Some study limitations should be noted. A genomewide significant effect was only observed with a meta-analysis of six studies (n=8021), which may reflect limited power. The top GWAS SNP remained significant (p < 5×10−8) after correction for genomic inflation (λ = 1.025); however, a spurious finding due to underlying ancestry differences within samples or to chance cannot be completely excluded. The observed effects related to NicW in an independent laboratory sample support the validity of the GWAS finding. Also, the GWAS sample included subjects recruited for genetic studies of alcohol, cocaine and opioid use disorder, while the laboratory study recruited just for tobacco use disorder. Rs31746 was associated only with nicotine dependence (pmeta = 5×10−4) in the combined GWAS sample and not alcohol, cocaine or opioid dependence (pmeta > 0.05), but the high prevalence of these co-occurring disorders in the GWAS sample could limit the generalizability of the results. Although, prior work has linked NicW symptoms to smoking relapse following a quit attempt 6, 7, 80, we could not evaluate a potential moderating effect of the NicW risk variant on
