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 Anders; Marino 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

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 journal › Article

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 language	English
Journal	Gastroenterology
Publication status	Accepted/In press - 16 Mar 2020

Keywords

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

Embargoed Document

Dong_etal_Gastro_Sex_specific_GWAS_AAM
Accepted author manuscript, 299 KB
Licence: CC BY-NC-ND
Embargo ends: 16/03/21

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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.

Sex-Specific Genetic Associations for Barrett’s Esophagus and Esophageal Adenocarcinoma. / Dong, Jing; Maj, Carlo; Tsavachidis, Spiridon; Ostrom, Quinn; Gharahkhani, Puja; Anderson, Lesley; Wu, Anna H.; Ye, Weimin; Bernstein, L; Borisov, Oleg; Schroder, Julia; Chow, Wong-Ho; Gammon, Marilie D.; Liu, Geoffrey; Caldas, Carlos; Pharoah, Paul; Risch, Harvey A.; May, Andrea; Gerges, Christian; Anders, Mario; Venerito, Marino; Schmidt, Thomas; Izbicki, Jakob R.; Hölscher, Arnulf H.; Schumacher, Brigitte; Vashist, Yogesh; neuhaus, horst; rosch, thomas; Knapp, Michael; krawitz, Peter; Böhmer, Anne C; Iyer, Prasad G.; Reid, Brian T; Lagergren, Jesper; Shaheen, Nicholas J.; Corley, Douglas A.; Gockel, Ines; Fitzgerald, Rebecca C.; Cook, Michael B.; Whiteman, David C.; Vaughan, Thomas L; Schumacher, Johannes; Thrift, Aaron (Corresponding Author).

In: Gastroenterology, 16.03.2020.

Research output: Contribution to journal › Article

Dong, J, Maj, C, Tsavachidis, S, Ostrom, Q, Gharahkhani, P, Anderson, L, Wu, AH, Ye, W, Bernstein, L, Borisov, O, Schroder, J, Chow, W-H, Gammon, MD, Liu, G, Caldas, C, Pharoah, P, Risch, HA, May, A, Gerges, C, Anders, M, Venerito, M, Schmidt, T, Izbicki, JR, Hölscher, AH, Schumacher, B, Vashist, Y, neuhaus, H, rosch, T, Knapp, M, krawitz, P, Böhmer, AC, Iyer, PG, Reid, BT, Lagergren, J, Shaheen, NJ, Corley, DA, Gockel, I, Fitzgerald, RC, Cook, MB, Whiteman, DC, Vaughan, TL, Schumacher, J & Thrift, A 2020, 'Sex-Specific Genetic Associations for Barrett’s Esophagus and Esophageal Adenocarcinoma', Gastroenterology.

Dong, Jing ; Maj, Carlo ; Tsavachidis, Spiridon ; Ostrom, Quinn ; Gharahkhani, Puja ; Anderson, Lesley ; Wu, Anna H. ; Ye, Weimin ; Bernstein, L ; Borisov, Oleg ; Schroder, Julia ; Chow, Wong-Ho ; Gammon, Marilie D. ; Liu, Geoffrey ; Caldas, Carlos ; Pharoah, Paul ; Risch, Harvey A. ; May, Andrea ; Gerges, Christian ; Anders, Mario ; Venerito, Marino ; Schmidt, Thomas ; Izbicki, Jakob R. ; Hölscher, Arnulf H. ; Schumacher, Brigitte ; Vashist, Yogesh ; neuhaus, horst ; rosch, thomas ; Knapp, Michael ; krawitz, Peter ; Böhmer, Anne C ; Iyer, Prasad G. ; Reid, Brian T ; Lagergren, Jesper ; Shaheen, Nicholas J. ; Corley, Douglas A. ; Gockel, Ines ; Fitzgerald, Rebecca C. ; Cook, Michael B. ; Whiteman, David C. ; Vaughan, Thomas L ; Schumacher, Johannes ; Thrift, Aaron. / Sex-Specific Genetic Associations for Barrett’s Esophagus and Esophageal Adenocarcinoma. In: Gastroenterology. 2020.

