Sex-Specific Genetic Associations for Barrett’s Esophagus and Esophageal Adenocarcinoma

ABSTRACT Background and Aims Esophageal adenocarcinoma (EA) and its premalignant lesion, Barrett’s esophagus (BE), are characterized by a strong and yet unexplained male predominance (with a male-to-female ratio in EA incidence of up to 6:1). Genome-wide association studies (GWAS) have identified more than 20 susceptibility loci for these conditions. However, potential sex differences in genetic associations with BE/EA remain largely unexplored. Methods Given strong genetic overlap, BE and EA cases were combined into a single case group for analysis. These were compared with population-based controls. We performed sex-specific GWAS of BE/EA in three separate studies and then used fixed-effects meta-analysis to provide summary estimates for > 9 million variants for males and females. A series of downstream analyses were conducted separately in males and females to identify genes associated with BE/EA and the genetic correlations between BE/EA and other traits. Results We included 6,758 male BE/EA cases, 7,489 male controls, 1,670 female BE/EA cases and 6,174 female controls. After Bonferroni correction, our meta-analysis of sex-specific GWAS identified one variant at chromosome 6q11.1 (rs112894788, KHDRBS2-MTRNR2L9, PBONF = 0.039) that was statistically significantly associated with BE/EA risk in males only, and one variant at chromosome 8p23.1 (rs13259457, PRSS55-RP1L1, PBONF = 0.057) associated, at borderline significance, with BE/EA risk in females only. We also observed strong genetic correlations of BE/EA with gastroesophageal reflux disease in males and obesity in females. Conclusions The identified novel sex-specific variants associated with BE/EA could improve the understanding of the genetic architecture of the disease and the reasons for the male predominance.