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 for nicotine dependence. The gene discussed is CHRNA4; the disease is nicotine dependence.