| Title: | Genome-wide association analysis of diverticular disease points towards neuromuscular, connective tissue and epithelial pathomechanisms |
| Journal: | Gut |
| Published: | 19 Jan 2019 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/30661054/ |
| DOI: | https://doi.org/10.1136/gutjnl-2018-317619 |
Publication 13761
WARNING: the interactive features of this website use CSS3, which your browser does not support. To use the full features of this website, please update your browser.
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.</p>
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.</p>
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).</p>
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.</p>
16 Keywords
- Adult
- Aged
- Case-Control Studies
- Colonic Diseases
- Connective Tissue
- Databases, Genetic
- Diverticular Diseases
- Epithelium
- Female
- Genetic Predisposition to Disease
- Genome-Wide Association Study
- Humans
- Male
- Middle Aged
- Neuromuscular Junction
- United Kingdom
63 Authors
- Clemens Schafmayer
- James William Harrison
- Stephan Buch
- Christina Lange
- Matthias C Reichert
- Philipp Hofer
- François Cossais
- Juozas Kupcinskas
- Witigo von Schönfels
- Bodo Schniewind
- Wolfgang Kruis
- Jürgen Tepel
- Myrko Zobel
- Jonas Rosendahl
- Thorsten Jacobi
- Andreas Walther-Berends
- Michael Schroeder
- Ilka Vogel
- Petr Sergeev
- Hans Boedeker
- Holger Hinrichsen
- Andreas Volk
- Jens-Uwe Erk
- Greta Burmeister
- Alexander Hendricks
- Sebastian Hinz
- Sebastian Wolff
- Martina Böttner
- Andrew R Wood
- Jessica Tyrrell
- Robin N Beaumont
- Melanie Langheinrich
- Torsten Kucharzik
- Stefanie Brezina
- Ursula Huber-Schönauer
- Leonora Pietsch
- Laura Sophie Noack
- Mario Brosch
- Alexander Herrmann
- Raghavan Veera Thangapandi
- Hans Wolfgang Schimming
- Sebastian Zeissig
- Stefan Palm
- Gerd Focke
- Anna Andreasson
- Peter T Schmidt
- Juergen Weitz
- Michael Krawczak
- Henry Völzke
- Gernot Leeb
- Patrick Michl
- Wolfgang Lieb
- Robert Grützmann
- Andre Franke
- Frank Lammert
- Thomas Becker
- Limas Kupcinskas
- Mauro D'Amato
- Thilo Wedel
- Christian Datz
- Andrea Gsur
- Michael N Weedon
- Jochen Hampe
Enabling scientific discoveries that improve human health