CHRNA4 has strong biological plausibility for influencing nicotine dependence and consequently its adverse health effects. Nicotinic acetylcholine receptor genes, including CHRNA4, encode subunits that assemble together to form ligand-gated ion channels that respond to the neurotransmitter acetylcholine. Nicotine exposure from cigarette smoking also activates the receptors, triggering dopamine release and influencing the reinforcing effect of nicotine.59, 60, 61 The subunits encoded by CHRNA4 and CHRNB2 comprise α4β2 receptors, the most abundantly expressed nicotine acetylcholine receptors in the brain. They have a high affinity for nicotine and serve critical roles in nicotine self-administration and its positive reinforcement.62, 63 Knock-out mouse models64, 65 and knock-in mice with a hypersensitive receptor66, 67 have demonstrated that CHRNA4 is a necessary and sufficient factor for many characteristic behaviors of nicotine dependence, including nicotine-induced reward, tolerance and anxiety relief. A knockdown rat model suggested that α4-containing receptors have a role in nicotine-mediated analgesia, showing that reduced CHRNA4 expression in brain significantly attenuated sensitivity to nicotine agonist.68 This is consistent with our finding that rs2273500-C decreases CHRNA4 expression and, by lowering sensitivity to nicotine's effects, confers risk
