Association between inflammatory bowel disease and all-cause dementia: A two-sample Mendelian randomization study

Abstract

Background: Numerous observational studies have documented a correlation between inflammatory bowel disease (IBD) and an increased risk of dementia. However, the causality of their associations remains elusive.

Aim: To assess the causal relationship between IBD and the occurrence of all-cause dementia using the two-sample Mendelian randomization (MR) method.

Methods: Genetic variants extracted from the large genome-wide association study (GWAS) for IBD (the International IBD Genetics Consortium, n = 34652) were used to identify the causal link between IBD and dementia (FinnGen, n = 306102). The results of the study were validated via another IBD GWAS (United Kingdom Biobank, n = 463372). Moreover, MR egger intercept, MR pleiotropy residual sum and outlier, and Cochran's Q test were employed to evaluate pleiotropy and heterogeneity. Finally, multiple MR methods were performed to estimate the effects of genetically predicted IBD on dementia, with the inverse variance wei-ghted approach adopted as the primary analysis.

Results: The results of the pleiotropy and heterogeneity tests revealed an absence of significant pleiotropic effects or heterogeneity across all genetic variants in outcome GWAS. No evidence of a causal effect between IBD and the risk of dementia was identified in the inverse variance weighted [odds ratio (OR) = 0.980, 95%CI : 0.942-1.020, P value = 0.325], weighted median (OR = 0.964, 95%CI : 0.914-1.017, P value = 0.180), and MR-Egger (OR = 0.963, 95%CI : 0.867-1.070, P value = 0.492) approaches. Consistent results were observed in validation analyses. Reverse MR analysis also showed no effect of dementia on the development of IBD. Furthermore, MR analysis suggested that IBD and its subtypes did not causally affect all-cause dementia and its four subtypes, including dementia in Alzheimer's disease, vascular dementia, dementia in other diseases classified elsewhere, and unspecified dementia.

Conclusion: Taken together, our MR study signaled that IBD and its subentities were not genetically associated with all-cause dementia or its subtypes. Further large prospective studies are warranted to elucidate the impact of intestinal inflammation on the development of dementia.

Keywords: All-cause dementia; Causal effect; Inflammatory bowel disease; Mendelian randomization; Risk factor.