TY - JOUR
T1 - Sex-Specific Genetic Associations for Barrett's Esophagus and Esophageal Adenocarcinoma
AU - Stomach and Oesophageal Cancer Study (SOCS) consortium
AU - Dong, Jing
AU - Maj, Carlo
AU - Tsavachidis, Spiridon
AU - Ostrom, Quinn T.
AU - Gharahkhani, Puya
AU - Anderson, Lesley A.
AU - Wu, Anna H.
AU - Ye, Weimin
AU - Bernstein, Leslie
AU - Borisov, Oleg
AU - Schröder, Julia
AU - Chow, Wong Ho
AU - Gammon, Marilie D.
AU - Liu, Geoffrey
AU - Caldas, Carlos
AU - Pharoah, Paul D.
AU - Risch, Harvey A.
AU - May, Andrea
AU - Gerges, Christian
AU - Anders, Mario
AU - Venerito, Marino
AU - Schmidt, Thomas
AU - Izbicki, Jakob R.
AU - Hölscher, Arnulf H.
AU - Schumacher, Brigitte
AU - Vashist, Yogesh
AU - Neuhaus, Horst
AU - Rösch, Thomas
AU - Knapp, Michael
AU - Krawitz, Peter
AU - Böhmer, Anne
AU - Iyer, Prasad G.
AU - Reid, Brian J.
AU - Lagergren, Jesper
AU - Shaheen, Nicholas J.
AU - Corley, Douglas A.
AU - Gockel, Ines
AU - Fitzgerald, Rebecca C.
AU - Cook, Michael B.
AU - Whiteman, David C.
AU - Vaughan, Thomas L.
AU - Schumacher, Johannes
AU - Thrift, Aaron P.
N1 - Publisher Copyright:
© 2020 AGA Institute
PY - 2020/12
Y1 - 2020/12
N2 - Background & 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 3 separate studies and then used fixed-effects meta-analysis to provide summary estimates for >9 million variants for male and female individuals. A series of downstream analyses were conducted separately in male and female individuals to identify genes associated with BE/EA and the genetic correlations between BE/EA and other traits. Results: We included 6758 male BE/EA cases, 7489 male controls, 1670 female BE/EA cases, and 6174 female controls. After Bonferroni correction, our meta-analysis of sex-specific GWAS identified 1 variant at chromosome 6q11.1 (rs112894788, KHDRBS2-MTRNR2L9, PBONF =.039) that was statistically significantly associated with BE/EA risk in male individuals only, and 1 variant at chromosome 8p23.1 (rs13259457, PRSS55-RP1L1, PBONF = 0.057) associated, at borderline significance, with BE/EA risk in female individuals only. We also observed strong genetic correlations of BE/EA with gastroesophageal reflux disease in male individuals and obesity in female individuals. 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.
AB - Background & 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 3 separate studies and then used fixed-effects meta-analysis to provide summary estimates for >9 million variants for male and female individuals. A series of downstream analyses were conducted separately in male and female individuals to identify genes associated with BE/EA and the genetic correlations between BE/EA and other traits. Results: We included 6758 male BE/EA cases, 7489 male controls, 1670 female BE/EA cases, and 6174 female controls. After Bonferroni correction, our meta-analysis of sex-specific GWAS identified 1 variant at chromosome 6q11.1 (rs112894788, KHDRBS2-MTRNR2L9, PBONF =.039) that was statistically significantly associated with BE/EA risk in male individuals only, and 1 variant at chromosome 8p23.1 (rs13259457, PRSS55-RP1L1, PBONF = 0.057) associated, at borderline significance, with BE/EA risk in female individuals only. We also observed strong genetic correlations of BE/EA with gastroesophageal reflux disease in male individuals and obesity in female individuals. 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.
KW - Barrett's esophagus
KW - Genome-Wide Association Study
KW - Interaction
KW - Sex Difference
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U2 - 10.1053/j.gastro.2020.08.052
DO - 10.1053/j.gastro.2020.08.052
M3 - Article
C2 - 32918910
AN - SCOPUS:85097370016
SN - 0016-5085
VL - 159
SP - 2065-2076.e1
JO - Gastroenterology
JF - Gastroenterology
IS - 6
ER -