 expression is decreased from the chromosome harboring the rs10166942[C] allele in the human dorsal root ganglia. Moreover, carriers of rs10166942[C] required significantly lower temperatures and longer duration of exposure to reach a cold pain threshold (CPTh), which correlated with decreased TRPM8 expression expected in the carriers. This study provides evidence for a genotype-dependent influence on cold pain sensation suggesting that carriers of the reduced migraine risk allele have reduced sensitivity to cold stimuli and that TRPM8 acts as a cold thermosensor and cold pain transducer in humans. Reduced TRPM8 expression and function underpins the migraine protection in carriers of rs10166942[C]; thus, the evaluation of TRPM8 antagonists as migraine therapeutics is warranted. Furthermore, these results provide mechanistic insights for evolutionary positive selection of rs10166942[T] allele in adaptation along latitudinal cline to colder climates.