Discovery of genetic risk factors for diverticulosis and diverticulitis

• Applicants: Professor Dr. Jochen Hampe; Professor Dr. Wolfgang Lieb; Professor Dr. Clemens Schafmayer; Professor Dr. Henry Völzke; Professor Dr. Thilo Wedel
• Subject Area: Gastroenterology ; Human Genetics
• Term: from 2014 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 246642874

Up to 50% of individuals over 60 years of age are affected by diverticulosis and 10 to 25% of these patients progress to develop diverticulitis or bleeding. Severe complications such as abscess, perforation and acute bleeding occur in approximately 15% of diverticulitis cases resulting in an annual mortality 2.5 per 100,000. The incidence of diverticular disease has increased substantially over the last decades. Due to its high prevalence and the associated complications, diverticular disease represents the 5th most important gastrointestinal disease in terms of direct and indirect cost. The heritability of diverticulosis was estimated at ~42% in a Swedish twin study. A Danish population-based epidemiological study confirmed this high heritability estimate at 53%. Despite this strong and established genetic component in the etiology of the disease, no systematic or genome-wide genetic studies have been performed in the disease up to now. This project proposes to perform the first genome-wide association study using each 1,700 patients with diverticulosis, diverticulitis and diverticular-free controls plus the appropriate validation experiments. We expect the identification of distinct risk loci for intestinal wall integrity / motility and intestinal barrier function from the pair-wise association analysis comparing controls vs. diverticulosis and diverticulitis vs. diverticulosis, respectively. This proposal uses the D-A-CH mechanism to bring together large and complementary patient cohorts and existing genotype resources of German and Austrian groups (in total 15,000 patients and 2,300 with existing GWAS data). Only this combination of the patient resources and funding options through the two agencies DFG and FWF enables a competitive experiment. Inclusion of two centers of the German National Cohort and a group with strong functional expertise in diverticulosis and intestinal motility provide for the future development of integrated, population-based risk models and for mechanistic follow-up studies to translate the risk genes findings into novel pathophysiological insights. Given the firmly established heritable component of diverticulosis from twin and population analyses and the complete lack of previous studies, the chances for robust gene discoveries to yield a deeper understanding of its genetic disease etiology are very high. We expect distinct etiological pathways for diverticular disease and diverticulitis. Both will allow exciting new insights into disease etiology and novel prevention and treatment options for these common disorders.

• DFG Programme: Research Grants
• International Connection: Austria
• Partner Organisation: Fonds zur Förderung der wissenschaftlichen Forschung (FWF)
• Participating Persons: Professor Dr. Christian Datz; Professor Dr. Andre Franke; Professorin Dr. Andrea Gsur; Professor Dr. Michael Krawczak