In this region, at least one functional locus responsible for the statistical signal is a nonsynonymous (aspartic acid, Asp [D] to asparagine, Asn [N]; rs16969968) SNP at codon 398 of CHRNA5. The Asn398 allele has been associated with nicotine dependence/heavy smoking,99,100 pleasurable response to smoking,101 smoking quantity,38 smoking persistence, increased susceptibility to develop lung cancer and vascular disease among smokers,38,103,104 serum cotinune levels among current smokers,105 and smoking cessation.106 According to a recent meta-analysis, each copy of the risk allele accounts only for approximately 0.5% of the variance in number of cigarettes smoked/day, reflecting the crude nature of the phenotype being studied107 (see Fig. 9C). Potentially explaining the neural pathways by which the Asp398Asn locus alters propensity to nicotine addiction, the Asn398 allele was found to predict the strength of a brain circuit connecting the anterior cingulate to the ventral striatum107 (Fig. 10A). The anterior cingulate is a component of the limbic system involved in emotional modulation, and the ventral striatum is a principle reward region of the brain. Strength of this circuit itself was associated with smoking status and severity of smoking (see Fig. 10B), and this genotype predicted the circuit strength in both smokers and nonsmokers.108
