Inflammatory Bowel Disease and Neurodegenerative Disorders: Integrated Evidence from Mendelian Randomization, Shared Genetic Architecture and Transcriptomics

Abstract

AbstractObjectivePublished observational studies have revealed the connection between inflammatory bowel disease (IBD) and neurodegenerative disorders, whereas the causality remains largely unclear. Our study aims to assess the causality and identify the shared genetic architecture between IBD and neurodegenerative disorders.DesignA series of two-sample Mendelian randomization analyses were performed to assess the causality between IBD and neurodegenerative disorders (amyotrophic lateral sclerosis [ALS], Alzheimer’s disease [AD], Parkinson’s disease [PD], and multiple sclerosis [MS]). Shared genetic loci and functional interpretation were further investigated for IBD and ALS. The transcriptomic expressions of shared genes were evaluated in patients with IBD and ALS.ResultsGenetic predisposition to IBD is associated with lower odds of ALS (odds ratio [OR] 0.96, 95% confidence interval [CI] 0.94 to 0.99). In contrast, IBD is not genetically associated with an increased risk of AD, PD, or MS. Four shared genetic loci (rs6571361, rs10136727, rs7154847, and rs447853) were derived, and SCFD1, G2E3, HEATR5A were further identified as novel risk genes with enriched function related to membrane trafficking. G2E3 was differentially expressed and significantly correlated with SCFD1 in patients with IBD or ALS.ConclusionOur study reveals the casually protective role of IBD on ALS, and does not support the causality of IBD on AD, PD, or MS. Our findings indicate possible shared genetic architecture and pathways between IBD and ALS. The altered expressions of shared risk genes might contribute to the susceptibility to IBD and the protective effects for ALS. These results provide insights into the pathogenesis and therapeutics of IBD and neurodegenerative disorders.What is already known on this topicEmerging evidence has supported the communication between the gastrointestinal tract and central nervous system (the “gut-brain axis”).Published epidemiological studies have revealed the association between inflammatory bowel disease (IBD) and neurodegenerative disorders.The causality remains largely unclear.What this study addsGenetic liability to IBD is associated with a decreased risk of amyotrophic lateral sclerosis (ALS), whereas the susceptibility to IBD does not lead to Alzheimer’s disease, Parkinson’s disease, or multiple sclerosis.Shared genetic loci (rs6571361, rs10136727, rs7154847, and rs447853) and risk genes (SCFD1, G2E3, HEATR5A) are identified in IBD and ALS.Transcriptomic profiles in patients with IBD or ALS indicate that G2E3 is differentially expressed and significantly correlated with SCFD1.How this study might affect research, practice or policyThe findings provide insights into the pathogenesis and therapeutics of IBD and neurodegenerative disorders.Lower expression of G2E3 in IBD might serve as a protective factor to ALS.Unsubstantiated concerns among patients with IBD could be alleviated.