Two novel variant loci were identified. rs4767364 located at 12q24 (preplication = 4×10−4; pcombined = 2×10−8) was one of multiple highly correlated SNPs (r2≥0.8) that presented evidence for association in the GWAS stage. It is located in a LD region including multiple genes including the aldehyde dehydrogenase 2 (ALDH2) (Figure 2), another key gene in alcohol metabolism (Figure 2). In stratified analysis in the combined 8,744 UADT cancer cases and 11,982 controls (Table S3), the association was more pronounced in esophageal cancers compared to other UADT cancer subsites (p heterogeneity = 0.01) and exhibited borderline heterogeneity when stratifying by alcohol use (Figure 3). Some heterogeneity was noted by when stratifying by country (p = 0.004), although there was no discernable geographic distribution that could explain this heterogeneity (data not shown). We noted little evidence for association between alcohol consumption and rs4767364 (Table 2), nor was there evidence for any gene-gene interactions between associated variants in ADH gene cluster and rs4767364 (data not shown).
