Dong, Jing ORCID: 0000-0001-9856-5963, Maj, Carlo, Tsavachidis, Spiridon, Ostrom, Quinn T., Gharahkhani, Puya, Anderson, Lesley A., Wu, Anna H., Ye, Weimin, Bernstein, Leslie, Borisov, Oleg, Schroeder, Julia, Chow, Wong-Ho, Gammon, Marilie D., Liu, Geoffrey, Caldas, Carlos, Pharoah, Paul D., Risch, Harvey A., May, Andrea, Gerges, Christian, Anders, Mario, Venerito, Marino, Schmidt, Thomas, Izbicki, Jakob R., Hoelscher, Arnulf H., Schumacher, Brigitte, Vashist, Yogesh, Neuhaus, Horst, Roesch, Thomas, Knapp, Michael, Krawitz, Peter, Boehmer, Anne, Iyer, Prasad G., Reid, Brian J., Lagergren, Jesper, Shaheen, Nicholas J., Corley, Douglas A., Gockel, Ines, Fitzgerald, Rebecca C., Cook, Michael B., Whiteman, David C., Vaughan, Thomas L., Schumacher, Johannes and Thrift, Aaron P. (2020). Sex-Specific Genetic Associations for Barrett's Esophagus and Esophageal Adenocarcinoma. Gastroenterology, 159 (6). PHILADELPHIA: W B SAUNDERS CO-ELSEVIER INC. ISSN 1528-0012

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Abstract

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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Dong, JingUNSPECIFIEDorcid.org/0000-0001-9856-5963UNSPECIFIED
Maj, CarloUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tsavachidis, SpiridonUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ostrom, Quinn T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gharahkhani, PuyaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Anderson, Lesley A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wu, Anna H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ye, WeiminUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bernstein, LeslieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Borisov, OlegUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schroeder, JuliaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chow, Wong-HoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gammon, Marilie D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Liu, GeoffreyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Caldas, CarlosUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pharoah, Paul D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Risch, Harvey A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
May, AndreaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gerges, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Anders, MarioUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Venerito, MarinoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmidt, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Izbicki, Jakob R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoelscher, Arnulf H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schumacher, BrigitteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vashist, YogeshUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Neuhaus, HorstUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Roesch, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Knapp, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Krawitz, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Boehmer, AnneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Iyer, Prasad G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reid, Brian J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lagergren, JesperUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Shaheen, Nicholas J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Corley, Douglas A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gockel, InesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fitzgerald, Rebecca C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cook, Michael B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Whiteman, David C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vaughan, Thomas L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schumacher, JohannesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thrift, Aaron P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-309688
DOI: 10.1053/j.gastro.2020.08.052
Journal or Publication Title: Gastroenterology
Volume: 159
Number: 6
Date: 2020
Publisher: W B SAUNDERS CO-ELSEVIER INC
Place of Publication: PHILADELPHIA
ISSN: 1528-0012
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
Gastroenterology & HepatologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/30968

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