We conducted a genome-wide association study (GWAS) and a genome-wide gene-environment interaction analysis of esophageal squamous-cell carcinoma (ESCC) in 2,031 affected individuals (cases) and 2,044 controls with independent validation in 8,092 cases and 8,620 controls. We identified nine new ESCC susceptibility loci, of which seven, at chromosomes 4q23, 16q12.1, 17q21, 22q12, 3q27, 17p13 and 18p11, had a significant marginal effect (P = 1.78 × 10-39 to P = 2.49 × 10-11) and two of which, at 2q22 and 13q33, had a significant association only in the gene-alcohol drinking interaction (gene-environment interaction P (P G × E) = 4.39 × 10-11 and P G × E = 4.80 × 10-8, respectively). Variants at the 4q23 locus, which includes the ADH cluster, each had a significant interaction with alcohol drinking in their association with ESCC risk (P G × E = 2.54 × 10-7 to P G × E = 3.23 × 10-2). We confirmed the known association of the ALDH2 locus on 12q24 to ESCC, and a joint analysis showed that drinkers with both of the ADH1B and ALDH2 risk alleles had a fourfold increased risk for ESCC compared to drinkers without these risk alleles. Our results underscore the direct genetic contribution to ESCC risk, as well as the genetic contribution to ESCC through interaction with alcohol consumption.
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