Nicotine withdrawal (NicW) is common among tobacco smokers and its symptoms contribute to smoking relapse following quit attempts. Using GWAS, we identified three highly correlated SNPs in the PCDH-α, -β and -γ gene cluster that were associated with DSM-IV NicW. Subsequently, we evaluated the influence of one of these SNPs, rs31746, on smoking withdrawal behavior in an independent sample of current tobacco smokers who had abstained from smoking for ~10 hours. Following IV nicotine infusion, the NicW risk allele was associated with a greater reduction in the urge to smoke, a clinically relevant characteristic of NicW.6 That is, individuals with the NicW risk allele experienced greater alleviation of their withdrawal symptoms in a laboratory setting following nicotine infusion. Rs31746 is located within a previously characterized PCDH-α, -β and –γ gene cluster neuron-specific enhancer element, HS5-1. Using publically available data, we observed a robust association between rs31746 and PCDHβ8 mRNA expression in postmortem human prefrontal cortex tissue. Our results indicate that NicW risk is influenced by regulatory variation in the PCDH-α, -β and -γ gene cluster.