@article{8987fe1490eb40c8bd42b8aeb9585b2f,

title = "Sex-Specific Genetic Associations for Barrett{\textquoteright}s Esophagus and Esophageal Adenocarcinoma",

abstract = "Background and Aims: Esophageal adenocarcinoma (EA) and its premalignant lesion, Barrett{\textquoteright}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.",

keywords = "esophageal adenocarcinoma, Barrett{\textquoteright}s esophagus, sex difference, genome-wide association study, interaction",

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

note = "Grant support: This work was primarily funded by National Institutes of Health (R01CA136725). The funders of the study had no role in the design, analysis, or interpretation of the data, nor in writing or publication decisions related to this article. JD and QTO were supported by a Research Training Grant from the Cancer Prevention and Research Institute of Texas (CPRIT; RP160097). PG was supported by a grant from National Health and Medical Research Council of Australia (1123248). GL was supported by the Alan B. Brown Chair in Molecular Genomics and by the CCO Chair in Experimental Therapeutics and Population Studies. The University of Cambridge received salary support for PDP from the NHS in the East of England through the Clinical Academic Reserve. BJR was supported by a grant (P01CA91955) from the National Institutes of Health /National Cancer Institute. NJS was supported by a grant (P30 DK034987) from the National Institutes of Health. TLV was supported by National Institutes of Health Established Investigator Award K05CA124911. SM was supported by an Australian Research Council Future Fellowship. DCW was supported by a Research Fellowship from the National Health and Medical Research Council of Australia (APP1058522). MBC was supported by the Intramural Research Program of the United States National Cancer Institute, NIH, DHHS. DAC was supported by the United States National Institutes of Health grants R03 KD 58294, R21DK077742, and RO1 DK63616 and National Cancer Institute grant R01CA136725. CM was supported by the BONFOR-program of the Medical Faculty, University of Bonn (O-147.0002).",

year = "2020",

month = mar,

day = "16",

language = "English",

journal = "Gastroenterology",

issn = "0016-5085",

publisher = "W B SAUNDERS CO-ELSEVIER INC",

}

TY - JOUR

T1 - Sex-Specific Genetic Associations for Barrett’s Esophagus and Esophageal Adenocarcinoma

AU - Dong, Jing

AU - Maj, Carlo

AU - Tsavachidis, Spiridon

AU - Ostrom, Quinn

AU - Gharahkhani, Puja

AU - Anderson, Lesley

AU - Wu, Anna H.

AU - Ye, Weimin

AU - Bernstein, L

AU - Borisov, Oleg

AU - Schroder, Julia

AU - Chow, Wong-Ho

AU - Gammon, Marilie D.

AU - Liu, Geoffrey

AU - Caldas, Carlos

AU - Pharoah, Paul

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 - rosch, thomas

AU - Knapp, Michael

AU - krawitz, Peter

AU - Böhmer, Anne C

AU - Iyer, Prasad G.

AU - Reid, Brian T

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

N1 - Grant support: This work was primarily funded by National Institutes of Health (R01CA136725). The funders of the study had no role in the design, analysis, or interpretation of the data, nor in writing or publication decisions related to this article. JD and QTO were supported by a Research Training Grant from the Cancer Prevention and Research Institute of Texas (CPRIT; RP160097). PG was supported by a grant from National Health and Medical Research Council of Australia (1123248). GL was supported by the Alan B. Brown Chair in Molecular Genomics and by the CCO Chair in Experimental Therapeutics and Population Studies. The University of Cambridge received salary support for PDP from the NHS in the East of England through the Clinical Academic Reserve. BJR was supported by a grant (P01CA91955) from the National Institutes of Health /National Cancer Institute. NJS was supported by a grant (P30 DK034987) from the National Institutes of Health. TLV was supported by National Institutes of Health Established Investigator Award K05CA124911. SM was supported by an Australian Research Council Future Fellowship. DCW was supported by a Research Fellowship from the National Health and Medical Research Council of Australia (APP1058522). MBC was supported by the Intramural Research Program of the United States National Cancer Institute, NIH, DHHS. DAC was supported by the United States National Institutes of Health grants R03 KD 58294, R21DK077742, and RO1 DK63616 and National Cancer Institute grant R01CA136725. CM was supported by the BONFOR-program of the Medical Faculty, University of Bonn (O-147.0002).

PY - 2020/3/16

Y1 - 2020/3/16

N2 - 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.

AB - 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.

KW - esophageal adenocarcinoma

KW - Barrett’s esophagus

KW - sex difference

KW - genome-wide association study

KW - interaction

M3 - Article

JO - Gastroenterology

JF - Gastroenterology

SN - 0016-5085

ER -