In summary, our meta-analysis demonstrates significant, robust association of locus 1, representing the non-synonymous CHRNA5 SNP rs16969968 as well as rs1051730 and rs55853698, with smoking heaviness across very diverse datasets. Our study also demonstrates strong evidence that at least one additional distinct locus in this region affects risk for heavy smoking. In particular, we have identified for the first time that locus 3 – representing the CHRNA5 expression-associated SNPs rs588765 and correlates – surpasses GWAS-level significance for association with heavy smoking in European-ancestry subjects; this effect is detectable after adjusting for the effect of rs16969968. This new result for locus 3 raises the corresponding SNPs (rs588765 and correlates) to the level of interest already accorded to the two loci which have previously been detected at GWAS-level significance in single-SNP analyses: locus 1 (rs16969968 and correlates) and locus 2 (rs578776 and correlates). Our result also has implications for all genetic association studies, as it illustrates that joint analysis of SNPs is an important tool for identifying genome-wide significant effects that, soberingly, may be obscured in single SNP analyses.
