Similarly, rs6265 in BDNF, a missense SNP (Val66Met), was associated with smoking initiation and with lifetime cannabis use. In the TAG meta-analysis, rs6265 was one of several genomewide significant SNPs associated with smoking initiation, however, its genomewide significance level was achieved only after sample sizes exceeded 143,000. In this context, the significant p-value in our sample served as replication. Carriers of the A (Met) allele were less likely to smoke 100 or more cigarettes during their lifetime, which is consistent with the meta-analysis which reported that the alternate G (or C) allele was associated with a 6% increase in relative risk for smoking initiation. This SNP has been implicated in a wide array of psychopathology, most notably affective disorders, with meta-analyses suggesting that the Met allele is associated with increased risk for major depressive disorder (Verhagen et al., 2010), schizophrenia and eating disorders but decreased risk for substance use disorders. We see a similar protective effect of the Met allele on cannabis use in this study (Table 2) and this decreased risk is consistent with neurobiological models of stress response that implicate this variant in blunted dopamine activity during reward processing (Pecina et al., 2014).
