Identification of loci of functional relevance to Barrett’s esophagus and esophageal adenocarcinoma: Cross-referencing of expression quantitative trait loci data from disease-relevant tissues with genetic association data

Autoři: Julia Schröder aff001;  Vitalia Schüller aff002;  Andrea May aff003;  Christian Gerges aff004;  Mario Anders aff005;  Jessica Becker aff001;  Timo Hess aff001;  Nicole Kreuser aff008;  René Thieme aff008;  Kerstin U. Ludwig aff001;  Tania Noder aff005;  Marino Venerito aff009;  Lothar Veits aff010;  Thomas Schmidt aff011;  Claudia Fuchs aff012;  Jakob R. Izbicki aff013;  Arnulf H. Hölscher aff012;  Dani Dakkak aff014;  Boris Jansen-Winkeln aff008;  Yusef Moulla aff008;  Orestis Lyros aff008;  Stefan Niebisch aff008;  Matthias Mehdorn aff008;  Hauke Lang aff015;  Dietmar Lorenz aff016;  Brigitte Schumacher aff014;  Rupert Mayershofer aff017;  Yogesh Vashist aff013;  Katja Ott aff011;  Michael Vieth aff010;  Josef Weismüller aff020;  Elisabeth Mangold aff001;  Markus M. Nöthen aff001;  Susanne Moebus aff021;  Michael Knapp aff002;  Horst Neuhaus aff004;  Thomas Rösch aff005;  Christian Ell aff003;  Ines Gockel aff008;  Johannes Schumacher aff007;  Anne C. Böhmer aff001
Působiště autorů: Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany aff001;  Institute for Medical Biometry, Informatics, and Epidemiology, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany aff002;  Department of Medicine II, Sana Klinikum, Offenbach, Germany aff003;  Department of Internal Medicine II, Evangelisches Krankenhaus, Düsseldorf, Germany aff004;  Department of Interdisciplinary Endoscopy, University Hospital Hamburg-Eppendorf, Hamburg, Germany aff005;  Department of Gastroenterology and Interdisciplinary Endoscopy, Vivantes Wenckebach-Klinikum, Berlin, Germany aff006;  Center for Human Genetics, University Hospital Marburg, Marburg, Germany aff007;  Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany aff008;  Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Hospital, Magdeburg, Germany aff009;  Institute of Pathology, Klinikum Bayreuth, Bayreuth, Germany aff010;  Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany aff011;  Department of General, Visceral, and Cancer Surgery, University of Cologne, Cologne, Germany aff012;  Department of General, Visceral, and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, University of Hamburg, Hamburg, Germany aff013;  Department of Internal Medicine and Gastroenterology, Elisabeth Hospital, Essen, Germany aff014;  Department of General, Visceral, and Transplant Surgery, University Medical Center, University of Mainz, Mainz, Germany aff015;  Department of General, Visceral, and Thoracic Surgery, Klinikum Darmstadt, Darmstadt, Germany aff016;  Gastroenterologie am Burgweiher, Bonn, Germany aff017;  Kantonsspital Aarau, Aarau, Switzerland aff018;  Department of General, Visceral, and Thorax Surgery, RoMed Klinikum Rosenheim, Rosenheim, Germany aff019;  Gastroenterologische Gemeinschaftspraxis, Koblenz, Germany aff020;  Centre of Urban Epidemiology, Institute of Medical Informatics, Biometry, and Epidemiology, University of Essen, Essen, Germany aff021
Vyšlo v časopise: PLoS ONE 14(12)
Kategorie: Research Article


