eQTL Set–Based Association Analysis Identifies Novel Susceptibility Loci for Barrett Esophagus and Esophageal Adenocarcinoma-Reference-Cited by-同舟云学术

eQTL Set–Based Association Analysis Identifies Novel Susceptibility Loci for Barrett Esophagus and Esophageal Adenocarcinoma

Published:2022-06-16 Issue:9 Volume:31 Page:1735-1745
ISSN:1055-9965
Container-title:Cancer Epidemiology, Biomarkers & Prevention
language:en
Short-container-title:

Author:

Wang Xiaoyu¹^ORCID,Gharahkhani Puya²^ORCID,Levine David M.³^ORCID,Fitzgerald Rebecca C.⁴^ORCID,Gockel Ines⁵^ORCID,Corley Douglas A.⁶⁷^ORCID,Risch Harvey A.⁸^ORCID,Bernstein Leslie⁹^ORCID,Chow Wong-Ho¹⁰^ORCID,Onstad Lynn¹^ORCID,Shaheen Nicholas J.¹¹^ORCID,Lagergren Jesper¹²¹³^ORCID,Hardie Laura J.¹⁴^ORCID,Wu Anna H.¹⁵^ORCID,Pharoah Paul D.P.¹⁶¹⁷^ORCID,Liu Geoffrey¹⁸^ORCID,Anderson Lesley A.¹⁹^ORCID,Iyer Prasad G.²⁰^ORCID,Gammon Marilie D.²¹,Caldas Carlos²²^ORCID,Ye Weimin¹²^ORCID,Barr Hugh²³^ORCID,Moayyedi Paul²⁴^ORCID,Harrison Rebecca²⁵^ORCID,Watson R.G. Peter²⁶^ORCID,Attwood Stephen²⁷^ORCID,Chegwidden Laura²⁸^ORCID,Love Sharon B.²⁹^ORCID,MacDonald David³⁰^ORCID,deCaestecker John³¹^ORCID,Prenen Hans³²^ORCID,Ott Katja³³³⁴^ORCID,Moebus Susanne³⁵^ORCID,Venerito Marino³⁶^ORCID,Lang Hauke³⁷^ORCID,Mayershofer Rupert³⁸^ORCID,Knapp Michael³⁹^ORCID,Veits Lothar⁴⁰^ORCID,Gerges Christian⁴¹^ORCID,Weismüller Josef⁴²^ORCID,Reeh Matthias⁴³^ORCID,Nöthen Markus M.⁴⁴^ORCID,Izbicki Jakob R.⁴⁵^ORCID,Manner Hendrik⁴⁶^ORCID,Neuhaus Horst⁴¹^ORCID,Rösch Thomas⁴⁷^ORCID,Böhmer Anne C.⁴⁴^ORCID,Hölscher Arnulf H.⁴⁸^ORCID,Anders Mario⁴⁷⁴⁹^ORCID,Pech Oliver⁵⁰^ORCID,Schumacher Brigitte⁴¹⁵¹^ORCID,Schmidt Claudia⁵²^ORCID,Schmidt Thomas³³^ORCID,Noder Tania⁴⁷^ORCID,Lorenz Dietmar⁵³^ORCID,Vieth Michael⁴⁰^ORCID,May Andrea⁵⁴^ORCID,Hess Timo⁵⁵^ORCID,Kreuser Nicole⁵^ORCID,Becker Jessica⁴⁴^ORCID,Ell Christian⁵⁶^ORCID,Tomlinson Ian⁵⁷^ORCID,Palles Claire⁵⁸^ORCID,Jankowski Janusz A.⁵⁹^ORCID,Whiteman David C.⁶⁰^ORCID,MacGregor Stuart²^ORCID,Schumacher Johannes⁵⁵^ORCID,Vaughan Thomas L.¹⁶¹^ORCID,Buas Matthew F.⁶²^ORCID,Dai James Y.¹³^ORCID

Affiliation:

1. 1Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington.

2. 2QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.

3. 3Department of Biostatistics, University of Washington, School of Public Health, Seattle, Washington.

4. 4Medical Research Council (MRC) Cancer Unit, Hutchison-MRC Research, Centre, University of Cambridge, Cambridge, UK.

5. 5Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany.

6. 6Division of Research, Kaiser Permanente Northern California, Oakland, California.

7. 7San Francisco Medical Center, Kaiser Permanente Northern California, San Francisco, California.

8. 8Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut.

9. 9Department of Population Sciences, Beckman Research Institute and City of Hope Comprehensive Cancer Center, Duarte, California.

10. 10Department of Epidemiology, MD Anderson Cancer Center, Houston, Texas.

11. 11Division of Gastroenterology and Hepatology, University of North Carolina School of Medicine, University of North Carolina, Chapel Hill, North Carolina.

12. 12Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden.

13. 13School of Cancer and Pharmaceutical Sciences, King's College London, London, UK.

14. 14Division of Epidemiology, University of Leeds, Leeds, UK.

15. 15Department of Population and Public Health Sciences, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, California.

16. 16Department of Oncology, University of Cambridge, Cambridge, UK.

17. 17Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.

18. 18Pharmacogenomic Epidemiology, Ontario Cancer Institute, Toronto, Ontario, Canada.

19. 19Department of Epidemiology and Public Health, Queen's University of Belfast, Royal Group of Hospitals, Northern Ireland.

20. 20Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.

21. 21Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina.

22. 22Cancer Research UK, Cambridge Institute, Cambridge, UK.

