The GWAS-identified SNPs each explain a small percent of the variance in nicotine dependence or related smoking phenotypes, but their discoveries have revealed important neurobiology that impacts susceptibility to developing addiction and exerts clinically important effects downstream, as best illustrated by CHRNA5. Following the discovery of its association with nicotine dependence (Table 1), the CHRNA5 missense SNP rs16969968 was found to alter α5 receptor function [45] and later its high-risk rs16969968-AA genotype was associated with a 4-year median delay in quitting smoking and a 4-year earlier median age of lung cancer diagnosis, even when adjusted for CPD [46]. Moreover, the haplotype carrying the rs16969968-A risk allele interacts with cessation treatment, with smokers at highest nicotine dependence risk being less likely to quit smoking overall but responding most effectively to pharmacologic treatment [47], demonstrating the potential for personalized cessation treatment based on genetic risk variants for nicotine dependence. Independent of rs16969968, noncoding CHRNA5 SNPs have been found to tag cis-expression quantitative trait loci (cis-eQTL) and cis-methylation QTL (cis-meQTL) variants that regulate CHRNA5 RNA expression (rs588765 [48] and rs880395 [49]) and DNA
