Causality between ageing and 24 gastrointestinal diseases: a bidirectional Mendelian randomization study

Abstract Purpose The relationship between aging and gastrointestinal diseases has not been extensively studied. This study aims to investigate the correlation between various proxies of aging and the risk of 24 gastrointestinal diseases using a Mendelian randomization approach. Methods The latest genome-wide association studies were used to collect summary data on telomere(definition) length, 4 epigenetic clocks ( like the Horvathage clock) and 24 gastrointestinal diseases (like gastric cancer). The instrumental variables were obtained from the summary data on exposure based on assumptions of correlation, independence and exclusivity.. Causal inferences were made using three methods of Mendelian randomization (such as inverse variance weighting). Four sensitivity analyses were used to assess the results' credibility. Result The analysis using inverse variance weighting indicates that longer telomere length is association with a lower risk of alcoholic liver disease and cirrhosis. (P = 0.009, P = 0.01), but a higher risk of cholelithiasis, cholecystitis, and pancreatic cancer (P = 0.006, P = 0.049, P = 0.028). Additionally, the genetically predicted HorvathAge acceleration was found to reduce the risk of developing chronic gastritis and gastric cancer (P = 0.003, P = 0.038). The analysis of reverse MR did not indicate any reverse causality for the aforementioned results. The presence of Celiac disease and ulcerative colitis may shorten telomere length (P < 0.001, P = 0.016), while the presence of Celiac disease may accelerate GrimAge and PhenoAge (P = 0.045, P = 0.032). Additionally, the presence of Cholangitis may accelerate GrimAge and HannumAge (P = 0.004, P = 0.008). Conclusion Telomere length was found to reduce the risk of alcoholic liver disease and cirrhosis, but increase the risk of gallstone disease, cholecystitis and pancreatic cancer. Additionally, genetically predicted HorvathAge acceleration was associated with a decreased risk of chronic gastritis and gastric cancer. Telomere length (TL) and epigenetic clock(definition) (EC) are two independent biomarkers of aging, therefore further research is needed to investigate the relationship between aging and the genetic predisposition to gastrointestinal diseases.