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Gut. 2019 May;68(5):854-865. doi: 10.1136/gutjnl-2018-317619. Epub 2019 Jan 19.

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

Author information

1
Department of Visceral and Thoracic Surgery, Kiel University, Kiel, Germany.
2
University of Exeter Medical School, University of Exeter, United Kingdom, Exeter, UK.
3
Medical Department 1, University Hospital Dresden, Technische Universität Dresden (TU Dresden), Dresden, Germany.
4
Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden (TU Dresden), Dresden, Germany.
5
Institute of Anatomy, Kiel University, Kiel, Germany.
6
Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany.
7
Institute of Cancer Research, Department of Medicine I, Medical University Vienna, Vienna, Austria.
8
Department of Gastroenterology and Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania.
9
General Hospital Lüneburg, Lüneburg, Germany.
10
Department of Internal Medicine, Gastroenterology and Pulmonology, Evangelic Hospital Köln-Kalk, Cologne, Germany.
11
Department of General and Thoracic Surgery, Hospital Osnabrück, Osnabrück, Germany.
12
Department of Gastroenterology, Helios Hospital Weißeritztal, Freital, Germany.
13
Medical Department 1, University Hospital Halle, Martin-Luther Universität Halle-Wittenberg, Halle, Germany.
14
Diakonissenanstalt, Hospital Dresden, Dresden, Germany.
15
Gastroenterology Outpatient Center Fördepraxis, Kiel, Germany.
16
Center for Gastroenterology and Hepatology, Kiel, Germany.
17
Department of Surgery, Community Hospital Kiel, Kiel, Germany.
18
Department of Internal Medicine II, Hospital Riesa, Kiel, Germany.
19
Department of Internal Medicine, Hospital Freiberg, Freiberg, Germany.
20
Department of Visceral, Thoracic and Vascular Surgery, Technische Universität Dresden (TU Dresden), Dresden, Germany.
21
Department of Surgery, University Hospital Erlangen, Erlangen, Germany.
22
Department of Internal Medicine, Hospital Oberndorf, Teaching Hospital of the Paracelsus Private Medical University of Salzburg, Oberndorf, Austria.
23
Outpatient Center for Gastroenterology, Dippoldiswalde, Germany.
24
Outpatient Center for Gastroenterology Dresden-Blasewitz, Dresden, Germany.
25
Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
26
Stress Research Institute, Stockholm University, Stockholm, Sweden.
27
Department of Medicine Solna and Centre for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
28
Institute of Medical Informatics and Statistics, Kiel University, Kiel, Germany.
29
Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
30
Department of Gastroenterology, Hospital Oberpullendorf, Oberpullendorf, Austria.
31
Institute of Epidemiology & Popgen Biobank, Kiel University, Kiel, Germany.
32
Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
#
Contributed equally

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.

KEYWORDS:

diverticular disease; genetic polymorphisms; intestinal motility

PMID:
30661054
DOI:
10.1136/gutjnl-2018-317619
[Indexed for MEDLINE]

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