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

Jing Dong, Carlo Maj, Spiridon Tsavachidis, Quinn T Ostrom, Puya Gharahkhani, Lesley A Anderson, Anna H Wu, Weimin Ye, Leslie Bernstein, Oleg Borisov, Julia Schröder, Wong-Ho Chow, Marilie D Gammon, Geoffrey Liu, Carlos Caldas, Paul D 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 Rösch, Michael Knapp, Peter Krawitz, Anne Böhmer, Prasad G Iyer, Brian J 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 P Thrift* (Corresponding Author), Stomach and Oesophageal Cancer Study (SOCS) Consortium

*Corresponding author for this work

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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, P BONF = .039) that was statistically significantly associated with BE/EA risk in male individuals only, and 1 variant at chromosome 8p23.1 (rs13259457, PRSS55-RP1L1, P BONF = 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.

Original languageEnglish
Pages (from-to)2065-2076.E1
Number of pages12
Issue number6
Early online date9 Sept 2020
Publication statusPublished - 1 Dec 2020

Bibliographical note

We thank Dr Stuart MacGregor for his input on the study proposal and review of prior versions of this manuscript. We also thank all patients and controls for participating in this study. The MD Anderson controls were drawn from dbGaP (study accession: phs000187.v1.p1). Genotyping of these controls were done through the University of Texas MD Anderson Cancer Center (UTMDACC) and the Johns Hopkins University Center for Inherited Disease Research (CIDR). We acknowledge the principal investigators of this study: Christopher Amos, Qingyi Wei, and Jeffrey E. Lee. Controls from the Genome-Wide Association Study of Parkinson Disease were obtained from dbGaP (study accession: phs000196.v2.p1). This work, in part, used data from the National Institute of Neurological Disorders and Stroke (NINDS) dbGaP database from the CIDR: NeuroGenetics Research Consortium Parkinson’s disease study. We acknowledge the principal investigators and coinvestigators of this study: Haydeh Payami, John Nutt, Cyrus Zabetian, Stewart Factor, Eric Molho, and Donald Higgins. Controls from the Chronic Renal Insufficiency Cohort (CRIC) were drawn from dbGaP (study accession: phs000524.v1.p1). The CRIC study was done by the CRIC investigators and supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Data and samples from CRIC reported here were supplied by NIDDK Central Repositories. This report was not prepared in collaboration with investigators of the CRIC study and does not necessarily reflect the opinions or views of the CRIC study, the NIDDK Central Repositories, or the NIDDK. We acknowledge the principal investigators and the project officer of this study: Harold I Feldman, Raymond R Townsend, Lawrence J. Appel, Mahboob Rahman, Akinlolu Ojo, James P. Lash, Jiang He, Alan S Go, and John W. Kusek.
The following UK hospitals participated in sample collection through the Stomach and Oesophageal Cancer Study (SOCS) collaboration network:
Addenbrooke’s Hospital, University College London, Bedford Hinchingbrooke Hospital, Peterborough City Hospital, West Suffolk
Norfolk and Norwich University Hospital, Churchill Hospital, John
Hospital, Velindre Hospital, St Bartholomew’s Hospital, Queen’s
Burton, Queen Elisabeth Hospital, Diana Princess of Wales, Scunthorpe General Hospital, Royal Devon & Exeter Hospital, New Cross Hospital, Belfast City Hospital, Good Hope Hospital, Heartlands Hospital, South Tyneside District General Hospital, Cumberland Infirmary, West Cumberland Hospital, Withybush General Hospital, Stoke Mandeville Hospital, Wycombe General Hospital, Wexham Park Hospital, Southend Hospital, Guy’s Hospital, Southampton General Hospital, Bronglais General Hospital, Aberdeen Royal Infirmary, Manor Hospital, Clatterbridge Centre for Oncology, Lincoln County Hospital, Pilgrim Hospital, Grantham & District Hospital, St Mary’s Hospital London, Croydon University Hospital, Whipps Cross University Hospital, Wansbeck General Hospital, Hillingdon Hospital, Milton Keynes General Hospital, Royal Gwent Hospital, Tameside