PROJECT SUMMARY Colonic diverticulosis is a common condition in the United States. Diverticulosis can be complicated by acute inflammation, infection, hemorrhage, collectively termed diverticular disease. The burden of diverticular disease is estimated at $4 billion dollars annually. The first phase of this study collected detailed information about diverticula on more than 600 individuals who underwent screening colonoscopy. The results have challenged conventional wisdom. Contrary to expectation, there was no protective association with increased fiber, physical activity or regular bowel movements. There was no evidence of chronic inflammation in the colons of individuals with diverticulosis. There was a different colonic distribution of diverticula by race, with more right-sided diverticula for blacks. Compelling evidence from others indicates that genetic factors may be responsible for approximately half of the risk for diverticular disease, but there have been no association studies in large numbers of patients. The proposed research builds on the infrastructure and information already assembled to address four specific aims: 1) To perform a genome-wide association study on archived DNA from 624 well-characterized patients to identify possible genetic determinants of diverticulosis. 2) To assess differential gene expression associated with diverticulosis. 3) To perform a targeted association study using candidates identified from GWAS and differential gene expression on archived DNA to confirm genetic determinants of diverticulosis using stored DNA from a second population of 1824 colonoscopy patients. 4) To follow-up individuals in the diverticulosis cohort to determine whether the presence of diverticulosis is associated with the development of chronic gastrointestinal symptoms. The laboratory-based aims will be accomplished using specimens that have already been collected. Previously described GWAS methods will identify genetic variants that may contribute to diverticulosis. RNAseq will comprehensively compare the transcriptomes of diverticulosis cases compared to controls. Follow-up interviews on previously enrolled subjects will evaluate symptom development. The study is innovative because it will be the first large prospective cohort that has used a structural exam (colonoscopy) to accurately classify diverticulosis cases. Similarly, there are no large genetic studies based on structural exams. Successful completion of this study could open new avenues for research and patient care.