To investigate whether the association with cotinine at 4q13.2 could be completely explained by rs114612145, we repeated the association analysis conditioning on this SNP (Figure S1, bottom panel). No residual signal was detected, suggesting that the variants identified in this region represent a single independent signal. For further confirmation of the cotinine association signal at 4q13.2, selected variants from this region were examined in relation to cotinine levels in two independent samples (see Tables S3 and S4). Strong evidence for association was observed in both (Table S4). The rs114612145 SNP identified in our sample is in high LD with a functional missense variant in UGT2B10, rs144647471 (also known as Asp67Tyr or rs61750900 in build GRCh38) (r2 = 0.90). Whilst this missense variant did not reach the threshold for genome-wide significance in our discovery sample (p = 1.91 × 10−5), this is likely due to the reduced sample size upon which association was determined (SNP imputed in only 2,585 individuals). However, we observed evidence of association in an independent sample, in the same direction to that observed in the discovery sample (p = 0.020; Table S3).
