Genome-wide association analysis of diverticular disease points towards neuromuscular, connective tissue and epithelial pathomechanisms.
dc.contributor.author | Schafmayer, C | |
dc.contributor.author | Harrison, JW | |
dc.contributor.author | Buch, S | |
dc.contributor.author | Lange, C | |
dc.contributor.author | Reichert, MC | |
dc.contributor.author | Hofer, P | |
dc.contributor.author | Cossais, F | |
dc.contributor.author | Kupcinskas, J | |
dc.contributor.author | von Schönfels, W | |
dc.contributor.author | Schniewind, B | |
dc.contributor.author | Kruis, W | |
dc.contributor.author | Tepel, J | |
dc.contributor.author | Zobel, M | |
dc.contributor.author | Rosendahl, J | |
dc.contributor.author | Jacobi, T | |
dc.contributor.author | Walther-Berends, A | |
dc.contributor.author | Schroeder, M | |
dc.contributor.author | Vogel, I | |
dc.contributor.author | Sergeev, P | |
dc.contributor.author | Boedeker, H | |
dc.contributor.author | Hinrichsen, H | |
dc.contributor.author | Volk, A | |
dc.contributor.author | Erk, J-U | |
dc.contributor.author | Burmeister, G | |
dc.contributor.author | Hendricks, A | |
dc.contributor.author | Hinz, S | |
dc.contributor.author | Wolff, S | |
dc.contributor.author | Böttner, M | |
dc.contributor.author | Wood, AR | |
dc.contributor.author | Tyrrell, J | |
dc.contributor.author | Beaumont, RN | |
dc.contributor.author | Langheinrich, M | |
dc.contributor.author | Kucharzik, T | |
dc.contributor.author | Brezina, S | |
dc.contributor.author | Huber-Schönauer, U | |
dc.contributor.author | Pietsch, L | |
dc.contributor.author | Noack, LS | |
dc.contributor.author | Brosch, M | |
dc.contributor.author | Herrmann, A | |
dc.contributor.author | Thangapandi, RV | |
dc.contributor.author | Schimming, HW | |
dc.contributor.author | Zeissig, S | |
dc.contributor.author | Palm, S | |
dc.contributor.author | Focke, G | |
dc.contributor.author | Andreasson, A | |
dc.contributor.author | Schmidt, PT | |
dc.contributor.author | Weitz, J | |
dc.contributor.author | Krawczak, M | |
dc.contributor.author | Völzke, H | |
dc.contributor.author | Leeb, G | |
dc.contributor.author | Michl, P | |
dc.contributor.author | Lieb, W | |
dc.contributor.author | Grützmann, R | |
dc.contributor.author | Franke, A | |
dc.contributor.author | Lammert, F | |
dc.contributor.author | Becker, T | |
dc.contributor.author | Kupcinskas, L | |
dc.contributor.author | D'Amato, M | |
dc.contributor.author | Wedel, T | |
dc.contributor.author | Datz, C | |
dc.contributor.author | Gsur, A | |
dc.contributor.author | Weedon, MN | |
dc.contributor.author | Hampe, J | |
dc.date.accessioned | 2019-02-07T14:39:45Z | |
dc.date.issued | 2019-01-19 | |
dc.description.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. | en_GB |
dc.description.sponsorship | German Research Council | en_GB |
dc.description.sponsorship | Austrian Science Fund | en_GB |
dc.description.sponsorship | Faculty of Medicine, Saarland University | en_GB |
dc.description.sponsorship | Research Council of Lithuania | en_GB |
dc.description.sponsorship | Swedish Research Council | en_GB |
dc.description.sponsorship | Medical Research Council | en_GB |
dc.identifier.citation | Published online 19-01-2019 | en_GB |
dc.identifier.doi | 10.1136/gutjnl-2018-317619 | |
dc.identifier.grantnumber | DFG, Ha3091/9-1, WE2366/5-1 | en_GB |
dc.identifier.grantnumber | FWF, I1542-B13 | en_GB |
dc.identifier.grantnumber | HOMFOR grant T201000747 | en_GB |
dc.identifier.grantnumber | No. SEN-06/2015/PRM15-135 | en_GB |
dc.identifier.grantnumber | VR grant 2017-02403 | en_GB |
dc.identifier.other | gutjnl-2018-317619 | |
dc.identifier.uri | http://hdl.handle.net/10871/35810 | |
dc.language.iso | en | en_GB |
dc.publisher | BMJ | en_GB |
dc.relation.url | https://www.ncbi.nlm.nih.gov/pubmed/30661054 | en_GB |
dc.rights | © Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ. | en_GB |
dc.subject | diverticular disease | en_GB |
dc.subject | genetic polymorphisms | en_GB |
dc.subject | intestinal motility | en_GB |
dc.title | Genome-wide association analysis of diverticular disease points towards neuromuscular, connective tissue and epithelial pathomechanisms. | en_GB |
dc.type | Article | en_GB |
dc.date.available | 2019-02-07T14:39:45Z | |
dc.identifier.issn | 0017-5749 | |
exeter.place-of-publication | England | en_GB |
dc.description | This is the author accepted manuscript. | en_GB |
dc.identifier.journal | Gut | en_GB |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0/ | en_GB |
dcterms.dateAccepted | 2019-01-05 | |
exeter.funder | ::Medical Research Council (MRC) | en_GB |
rioxxterms.version | AM | en_GB |
rioxxterms.licenseref.startdate | 2019-01-19 | |
rioxxterms.type | Journal Article/Review | en_GB |
refterms.dateFCD | 2019-02-07T11:34:44Z | |
refterms.versionFCD | AM | |
refterms.dateFOA | 2019-02-07T14:39:48Z | |
refterms.panel | A | en_GB |
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