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  • Genome-wide association analysis of diverticular disease points towards neuromuscular, connective tissue and epithelial pathomechanisms

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Original article
Genome-wide association analysis of diverticular disease points towards neuromuscular, connective tissue and epithelial pathomechanisms
  1. Clemens Schafmayer1,
  2. James William Harrison2,
  3. Stephan Buch3,4,
  4. Christina Lange5,
  5. Matthias C Reichert6,
  6. Philipp Hofer7,
  7. François Cossais5,
  8. Juozas Kupcinskas8,
  9. Witigo von Schönfels1,
  10. Bodo Schniewind9,
  11. Wolfgang Kruis10,
  12. Jürgen Tepel11,
  13. Myrko Zobel12,
  14. Jonas Rosendahl13,
  15. Thorsten Jacobi14,
  16. Andreas Walther-Berends15,
  17. Michael Schroeder16,
  18. Ilka Vogel17,
  19. Petr Sergeev18,
  20. Hans Boedeker19,
  21. Holger Hinrichsen16,
  22. Andreas Volk20,
  23. Jens-Uwe Erk13,
  24. Greta Burmeister1,
  25. Alexander Hendricks1,
  26. Sebastian Hinz1,
  27. Sebastian Wolff10,
  28. Martina Böttner5,
  29. Andrew R Wood2,
  30. Jessica Tyrrell2,
  31. Robin N Beaumont2,
  32. Melanie Langheinrich21,
  33. Torsten Kucharzik9,
  34. Stefanie Brezina7,
  35. Ursula Huber-Schönauer22,
  36. Leonora Pietsch13,
  37. Laura Sophie Noack3,
  38. Mario Brosch3,4,
  39. Alexander Herrmann3,
  40. Raghavan Veera Thangapandi3,
  41. Hans Wolfgang Schimming12,
  42. Sebastian Zeissig3,4,
  43. Stefan Palm23,
  44. Gerd Focke24,
  45. Anna Andreasson25,26,
  46. Peter T Schmidt27,
  47. Juergen Weitz20,
  48. Michael Krawczak28,
  49. Henry Völzke29,
  50. Gernot Leeb30,
  51. Patrick Michl13,
  52. Wolfgang Lieb31,
  53. Robert Grützmann21,
  54. Andre Franke32,
  55. Frank Lammert6,
  56. Thomas Becker1,
  57. Limas Kupcinskas8,
  58. Mauro D’Amato27,
  59. Thilo Wedel5,
  60. Christian Datz22,
  61. Andrea Gsur7,
  62. Michael N Weedon2,
  63. Jochen Hampe3,4
  1. 1 Department of Visceral and Thoracic Surgery, Kiel University, Kiel, Germany
  2. 2 University of Exeter Medical School, University of Exeter, United Kingdom, Exeter, UK
  3. 3 Medical Department 1, University Hospital Dresden, Technische Universität Dresden (TU Dresden), Dresden, Germany
  4. 4 Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden (TU Dresden), Dresden, Germany
  5. 5 Institute of Anatomy, Kiel University, Kiel, Germany
  6. 6 Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany
  7. 7 Institute of Cancer Research, Department of Medicine I, Medical University Vienna, Vienna, Austria
  8. 8 Department of Gastroenterology and Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania
  9. 9 General Hospital Lüneburg, Lüneburg, Germany
  10. 10 Department of Internal Medicine, Gastroenterology and Pulmonology, Evangelic Hospital Köln-Kalk, Cologne, Germany
  11. 11 Department of General and Thoracic Surgery, Hospital Osnabrück, Osnabrück, Germany
  12. 12 Department of Gastroenterology, Helios Hospital Weißeritztal, Freital, Germany
  13. 13 Medical Department 1, University Hospital Halle, Martin-Luther Universität Halle-Wittenberg, Halle, Germany
  14. 14 Diakonissenanstalt, Hospital Dresden, Dresden, Germany
  15. 15 Gastroenterology Outpatient Center Fördepraxis, Kiel, Germany
  16. 16 Center for Gastroenterology and Hepatology, Kiel, Germany
  17. 17 Department of Surgery, Community Hospital Kiel, Kiel, Germany
  18. 18 Department of Internal Medicine II, Hospital Riesa, Kiel, Germany
  19. 19 Department of Internal Medicine, Hospital Freiberg, Freiberg, Germany
  20. 20 Department of Visceral, Thoracic and Vascular Surgery, Technische Universität Dresden (TU Dresden), Dresden, Germany
  21. 21 Department of Surgery, University Hospital Erlangen, Erlangen, Germany
  22. 22 Department of Internal Medicine, Hospital Oberndorf, Teaching Hospital of the Paracelsus Private Medical University of Salzburg, Oberndorf, Austria
  23. 23 Outpatient Center for Gastroenterology, Dippoldiswalde, Germany
  24. 24 Outpatient Center for Gastroenterology Dresden-Blasewitz, Dresden, Germany
  25. 25 Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
  26. 26 Stress Research Institute, Stockholm University, Stockholm, Sweden
  27. 27 Department of Medicine Solna and Centre for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
  28. 28 Institute of Medical Informatics and Statistics, Kiel University, Kiel, Germany
  29. 29 Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany
  30. 30 Department of Gastroenterology, Hospital Oberpullendorf, Oberpullendorf, Austria
  31. 31 Institute of Epidemiology & Popgen Biobank, Kiel University, Kiel, Germany
  32. 32 Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany
  1. Correspondence to Professor Jochen Hampe, Medical Department 1, University Hospital Dresden, Technische Universität Dresden (TU Dresden), Dresden 01307, Germany; jochen.hampe{at}uniklinikum-dresden.de