Esophageal adenocarcinoma (EA) and its precancerous condition Barrett’s esophagus (BE) are multifactorial diseases with rising prevalence rates in Western populations. A recent meta-analysis of genome-wide association studies (GWAS) data identified 14 BE/EA risk loci located in non-coding genomic regions. Knowledge about the impact of non-coding variation on disease pathology is incomplete and needs further investigation. The aim of the present study was (i) to identify candidate genes of functional relevance to BE/EA at known risk loci and (ii) to find novel risk loci among the suggestively associated variants through the integration of expression quantitative trait loci (eQTL) and genetic association data. eQTL data from two BE/EA-relevant tissues (esophageal mucosa and gastroesophageal junction) generated within the context of the GTEx project were cross-referenced with the GWAS meta-analysis data. Variants representing an eQTL in at least one of the two tissues were categorized into genome-wide significant loci (P < 5×10−8) and novel candidate loci (5×10−8 ≤ P ≤ 5×10−5). To follow up these novel candidate loci, a genetic association study was performed in a replication cohort comprising 1,993 cases and 967 controls followed by a combined analysis with the GWAS meta-analysis data. The cross-referencing of eQTL and genetic data yielded 2,180 variants that represented 25 loci. Among the previously reported genome-wide significant loci, 22 eQTLs were identified in esophageal mucosa and/or gastroesophageal junction tissue. The regulated genes, most of which have not been linked to BE/EA etiology so far, included C2orf43/LDAH, ZFP57, and SLC9A3. Among the novel candidate loci, replication was achieved for two variants (rs7754014, Pcombined = 3.16×10−7 and rs1540, Pcombined = 4.16×10−6) which represent eQTLs for CFDP1 and SLC22A3, respectively. In summary, the present approach identified candidate genes whose expression was regulated by risk variants in disease-relevant tissues. These findings may facilitate the elucidation of BE/EA pathophysiology.

Klíčová slova:

Gene expression – Gene regulation – Genetic loci – Genetics of disease – Genome-wide association studies – Molecular genetics – Replication studies


1. Reid BJ, Li X, Galipeau PC, Vaughan TL. Barrett’s oesophagus and oesophageal adenocarcinoma: time for a new synthesis. Nat Rev Cancer. 2010;10: 87–101. Available: doi: 10.1038/nrc2773 20094044

2. Ronkainen J, Aro P, Storskrubb T, Johansson SE, Lind T, Bolling-Sternevald E, et al. Prevalence of Barrett’s esophagus in the general population: An endoscopic study. Gastroenterology. 2005;129: 1825–1831. doi: 10.1053/j.gastro.2005.08.053 16344051

3. Spechler SJ, Souza RF. Barrett’s Esophagus. N Engl J Med. 2014;371: 836–845. doi: 10.1056/NEJMra1314704 25162890

4. Chak A, Ochs-Balcom H, Falk G, Grady WM, Kinnard M, Willis JE, et al. Familiality in Barrett’s esophagus, adenocarcinoma of the esophagus, and adenocarcinoma of the gastroesophageal junction. Cancer Epidemiol Biomarkers Prev. 2006;15: 1668–73. doi: 10.1158/1055-9965.EPI-06-0293 16985029

5. Poynton AR, Walsh TN, O’Sullivan G, Hennessy TP. Carcinoma arising in familial Barrett’s esophagus. Am J Gastroenterol. 1996;91: 1855–6. Available: 8792715

6. Ek WE, Levine DM, D’Amato M, Pedersen NL, Magnusson PKE, Bresso F, et al. Germline genetic contributions to risk for esophageal adenocarcinoma, Barrett’s esophagus, and gastroesophageal reflux. J Natl Cancer Inst. 2013;105: 1711–8. doi: 10.1093/jnci/djt303 24168968

7. Gharahkhani P, Fitzgerald RC, Vaughan TL, Palles C, Gockel I, Tomlinson I, et al. Genome-wide association studies in oesophageal adenocarcinoma and Barrett’s oesophagus: a large-scale meta-analysis. Lancet Oncol. 2016;17: 1363–1373. doi: 10.1016/S1470-2045(16)30240-6 27527254

8. Morley M, Molony CM, Weber TM, Devlin JL, Ewens KG, Spielman RS, et al. Genetic analysis of genome-wide variation in human gene expression. Nature. 2004;430: 743–747. doi: 10.1038/nature02797 15269782

9. Ghoussaini M, French JD, Michailidou K, Nord S, Beesley J, Canisus S, et al. Evidence that the 5p12 Variant rs10941679 Confers Susceptibility to Estrogen-Receptor-Positive Breast Cancer through FGF10 and MRPS30 Regulation. Am J Hum Genet. 2016;99: 903–911. doi: 10.1016/j.ajhg.2016.07.017 27640304

