Chunk #27 — From large-effect risk loci to disease biology — The CHRNA5–CHRNA3–CHRNB4 nicotinic receptor gene cluster and the CYP2A6 nicotine-metabolising gene.
The functional role of CHRNA5Asp398Asn (rs16969968) has been investigated via different approaches. The CHRNA5Asn398 allele encodes an α5 subunit that forms nACh receptors with lower activity, increased short-term desensitization, and lower calcium relative permeability62. In mice, nicotine negatively affected cognitive performance attention of wild-type mice but not α5 (Chrna5) knockouts, in line with the reduced nACh activity63. Viral-mediated expression of the α5 subunit in the medial habenula in brain restores the aversive effect of α5 knockouts to the levels observed in the wild-type animals. When their α5 expression is inhibited, wild-type animals showed nicotine aversion at the level of α5 knockouts64. In humans (overnight-abstinent smokers) who received intravenous administration of nicotine, CHRNA5Asn398 carriers showed an attenuated aversive response65. The mechanism proposed to explain these concordant results is that nAChRs containing α5 subunits limit nicotine effects due to the stimulation of the projections of the medial habenula into the interpeduncular nucleus that causes the aversive reaction. This illustrates an application of studies in model animals to further our understanding of the biologiocal effects of a genetic risk variant in humans.
