Genome Wide Association Analysis of Two Pore Domain Potassium Channel Gene Regions Reveals Multiple Pain-Associated Signals

Abstract Two-pore domain potassium (K2P) channels are novel analgesic drug targets with existing in vitro and in vivo validation, however genetic associations in large scale populations have not been widely reported. By examining two comprehensive genetic databases (UK Biobank & FinnGen) and 136 pain-related traits, we highlight that multiple pain-associated signals are present within 500 kb of K2P gene transcripts, with particularly strong evidence for KCNK5 (TASK-2) and headache-related traits. This data benchmarks remarkably well against gene targets already considered to be well validated pain targets (voltage-gated sodium and transient receptor potential channels) and is enhanced when examining populations regularly consuming analgesics who also report pain. This data supports a rationale for developing therapeutic strategies to modulate K2P function in patient populations experiencing pain.