Possible Linking and Treatment between Parkinson’s Disease and Inflammatory Bowel Disease: A Study of Mendelian Randomization Based on Gut–Brain Axis

Abstract Background: Mounting evidence suggests that Parkinson’s disease (PD) and inflammatory bowel disease (IBD) are closely associated and becoming global health burdens. However, the causal relationshipsand common pathogeneses between them are uncertain. Furthermore, they are uncurable. Thus, we aimedto identify the causal relationships and novel therapeutic targets shared between them based on their common pathophysiological mechanisms in gut-brain-axis (GBA). Methods: A meta-analysis on bidirectional Mendelian randomization (MR) utilizing various datasets was performed to estimate their causal relationship. Then, pleiotropicanalysis under the composite null hypothesis(PLACO) with functional mapping combined withannotation of genetic associations (FUMA) analysis were conducted to identify pleiotropic genes. Next, blood, brain and intestine expression quantitative trait locus (eQTL) were taken to perform drug-target MR finding common causal genes in two diseases. Colocalization analysis ensured the eQTLs of corresponding gene colocalized with disease. Enrichment analysis and protein‒proteininteraction (PPI) network were done to explorecommon pathogenesis pathways. Genes passed all analysis were regarded as drug targets. Results: Our MR meta-analysis revealed thebidirectional causal relationship between diseases, with combined ORs for PD on IBD, CD, UC (1.050 [95% CI: 1.014-1.086], 1.044 [95% CI: 0.995-1.095], 1.063 [95% CI: 1.016-1.120]); for IBD, CD, UC on PD (1.003 [95% CI: 0.973-1.034], 1.035 [95% CI: 1.004-1.067], 1.008 [95% CI: 0.977-1.040]). Overall, 277, 216 and 201 genes were identified as pleiotropic genes between PD and IBD, CD, UC. Total of733 genes were classified as tier 3 (found in only one tissue) druggable targets, 57 as tier 2 (found in two tissues, 51 protein-coding genes) and 9 as tier 3 (found in three tissues). Among 60 protein-coding druggable targets over tier 2, 18 overlapped with pleiotropic genes and enriched in mitochondria, antigen presentation, processing and immune cell regulation pathways. Three druggable genes (LRRK2, RAB29 and HLA-DQA2) passed colocalization analysis. LRRK2 and RAB29 were reported to be pleiotropic genes, and RAB29 and HLA-DQA2were reported for the first time as potential drug targets. Conclusions: This study established areliable causal relationship, possible shared drug targets and common pathogenesis pathways of two diseases, which had important implications for intervention and treatment of two diseases simultaneously.