Jing Dong1, Carlo Maj2, Spiridon Tsavachidis3, Quinn T Ostrom3, Puya Gharahkhani4, Lesley A Anderson5, Anna H Wu6, Weimin Ye7, Leslie Bernstein8, Oleg Borisov2, Julia Schröder9, Wong-Ho Chow10, Marilie D Gammon11, Geoffrey Liu12, Carlos Caldas13, Paul D Pharoah14, Harvey A Risch15, Andrea May16, Christian Gerges17, Mario Anders18, Marino Venerito19, Thomas Schmidt20, Jakob R Izbicki21, Arnulf H Hölscher22, Brigitte Schumacher23, Yogesh Vashist21, Horst Neuhaus17, Thomas Rösch24, Michael Knapp25, Peter Krawitz2, Anne Böhmer9, Prasad G Iyer26, Brian J Reid27, Jesper Lagergren28, Nicholas J Shaheen29, Douglas A Corley30, Ines Gockel31, Rebecca C Fitzgerald32, Michael B Cook33, David C Whiteman34, Thomas L Vaughan27, Johannes Schumacher35, Aaron P Thrift36. 1. Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas; Division of Hematology and Oncology, Department of Medicine, Cancer Center, and Genomic Sciences & Precision Medicine Center, Medical College of Wisconsin, Milwaukee, Wisconsin. 2. Institute for Genomic Statistics and Bioinformatics, Medical Faculty, University of Bonn, Germany. 3. Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas. 4. Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia. 5. Centre for Public Health, Queen's University Belfast, Belfast, Northern Ireland & Aberdeen Center for Health Data Science, University of Aberdeen, Scotland. 6. Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California. 7. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. 8. Department of Population Sciences, Beckman Research Institute and City of Hope Comprehensive Cancer Center, Duarte, California. 9. Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany. 10. Department of Epidemiology, MD Anderson Cancer Center, Houston, Texas. 11. Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina. 12. Pharmacogenomic Epidemiology, Ontario Cancer Institute, Toronto, Ontario, Canada. 13. Cancer Research UK, Cambridge Institute, Cambridge, UK. 14. Department of Oncology, University of Cambridge, Cambridge, UK; Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. 15. Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut. 16. Department of Medicine II, Sana Klinikum, Offenbach, Germany. 17. Department of Internal Medicine II, Evangelisches Krankenhaus, Düsseldorf, Germany. 18. Department of Gastroenterology and Interdisciplinary Endoscopy, Vivantes Wenckebach-Klinikum, Berlin, Germany. 19. Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Hospital, Magdeburg, Germany. 20. Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany. 21. Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, University of Hamburg, Hamburg, Germany. 22. Department of General, Visceral and Cancer Surgery, University of Cologne, Cologne, Germany. 23. Department of Internal Medicine and Gastroenterology, Elisabeth Hospital, Essen, Germany. 24. Department of Interdisciplinary Endoscopy, University Hospital Hamburg-Eppendorf, Hamburg, Germany. 25. Institute of Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany. 26. Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota. 27. Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington. 28. Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; School of Cancer and Pharmaceutical Sciences, King's College London, London, UK. 29. Division of Gastroenterology and Hepatology, University of North Carolina School of Medicine, Chapel Hill, North Carolina. 30. Division of Research, Kaiser Permanente Northern California, Oakland, California; San Francisco Medical Center, Kaiser Permanente Northern California, San Francisco, California. 31. Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany. 32. Medical Research Council (MRC) Cancer Unit, Hutchison-MRC Research Centre, University of Cambridge, Cambridge, UK. 33. Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland. 34. Cancer Control, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia. 35. Center for Human Genetics, University Hospital of Marburg, Marburg, Germany. 36. Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas; Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, Houston, Texas. Electronic address: aaron.thrift@bcm.edu.
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.
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.
Authors: Anne C Böhmer; Julian Hecker; Heide Fier; Johannes Schumacher; Julia Schröder; Puya Gharahkhani; Andrea May; Christian Gerges; Mario Anders; Jessica Becker; Timo Hess; Nicole Kreuser; René Thieme; Tania Noder; Marino Venerito; Lothar Veits; Thomas Schmidt; Claudia Fuchs; Jakob R Izbicki; Arnulf H Hölscher; Arne Dietrich; Yusef Moulla; Orestis Lyros; Hauke Lang; Dietmar Lorenz; Brigitte Schumacher; Rupert Mayershofer; Yogesh Vashist; Katja Ott; Michael Vieth; Josef Weismüller; Susanne Moebus; Michael Knapp; Horst Neuhaus; Thomas Rösch; Christian Ell; Markus M Nöthen; David C Whiteman; Ian Tomlinson; Janusz Jankowski; Rebecca C Fitzgerald; Claire Palles; Thomas L Vaughan; Ines Gockel; Aaron P Thrift Journal: Cancer Epidemiol Biomarkers Prev Date: 2019-11-20 Impact factor: 4.254
