significant association results included known loci associated with smoking and alcohol use phenotypes. These included associations between smoking phenotypes and variants within the CHRNA5-CHRNA3-CHRNB4 nicotinic receptor cluster, nicotine metabolism gene CYP2A6, and a locus near dopamine receptor DRD2. We also replicated previous associations between nonsynonymous variant rs1229984 in ADH1B and DrnkWk. Only one very rare variant was associated with any of our five phenotypes. This was rs36015615 (MAF=.0002), a nonsynonymous variant in STARD3, associated with CigDay (p=3.2×10 −8). This novel variant did not replicate in either of two replication consortium datasets, the CHD Exome+ Consortium (N=17,789, Beta=−.01, p=.94) or the Consortium for Genetics of Smoking Behaviour (N=28,583, Beta=.056, p=.84). Based upon the estimated genetic effects in the discovery sample (β = 1.2), the power for replication is >99%. However, if we assume the observed effect sizes in the replication datasets are correct, there is 5% power for replication based upon this estimated effect. The pattern of results may be due to winner’s curse, or the discovered variant may be a false positive finding. Additional studies are required to narrow the possible interpretations.