Abstract

Objective Diverticular disease is a common complex disorder characterised by mucosal outpouchings of the colonic wall that manifests through complications such as diverticulitis, perforation and bleeding. We report the to date largest genome-wide association study (GWAS) to identify genetic risk factors for diverticular disease.

Design Discovery GWAS analysis was performed on UK Biobank imputed genotypes using 31 964 cases and 419 135 controls of European descent. Associations were replicated in a European sample of 3893 cases and 2829 diverticula-free controls and evaluated for risk contribution to diverticulitis and uncomplicated diverticulosis. Transcripts at top 20 replicating loci were analysed by real-time quatitative PCR in preparations of the mucosal, submucosal and muscular layer of colon. The localisation of expressed protein at selected loci was investigated by immunohistochemistry.

Results We discovered 48 risk loci, of which 12 are novel, with genome-wide significance and consistent OR in the replication sample. Nominal replication (p<0.05) was observed for 27 loci, and additional 8 in meta-analysis with a population-based cohort. The most significant novel risk variant rs9960286 is located near CTAGE1 with a p value of 2.3×10−10 and 0.002 (ORallelic=1.14 (95% CI 1.05 to 1.24)) in the replication analysis. Four loci showed stronger effects for diverticulitis, PHGR1 (OR 1.32, 95% CI 1.12 to 1.56), FAM155A-2 (OR 1.21, 95% CI 1.04 to 1.42), CALCB (OR 1.17, 95% CI 1.03 to 1.33) and S100A10 (OR 1.17, 95% CI 1.03 to 1.33).

Conclusion In silico analyses point to diverticulosis primarily as a disorder of intestinal neuromuscular function and of impaired connective fibre support, while an additional diverticulitis risk might be conferred by epithelial dysfunction.

  • diverticular disease
  • intestinal motility
  • genetic polymorphisms

https://doi.org/10.1136/gutjnl-2018-317619

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    Footnotes

    • CS, JWH and SB contributed equally.

    • TW, CD, AG, MNW and JH contributed equally.

    • Contributors JWH, SB, CL, FC: performed the experiments, analysed the data and wrote the manuscript; JWH, AH, SB, AR, WR, NB: performed the bioinformatic analyses; CL, FC, MB: performed real-time PCR, histological, immunohistochemical analyses; CS, FL, LK, MZ, WvS, MCR, JR, TB coordinated, managed collection of samples, performed phenotyping; WL coordinated and supervised collection of samples; SN, UH-S, FR, PH, BS, WK, JT, MZ, JR, AW-B, TJ, JK, MS, IV, PS, HB, HH, AV, J-UE, GB, AH, S H, SW, ML, TK, SB, UH-S, LP, LSN, H-WS, SZ, SP, GF, AA, PTS, GL, JW, FL, TB, LK, PM, RG, VM: obtained the samples, performed phenotyping, interpretation of data; MK, MD’A, SZ, AF, MB, HV, WK, FL, RVT, JT gave conceptual advice, participated in the discussions, interpretation of the results, editing of the manuscript; CS, JH, MW, CD, AG, TW: conceived the experimental and analytical design, analysed data, wrote and reviewed the manuscript. All authors critically revised and contributed to the final manuscript.

    • Funding The work presented in this manuscript was supported by the German Research Council (DFG, Ha3091/9-1, WE2366/5-1) and the Austrian Science Fund (FWF, I1542-B13). Further support was received from SPAR Austria and from institutional funds from the Christian-Albrechts-University Kiel. The recruitment of the West German cohort was supported by a grant from the Faculty of Medicine, Saarland University (HOMFOR grant T201000747) to MCR. This study was supported by a grant of the Research Council of Lithuania No. SEN-06/2015/PRM15-135. AA, PTS were supported by the Stockholm County Council (ALF project). MD’A was supported by the Swedish Research Council (VR grant 2017-02403). Data access to the UK Biobank data was granted under project numbers 22691 and 9055.

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Patient consent for publication Not required.

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