Previous GWAS have identified three loci associated with COPD susceptibility: HHIP on chromosome 4q31 [12], [13], FAM13A on chromosome 4q22 [11], and a region on chromosome 15q25 encompassing candidate genes CHRNA5, CHRNA3 and IREB2, among others [12], [36]. On chromosome 15q25, cis-eQTL associations for IREB2 mapped to that gene (Figure 3a). Genetic regulation of CHRNA5 was more complex. Previous studies have demonstrated cis-acting effects of multiple SNPs on CHRNA5 expression. Saccone et al. defined 4 LD bins surrounding CHRNA5 with varying associations with cigarette smoking, lung cancer, and COPD [37]. Bins 1–3 were represented in our dataset, tagged by SNPs rs1051730, rs938682, and rs6495306, respectively (Table 4). SNPs in bins 1 and 3 were associated with CHRNA5 expression in sputum (Figure 2), as has been demonstrated in brain [38] and lung tissue [39]. SNPs in bin 2 were not eQTLs for CHRNA5. We added additional SNPs to these bins, based on strong LD with tag SNPs in the larger ECLIPSE GWAS dataset. We also identified 3 sets of SNPs (3a, b, c in Table 4) with cis-eQTL associations for CHRNA5