10. Rockman M V., Kruglyak L. Genetics of global gene expression. Nat Rev Genet. 2006;7: 862–872. doi: 10.1038/nrg1964 17047685

11. Guo X, Lin W, Bao J, Cai Q, Pan X, Bai M, et al. A Comprehensive cis-eQTL Analysis Revealed Target Genes in Breast Cancer Susceptibility Loci Identified in Genome-wide Association Studies. Am J Hum Genet. 2018;102: 890–903. doi: 10.1016/j.ajhg.2018.03.016 29727689

12. Li Q, Stram A, Chen C, Kar S, Gayther S, Pharoah P, et al. Expression QTL-based analyses reveal candidate causal genes and loci across five tumor types. Hum Mol Genet. 2014;23: 5294–5302. doi: 10.1093/hmg/ddu228 24907074

13. Small KS, Hedman ÅK, Grundberg E, Nica AC, Thorleifsson G, Kong A, et al. Identification of an imprinted master trans regulator at the KLF14 locus related to multiple metabolic phenotypes. Nat Genet. 2011;43: 561–564. doi: 10.1038/ng.833 21572415

14. Aguet F, Ardlie KG, Cummings BB, Gelfand ET, Getz G, Hadley K, et al. Genetic effects on gene expression across human tissues. Nature. 2017;550: 204–213. doi: 10.1038/nature24277 29022597

15. Giambartolomei C, Vukcevic D, Schadt EE, Franke L, Hingorani AD, Wallace C, et al. Bayesian Test for Colocalisation between Pairs of Genetic Association Studies Using Summary Statistics. PLoS Genet. 2014;10: e1004383. doi: 10.1371/journal.pgen.1004383 24830394

16. R Core Team, R Foundation for Statistical Computing. R: A language and environment for statistical computing. Vienna, Austria; 2017. Available:

17. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MAR, Bender D, et al. PLINK: A Tool Set for Whole-Genome Association and Population-Based Linkage Analyses. Am J Hum Genet. 2007;81: 559–575. doi: 10.1086/519795 17701901

18. Willer CJ, Li Y, Abecasis GR. METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics. 2010;26: 2190–2191. doi: 10.1093/bioinformatics/btq340 20616382

19. Szklarczyk D, Gable AL, Lyon D, Junge A, Wyder S, Huerta-Cepas J, et al. STRING v11: protein–protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res. 2019;47: D607–D613. doi: 10.1093/nar/gky1131 30476243

20. Levine DM, Ek WE, Zhang R, Liu X, Onstad L, Sather C, et al. A genome-wide association study identifies new susceptibility loci for esophageal adenocarcinoma and Barrett’s esophagus. Nat Genet. 2013;45: 1487–1493. doi: 10.1038/ng.2796 24121790

21. Palles C, Chegwidden L, Li X, Findlay JM, Farnham G, Castro Giner F, et al. Polymorphisms Near TBX5 and GDF7 Are Associated With Increased Risk for Barrett’s Esophagus. Gastroenterology. 2015;148: 367–378. doi: 10.1053/j.gastro.2014.10.041 25447851

22. Su Z, Gay LJ, Strange A, Palles C, Band G, Whiteman DC, et al. Common variants at the MHC locus and at chromosome 16q24.1 predispose to Barrett’s esophagus. Nat Genet. 2012;44: 1131–1136. doi: 10.1038/ng.2408 22961001

23. Messina G, Atterrato MT, Prozzillo Y, Piacentini L, Losada A, Dimitri P. The human Cranio Facial Development Protein 1 (Cfdp1) gene encodes a protein required for the maintenance of higher-order chromatin organization. Sci Rep. 2017;7: 45022. doi: 10.1038/srep45022 28367969

24. Kekuda R, Prasad PD, Wu X, Wang H, Fei YJ, Leibach FH, et al. Cloning and functional characterization of a potential-sensitive, polyspecific organic cation transporter (OCT3) most abundantly expressed in placenta. J Biol Chem. 1998;273: 15971–15979. doi: 10.1074/jbc.273.26.15971 9632645

