Identification of causal metabolites related to multiple autoimmune diseases.

Object Observational studies provide evidence that metabolites may be involved in the development of autoimmune diseases (ADs), but whether it is causal is still unknown. Methods Based on the large-scale GWAS summary statistics, two-sample Mendelian randomization (MR) was performed to evaluate the causal association between human serum metabolites and multiple ADs, which were inflammatory bowel disease (IBD), ulcerative Colitis (UC), crohn's disease (CD), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), type 1 diabetes (T1D), multiple sclerosis (MS), primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). Comprehensive sensitive analysis was used to validate the robustness of MR results and multivariable MR analysis was conducted to avoid potential pleiotropic effect of other complex traits. Finally, metabolic pathway analysis was performed based on causal metabolites for each ad, respectively. Results We identified 6 causal features of metabolite after Bonferroni adjustment, i.e. glycerol 2-phosphate for T1D, hexadecanedioate, phenylacetylglutamine and laurylcarnitine for RA, glycine and arachidonate (20:4n6) for CD. Then comprehensively sensitive analysis proved the robustness of the causal associations. We also observed some overlaps of metabolites among different ADs, indicating the similar mechanisms. After controlling for several common traits, multivariable MR analysis ruled out most of potential pleiotropic effects and validated the independence of identified metabolites. Additionally, a total of 6 metabolic pathways have been identified for different ADs. Conclusions This study provided novel insights into investigating causal role of serum metabolites in development of multiple ADs through a comprehensive genetic pathway.