A Mendelian Randomization Study on IBD and Aging

Abstract Background and Aims: Although observational studies have reported correlations between inflammatory bowel disease (IBD) and aging, there is no evidence supporting causal relationships between the two. Methods: Summary data from the Genome-Wide Association Study (GWAS) were subjected to two-sample and bidirectional Mendelian randomization (MR) to assess the causal relationships between biomarkers of IBD and aging. Following IEU GWAS database screening and single nucleotide polymorphism filtering, various MR methods, including the inverse-variance weighted method, were applied to qualified instrumental variables. The heterogeneity and pleiotropy of the instrumental variables were verified by sensitivity analyses. Results: Ulcerative colitis (UC) was associated with a 0.10 standard deviation (SD) unit increase in DNA methylation PhenoAge acceleration (adjusted P-value=0.010). SD unit increases in intrinsic epigenetic age acceleration were associated with increases in the probability of Crohn’s disease (CD) and IBD of 0.05 (adjusted P-value=0.032) and 0.04 (adjusted P-value=0.039), respectively. SD unit increases in physical activity and DNA methylation PhenoAge acceleration increased the probabilities of IBD by 0.03 and 0.04 (adjusted P-value=0.039), respectively. CD was associated with shorter telomere length; UC was associated with increased DNA methylation PhenoAge acceleration; and IBD was associated with decreased appendicular lean mass. Four factors associated with aging showed causal relationships: telomere length, DNA methylation GrimAge acceleration, DNA methylation Hannum age acceleration, and usual walking pace, with IBD ruled out. Conclusion: These findings provide new evidence for the causal relationship between IBD and aging in European populations, as well as providing suggestions for the prevention and treatment of IBD.