25. Wu X, Huang W, Ganapathy ME, Wang H, Kekuda R, Conway SJ, et al. Structure, function, and regional distribution of the organic cation transporter OCT3 in the kidney. Am J Physiol Renal Physiol. 2000;279: F449–58. doi: 10.1152/ajprenal.2000.279.3.F449 10966924

26. Fu L, Qin Y-R, Ming X-Y, Zuo X-B, Diao Y-W, Zhang L-Y, et al. RNA editing of SLC22A3 drives early tumor invasion and metastasis in familial esophageal cancer. Proc Natl Acad Sci U S A. 2017;114: E4631–E4640. doi: 10.1073/pnas.1703178114 28533408

27. Nishikura K. Oesophageal cancer: RNA editing of SLC22A3 mRNAs: causative relevance to familial ESCC? Nat Rev Gastroenterol Hepatol. 2017;14: 569–570. doi: 10.1038/nrgastro.2017.102 28743982

28. Goo Y-H, Son S-H, Kreienberg PB, Paul A. Novel lipid droplet-associated serine hydrolase regulates macrophage cholesterol mobilization. Arterioscler Thromb Vasc Biol. 2014;34: 386–96. doi: 10.1161/ATVBAHA.113.302448 24357060

29. Mohammed H, Hernando-Herraez I, Savino A, Scialdone A, Macaulay I, Mulas C, et al. Single-Cell Landscape of Transcriptional Heterogeneity and Cell Fate Decisions during Mouse Early Gastrulation. Cell Rep. 2017;20: 1215–1228. doi: 10.1016/j.celrep.2017.07.009 28768204

30. Umer HM, Cavalli M, Dabrowski MJ, Diamanti K, Kruczyk M, Pan G, et al. A Significant Regulatory Mutation Burden at a High-Affinity Position of the CTCF Motif in Gastrointestinal Cancers. Hum Mutat. 2016;37: 904–913. doi: 10.1002/humu.23014 27174533

31. Biemesderfer D, Pizzonia J, Abu-Alfa A, Exner M, Reilly R, Igarashi P, et al. NHE3: a Na+/H+ exchanger isoform of renal brush border. Am J Physiol. 1993;265: F736–F742. doi: 10.1152/ajprenal.1993.265.5.F736 8238556

32. Yang S-C, Chen C-L, Yi C-H, Liu T-T, Shieh K-R. Changes in Gene Expression Patterns of Circadian-Clock, Transient Receptor Potential Vanilloid-1 and Nerve Growth Factor in Inflamed Human Esophagus. Sci Rep. 2015;5: 13602. doi: 10.1038/srep13602 26337663

33. Zhu Z, Zhang F, Hu H, Bakshi A, Robinson MR, Powell JE, et al. Integration of summary data from GWAS and eQTL studies predicts complex trait gene targets. Nat Genet. 2016;48: 481–7. doi: 10.1038/ng.3538 27019110

34. Nica AC, Montgomery SB, Dimas AS, Stranger BE, Beazley C, Barroso I, et al. Candidate causal regulatory effects by integration of expression QTLs with complex trait genetic associations. PLoS Genet. 2010;6. doi: 10.1371/journal.pgen.1000895 20369022

35. Lusis AJ, Arnold AP, Schadt EE, Wang H, Ingram-Drake L, Wang S, et al. Tissue-specific expression and regulation of sexually dimorphic genes in mice. Genome Res. 2006;16: 995–1004. doi: 10.1101/gr.5217506 16825664

36. Wang DH. The Esophageal Squamous Epithelial Cell—Still a Reasonable Candidate for the Barrett’s Esophagus Cell of Origin? CMGH. Elsevier; 2017. pp. 157–160. doi: 10.1016/j.jcmgh.2017.01.015 28593187

37. Zhuang L, Fitzgerald RC. Cancer development: Origins in the oesophagus. Nature. 2017;550: 463–464. doi: 10.1038/nature24150 29019986

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2019 Číslo 12
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