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

ObjectivePublished 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], Alzheimers disease [AD], Parkinsons 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 topicO_LIEmerging evidence has supported the communication between the gastrointestinal tract and central nervous system (the "gut-brain axis"). C_LIO_LIPublished epidemiological studies have revealed the association between inflammatory bowel disease (IBD) and neurodegenerative disorders. C_LIO_LIThe causality remains largely unclear. C_LI What this study addsO_LIGenetic liability to IBD is associated with a decreased risk of amyotrophic lateral sclerosis (ALS), whereas the susceptibility to IBD does not lead to Alzheimers disease, Parkinsons disease, or multiple sclerosis. C_LIO_LIShared genetic loci (rs6571361, rs10136727, rs7154847, and rs447853) and risk genes (SCFD1, G2E3, HEATR5A) are identified in IBD and ALS. C_LIO_LITranscriptomic profiles in patients with IBD or ALS indicate that G2E3 is differentially expressed and significantly correlated with SCFD1. C_LI How this study might affect research, practice or policyO_LIThe findings provide insights into the pathogenesis and therapeutics of IBD and neurodegenerative disorders. C_LIO_LILower expression of G2E3 in IBD might serve as a protective factor to ALS. C_LIO_LIUnsubstantiated concerns among patients with IBD could be alleviated. C_LI