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

Jing Dong, Carlo Maj, Spiridon Tsavachidis, Quinn Ostrom, Puja Gharahkhani, Lesley Anderson, Anna H. Wu, Weimin Ye, L Bernstein, Oleg Borisov, Julia Schroder, Wong-Ho Chow, Marilie D. Gammon, Geoffrey Liu, Carlos Caldas, Paul Pharoah, Harvey A. Risch, Andrea May, Christian Gerges, Mario AndersMarino Venerito, Thomas Schmidt, Jakob R. Izbicki, Arnulf H. Hölscher, Brigitte Schumacher, Yogesh Vashist, horst neuhaus, thomas rosch, Michael Knapp, Peter krawitz, Anne C Böhmer, Prasad G. Iyer, Brian T Reid, Jesper Lagergren, Nicholas J. Shaheen, Douglas A. Corley, Ines Gockel, Rebecca C. Fitzgerald, Michael B. Cook, David C. Whiteman, Thomas L Vaughan, Johannes Schumacher, Aaron Thrift*

*Corresponding author for this work

Research output: Contribution to journalArticle

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. Meta-analysis of sex-specific GWAS identified three novel independent genome-wide significant loci for BE/EA, including one variant at chromosome 12p12.3 (rs35827298, MGST1-LMO3, P = 1.28×10-8) detected in males only, and two variants at chromosome 8p (rs13259457, PRSS55-RP1L1, P = 6.65×10-9, and rs17321041, DPYSL2, P = 4.98×10-8) detected 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.
Original languageEnglish
JournalGastroenterology
Publication statusAccepted/In press - 16 Mar 2020

Keywords

  • esophageal adenocarcinoma
  • Barrett’s esophagus
  • sex difference
  • genome-wide association study
  • interaction

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    Dong, J., Maj, C., Tsavachidis, S., Ostrom, Q., Gharahkhani, P., Anderson, L., Wu, A. H., Ye, W., Bernstein, L., Borisov, O., Schroder, J., Chow, W-H., Gammon, M. D., Liu, G., Caldas, C., Pharoah, P., Risch, H. A., May, A., Gerges, C., ... Thrift, A. (Accepted/In press). Sex-Specific Genetic Associations for Barrett’s Esophagus and Esophageal Adenocarcinoma. Gastroenterology.