23. 23Department of Upper GI Surgery, Gloucestershire Royal Hospital, Gloucester, UK.

24. 24Farncombe Family Digestive Health Research Institute, Department of Medicine, McMaster University, Hamilton, Ontario, Canada.

25. 25Department of Pathology, Leicester Royal Infirmary, Leicester, UK.

26. 26Department of Medicine, Institute of Clinical Science, Royal Victoria Hospital, Belfast, UK.

27. 27Department of General Surgery, North Tyneside General Hospital, North Shields, UK.

28. 28University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.

29. 29Centre for Statistics in Medicine and Oxford Clinical Trials Research Unit, Oxford, UK.

30. 30Department of Oral Biological and Medical Sciences, University of British Columbia, Vancouver, British Columbia, Canada.

31. 31Digestive Diseases Centre, University Hospitals of Leicester, Leicester, UK.

32. 32Oncology Department, University Hospital Antwerp, Edegem, Belgium.

33. 33Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany.

34. 34Department of General, Visceral and Thorax Surgery, RoMed Klinikum Rosenheim, Rosenheim, Germany.

35. 35Institute for Urban Public Health, University Hospitals, University of Duisburg-Essen, Essen, Germany.

36. 36Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Hospital, Magdeburg, Germany.

37. 37Department of General, Visceral and Transplant Surgery, University Medical Center, University of Mainz, Mainz, Germany.

38. 38Gastroenterologie am Burgweiher, Bonn, Germany.

39. 39Institute for Medical Biometry, Informatics, and Epidemiology, University of Bonn, Bonn, Germany.

40. 40Institute of Pathology, Friedrich-Alexander-University Erlangen-Nuremberg, Klinikum Bayreuth, Bayreuth, Germany.

41. 41Department of Internal Medicine, Evangelisches Krankenhaus, Düsseldorf, Germany.

42. 42Gastroenterologische Gemeinschaftspraxis, Koblenz, Germany.

43. 43Department of General, Visceral and Thoracic Surgery, Asklepios Harzklinik Goslar, Goslar, Germany.

44. 44Institute of Human Genetics, Medical Faculty, University of Bonn, Bonn, Germany.

45. 45General, Visceral and Thoracic Surgery Department and Clinic, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

46. 46Department of Internal Medicine II, Frankfurt Hoechst Hospital, Frankfurt, Germany.

47. 47Department of Interdisciplinary Endoscopy, University Hospital Hamburg-Eppendorf, Hamburg, Germany.

48. 48Clinic for General, Visceral and Trauma Surgery, Contilia Center for Esophageal Diseases, Elisabeth Hospital Essen, Germany.

49. 49Department of Gastroenterology and Interdisciplinary Endoscopy, Vivantes Wenckebach-Klinikum, Berlin, Germany.

50. 50Department of Gastroenterology and Interventional Endoscopy, St. John of God Hospital, Regensburg, Germany.

51. 51Department of Internal Medicine and Gastroenterology, Elisabeth Hospital, Essen, Germany.

52. 52Department of General, Visceral and Cancer Surgery, University of Cologne, Cologne, Germany.

53. 53Department of General and Visceral Surgery, Sana Klinikum, Offenbach, Germany.

54. 54Department of Gastroenterology, Oncology and Pneumology, Asklepios Paulinen Klinik, Wiesbaden, Germany.

55. 55Center for Human Genetics, University Hospital of Marburg, Marburg, Germany.

56. 56Department of Medicine II, Sana Klinikum, Offenbach, Germany.

57. 57Edinburgh Cancer Research Centre, IGMM, University of Edinburgh, Edinburgh, UK.

58. 58Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.

59. 59Comprehensive Clinical Trials Unit, University College London, London, UK.

60. 60Cancer Control, QIMR Berghofer Medical Research Institute, Brisbane, Australia.

61. 61Department of Epidemiology, University of Washington, School of Public Health, Seattle, Washington.

62. 62Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, New York.

Abstract

Abstract Background: Over 20 susceptibility single-nucleotide polymorphisms (SNP) have been identified for esophageal adenocarcinoma (EAC) and its precursor, Barrett esophagus (BE), explaining a small portion of heritability. Methods: Using genetic data from 4,323 BE and 4,116 EAC patients aggregated by international consortia including the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON), we conducted a comprehensive transcriptome-wide association study (TWAS) for BE/EAC, leveraging Genotype Tissue Expression (GTEx) gene-expression data from six tissue types of plausible relevance to EAC etiology: mucosa and muscularis from the esophagus, gastroesophageal (GE) junction, stomach, whole blood, and visceral adipose. Two analytical approaches were taken: standard TWAS using the predicted gene expression from local expression quantitative trait loci (eQTL), and set-based SKAT association using selected eQTLs that predict the gene expression. Results: Although the standard approach did not identify significant signals, the eQTL set–based approach identified eight novel associations, three of which were validated in independent external data (eQTL SNP sets for EXOC3, ZNF641, and HSP90AA1). Conclusions: This study identified novel genetic susceptibility loci for EAC and BE using an eQTL set–based genetic association approach. Impact: This study expanded the pool of genetic susceptibility loci for EAC and BE, suggesting the potential of the eQTL set–based genetic association approach as an alternative method for TWAS analysis.

Funder

NCI

NIH

Publisher

American Association for Cancer Research (AACR)

Subject

Oncology,Epidemiology

Link

https://aacrjournals.org/cebp/article-pdf/doi/10.1158/1055-9965.EPI-22-0096/3161913/epi-22-0096.pdf

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