Authors: Dana B Hancock; María Soler Artigas; Sina A Gharib; Amanda Henry; Ani Manichaikul; Adaikalavan Ramasamy; Daan W Loth; Medea Imboden; Beate Koch; Wendy L McArdle; Albert V Smith; Joanna Smolonska; Akshay Sood; Wenbo Tang; Jemma B Wilk; Guangju Zhai; Jing Hua Zhao; Hugues Aschard; Kristin M Burkart; Ivan Curjuric; Mark Eijgelsheim; Paul Elliott; Xiangjun Gu; Tamara B Harris; Christer Janson; Georg Homuth; Pirro G Hysi; Jason Z Liu; Laura R Loehr; Kurt Lohman; Ruth J F Loos; Alisa K Manning; Kristin D Marciante; Ma'en Obeidat; Dirkje S Postma; Melinda C Aldrich; Guy G Brusselle; Ting-hsu Chen; Gudny Eiriksdottir; Nora Franceschini; Joachim Heinrich; Jerome I Rotter; Cisca Wijmenga; O Dale Williams; Amy R Bentley; Albert Hofman; Cathy C Laurie; Thomas Lumley; Alanna C Morrison; Bonnie R Joubert; Fernando Rivadeneira; David J Couper; Stephen B Kritchevsky; Yongmei Liu; Matthias Wjst; Louise V Wain; Judith M Vonk; André G Uitterlinden; Thierry Rochat; Stephen S Rich; Bruce M Psaty; George T O'Connor; Kari E North; Daniel B Mirel; Bernd Meibohm; Lenore J Launer; Kay-Tee Khaw; Anna-Liisa Hartikainen; Christopher J Hammond; Sven Gläser; Jonathan Marchini; Peter Kraft; Nicholas J Wareham; Henry Völzke; Bruno H C Stricker; Timothy D Spector; Nicole M Probst-Hensch; Deborah Jarvis; Marjo-Riitta Jarvelin; Susan R Heckbert; Vilmundur Gudnason; H Marike Boezen; R Graham Barr; Patricia A Cassano; David P Strachan; Myriam Fornage; Ian P Hall; Josée Dupuis; Martin D Tobin; Stephanie J London Journal: PLoS Genet Date: 2012-12-20 Impact factor: 5.917
Authors: Mengzhen Liu; Yu Jiang; Robbee Wedow; Yue Li; David M Brazel; Fang Chen; Gargi Datta; Jose Davila-Velderrain; Daniel McGuire; Chao Tian; Xiaowei Zhan; Hélène Choquet; Anna R Docherty; Jessica D Faul; Johanna R Foerster; Lars G Fritsche; Maiken Elvestad Gabrielsen; Scott D Gordon; Jeffrey Haessler; Jouke-Jan Hottenga; Hongyan Huang; Seon-Kyeong Jang; Philip R Jansen; Yueh Ling; Reedik Mägi; Nana Matoba; George McMahon; Antonella Mulas; Valeria Orrù; Teemu Palviainen; Anita Pandit; Gunnar W Reginsson; Anne Heidi Skogholt; Jennifer A Smith; Amy E Taylor; Constance Turman; Gonneke Willemsen; Hannah Young; Kendra A Young; Gregory J M Zajac; Wei Zhao; Wei Zhou; Gyda Bjornsdottir; Jason D Boardman; Michael Boehnke; Dorret I Boomsma; Chu Chen; Francesco Cucca; Gareth E Davies; Charles B Eaton; Marissa A Ehringer; Tõnu Esko; Edoardo Fiorillo; Nathan A Gillespie; Daniel F Gudbjartsson; Toomas Haller; Kathleen Mullan Harris; Andrew C Heath; John K Hewitt; Ian B Hickie; John E Hokanson; Christian J Hopfer; David J Hunter; William G Iacono; Eric O Johnson; Yoichiro Kamatani; Sharon L R Kardia; Matthew C Keller; Manolis Kellis; Charles Kooperberg; Peter Kraft; Kenneth S Krauter; Markku Laakso; Penelope A Lind; Anu Loukola; Sharon M Lutz; Pamela A F Madden; Nicholas G Martin; Matt McGue; Matthew B McQueen; Sarah E Medland; Andres Metspalu; Karen L Mohlke; Jonas B Nielsen; Yukinori Okada; Ulrike Peters; Tinca J C Polderman; Danielle Posthuma; Alexander P Reiner; John P Rice; Eric Rimm; Richard J Rose; Valgerdur Runarsdottir; Michael C Stallings; Alena Stančáková; Hreinn Stefansson; Khanh K Thai; Hilary A Tindle; Thorarinn Tyrfingsson; Tamara L Wall; David R Weir; Constance Weisner; John B Whitfield; Bendik Slagsvold Winsvold; Jie Yin; Luisa Zuccolo; Laura J Bierut; Kristian Hveem; James J Lee; Marcus R Munafò; Nancy L Saccone; Cristen J Willer; Marilyn C Cornelis; Sean P David; David A Hinds; Eric Jorgenson; Jaakko Kaprio; Jerry A Stitzel; Kari Stefansson; Thorgeir E Thorgeirsson; Gonçalo Abecasis; Dajiang J Liu; Scott Vrieze Journal: Nat Genet Date: 2019-01-14 Impact factor: 38.330
Authors: Carlijn A M Roumans; Pauline A Zellenrath; Ewout W Steyerberg; Iris Lansdorp-Vogelaar; Michael Doukas; Katharina Biermann; Joyce Alderliesten; Gert van Ingen; Wouter B Nagengast; Arend Karrenbeld; Frank Ter Borg; Mariska Hage; Pieter C J Ter Borg; Michael A den Bakker; Alaa Alkhalaf; Frank C P Moll; Lieke Brouwer-Hol; Joop van Baarlen; Rutger Quispel; Arjan van Tilburg; Jordy P W Burger; Antonie J P van Tilburg; Ariadne H A G Ooms; Thjon J Tang; Mariëlle J L Romberg-Camps; Danny Goudkade; Marco J Bruno; Dimitris Rizopoulos; Manon C W Spaander Journal: Cancers (Basel) Date: 2022-07-01 Impact factor: 6.575