General Hospital, Castle Hill Hospital, St Richard’s Hospital, Ipswich Hospital, St Helens Hospital, Whiston Hospital, Countess of Chester Hospital, St Mary’s Hospital IOW, Queen Alexandra Hospital, Glan Clwyd Hospital, Wrexham Maelor Hospital, Darent Valley Hospital, Royal Derby Hospital, Derbyshire Royal Infirmary, Scarborough General Hospital, Kettering General Hospital, Kidderminster General Hospital, Royal Lancaster Infirmary, Furness General Hospital, Westmorland General Hospital, James Cook University Hospital, Friarage Hospital, Stepping Hill Hospital, St George’s Hospital London, Doncaster Royal Infirmary, Maidstone Hospital, Tunbridge Hospital, Prince Charles Hospital, Hartlepool Hospital, University Hospital of North Tees, Ysbyty Gwynedd, St. Jame’s University Hospital, Leeds General Infirmary, North Hampshire Hospital, Royal Preston Hospital, Chorley and District General, Airedale General Hospital, Huddersfield Royal Infirmary, Calderdale Royal Hospital, Torbay District General Hospital, Leighton Hospital, Royal Albert Edward Infirmary, Royal Surrey County Hospital, Bradford Royal Infirmary, Burnley General Hospital, Royal Blackburn Hospital, Royal Sussex County Hospital, Freeman Hospital, Royal Victoria Infirmary, Victoria Hospital Blackpool, Weston Park Hospital, Royal Hampshire County Hospital, Conquest Hospital, Royal Bournemouth General Hospital, Mount Vernon Hospital, Lister Hospital, William Harvey Hospital, Kent and Canterbury Hospital, Great Western Hospital, Dumfries and Galloway Royal Infirmary, Poole General Hospital, St Hellier Hospital, North Devon District Hospital, Salisbury District Hospital, Weston General Hospital, University Hospital Coventry, Warwick Hospital, George Eliot Hospital, Alexandra Hospital, Nottingham University Hospital, Royal Chesterfield Hospital, Yeovil District Hospital, Darlington Memorial Hospital, University Hospital of North Durham, Bishop Auckland General Hospital, Musgrove Park Hospital, Rochdale Infirmary, North Manchester General, Altnagelvin Area Hospital, Dorset County Hospital, James Paget Hospital, Derriford Hospital, Newham General Hospital, Ealing Hospital, Pinderfields General Hospital, Clayton Hospital, Dewsbury & District Hospital, Pontefract General Infirmary, Worthing Hospital, Macclesfield Hospital, University Hospital of North Staffordshire, Salford Royal Hospital, Royal Shrewsbury Hospital, and Manchester Royal Infirmary.
Conflict of interest
The authors disclose no conflicts.
This work was primarily funded by the National Institutes of Health (NIH) (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. Jing Dong was supported by a Research Training Grant from the Cancer Prevention and Research Institute of Texas (CPRIT; RP160097) and the Research and Education Program Fund, a component of the Advancing a Healthier Wisconsin endowment at the Medical College of Wisconsin (AHW). Quinn T. Ostrom was supported by RP160097. Puya Gharahkhani was supported by a grant from National Health and Medical Research Council of Australia (1123248). Geoffrey Liu 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 Paul D. Pharoah from the NHS in the East of England through the Clinical Academic Reserve. Brian J. Reid was supported by a grant (P01CA91955) from the NIH/National Cancer Institute (NCI). Nicholas J. Shaheen was supported by a grant (P30 DK034987) from NIH. Thomas L. Vaughan was supported by NIH Established Investigator Award K05CA124911. Michael B. Cook was supported by the Intramural Research Program of the NCI, NIH, Department of Health and Human Services. Douglas A. Corley was supported by the NIH grants R03 KD 58294, R21DK077742, and RO1 DK63616 and NCI grant R01CA136725. Carlo Maj was supported by the BONFOR-program of the Medical Faculty, University of Bonn (O-147.0002). Jesper Lagergren was supported by the United European Gastroenterology (UEG) Research Prize. David C. Whiteman was supported by fellowships from the National Health and Medical Research Council of Australia (1058522, 1155413).


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


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