These analyses provide increased support that variation at 15q25.1, 5p15.33, and 6p21.33 influences the risk of developing lung cancer. Our estimate of the contribution of 15q25.1, 5p15.33 and 6p21.33 loci to the excess familial risk of lung cancer is likely to be conservative as the effect of the causal variant will typically be larger than the association detected through a tag SNP. This is especially relevant with respect to the 15q25.1 association as we provide evidence for two independent loci. Furthermore, since a high proportion of UK-GWA study Phase 2 controls were spouses and unrelated friends of lung cancer cases, over-matching on life-time smoking exposure (i.e., cases and controls may have been more likely to be concordant on smoking status than individuals of the general population) may have impacted on study findings. Hence risk estimates for smoking-related SNPs identified in our analysis may be attenuated. In addition multiple causal variants may exist at each locus including low frequency variants with significantly larger effects on risk. This may impact significantly on the contribution of CHRNA5-A3 region to the familial risk of lung cancer, especially as our analysis provides evidence to support independent alleles at this locus.
