Discovery of genetic risk factors for diverticulosis and diverticulitis

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.

Diverticular disease is a common complex disorder and its complications such as acute diverticulitis, bleeding or perforation represent a serious burden for the healthcare system. The incidence of diverticular disease has increased to 50% for individuals older than 60 years and a significant rise of incidence rates has been seen in younger age groups. Due to its high prevalence and associated complications diverticular disease represents the 5th most important gastrointestinal disease in Western countries in terms of direct and indirect costs and mortality. The pathogenesis of diverticular disease is a multifactorial process that involves lifestyle factors (smoking, physical inactivity, BMI), aging and a genetic predisposition. Epidemiological and twin studies have estimated the heritability of diverticular disease at 40 to 53%. Despite its high clinical and economic impact, diverticular disease is pathophysiologically and genetically under-explored. Therefore, we performed within the D-A-CH project the largest genome-wide association study in patients with diverticulosis, diverticulitis and diverticular-free controls in 31,964 cases and 419,135 controls of European descent from UK biobank. We identified 48 risk loci, of which 45 were detected for the first time. For the replication study existing patient cohorts - partly with existing genome-wide genotype data - from Germany and Austria were jointly analyzed to increase statistical power. Furthermore, cohorts from Sweden and Lithuania were included in the replication analysis. Replication cohorts comprised 3,893 cases and 2,829 diverticula-free controls and yielded the replication of 27 identified loci. Functional analysis suggests novel mechanisms and points to diverticulosis primarily as a disorder of intestinal neuromuscular function and of impaired connective fiber support, while additional diverticulitis risk might be conferred by epithelial dysfunction. These findings provide new deep insights into the biology of human bowel function and the understanding of colonic biology and disease pathophysiology. The novel genetic risk signature identified within this D-A-CH project opens a new path for potential therapeutic intervention in this common disease.