Mendelian Randomization Reveals the Anatomical Site Differences and Reverse Causality in the Association Between Diverticular Disease and Colorectal Cancer

Abstract Purpose Colorectal cancer (CRC) is a leading global health concern due to its high incidence and mortality rates. Diverticular disease (DD), characterized by the formation of pouches in the colon wall, is prevalent in Western populations, and shares several risk factors with CRC. However, the causal relationship between DD and CRC, including its precancerous lesion, remains to be elucidated. Methods This study employed Mendelian randomization (MR) approach using genomic data from European cohort to investigate the potential causal link between DD and the risk of colorectal adenoma, CRC, and its anatomical subtypes (proximal colon cancer, distal colon cancer, and rectal cancer). Single nucleotide polymorphisms significantly associated with these conditions were utilized as instrumental variables in MR analysis to assess causality. Results The forward MR analysis indicated no significant causal effect of DD on the risk of colorectal adenoma (OR 0.87, 95% CI 0.74–1.03, p = 0.103), CRC (OR 0.94, 95% CI 0.87–1.02, p = 0.117), or its anatomical subtypes. In contrast, the reverse MR analysis showed that distal colon cancer may increase the risk of DD (OR 1.02, 95% CI 1-1.04, p = 0.026), while proximal colon cancer and rectal Cancer did not show this association. Conclusion The study findings do not support DD as a risk factor for CRC or its precancerous lesion (colorectal adenoma). However, a possible association between distal colon cancer and an increased risk of DD was found, providing new insights into the prevention and treatment of both diseases.