Genome-wide association analysis of diverticular disease points towards neuromuscular, connective tissue and epithelial pathomechanisms.
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Schafmayer Clemens, Harrison James William, Buch Stephan, Lange Christina, Reichert Matthias C, Hofer Philipp, Cossais François, Kupcinskas Juozas, von Schönfels Witigo, Schniewind Bodo, Kruis Wolfgang, Tepel Jürgen, Zobel Myrko, Rosendahl Jonas, Jacobi Thorsten, Walther-Berends Andreas, Schroeder Michael, Vogel Ilka, Sergeev Petr, Boedeker Hans, Hinrichsen Holger, Volk Andreas, Erk Jens-Uwe, Burmeister Greta, Hendricks Alexander, Hinz Sebastian, Wolff Sebastian, Böttner Martina, Wood Andrew R, Tyrrell Jessica, Beaumont Robin N, Langheinrich Melanie, Kucharzik Torsten, Brezina Stefanie, Huber-Schönauer Ursula, Pietsch Leonora, Noack Laura Sophie, Brosch Mario, Herrmann Alexander, Thangapandi Raghavan Veera, Schimming Hans Wolfgang, Zeissig Sebastian, Palm Stefan, Focke Gerd, Andreasson Anna, Schmidt Peter T, Weitz Juergen, Krawczak Michael, Völzke Henry, Leeb Gernot, Michl Patrick, Lieb Wolfgang, Grützmann Robert, Franke Andre, Lammert Frank, Becker Thomas, Kupcinskas Limas, D'Amato Mauro, Wedel Thilo, Datz Christian, Gsur Andrea, Weedon Michael N, Hampe Jochen
Аннотация
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.