Observational studies provide evidence that metabolites may be involved in the development of autoimmune diseases (ADs), but whether it is causal is still unknown. Based on the large-scale genome-wide association studies (GWAS) summary statistics, we performed two-sample Mendelian randomization (MR) to evaluate the causal associations between human blood metabolites and multiple ADs, which were inflammatory bowel disease (IBD), ulcerative colitis (UC), crohns 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). After Bonferroni adjustment, we identified 6 causal features of metabolites, i.e., glycerol 2-phosphate for T1D, hexadecanedioate, phenylacetylglutamine and laurylcarnitine for RA, glycine and arachidonate (20:4n6) for CD. Comprehensive sensitive analysis was further performed to validate the robustness of associations. We also observed some overlaps of metabolites among different ADs, implying similar or shared underlying mechanisms in such pathogenic processes. Multivariable MR analysis was then conducted to avoid potential pleiotropic effect of other complex traits. After controlling for several common traits, multivariable MR analysis ruled out most of potential pleiotropic effects and validated independence of identified metabolites. Finally, metabolic pathway analysis was performed based on suggestive metabolites for each AD respectively and a total of seven metabolic pathways were identified. In conclusion, this study provided novel insights into investigating causal role of blood metabolites in development of multiple ADs through a comprehensive genetic pathway.

中文翻译：

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鉴定与多种自身免疫性疾病相关的因果代谢物

观察性研究提供的证据表明代谢物可能与自身免疫性疾病 (AD) 的发展有关，但是否是因果关系尚不清楚。基于大规模全基因组关联研究 (GWAS) 汇总统计数据，我们进行了两样本孟德尔随机化 (MR) 以评估人类血液代谢物与多种 AD 之间的因果关系，这些 AD 包括炎症性肠病 (IBD)、溃疡性结肠炎 (UC)、克罗恩病 (CD)、类风湿性关节炎 (RA)、系统性红斑狼疮 (SLE)、1 型糖尿病 (T1D)、多发性硬化症 (MS)、原发性胆汁性肝硬化 (PBC) 和原发性硬化性胆管炎 (PSC) . 在 Bonferroni 调整后，我们确定了代谢物的 6 个因果特征，即 2-磷酸甘油用于 T1D、十六烷二酸、苯乙酰谷氨酰胺和月桂基肉碱用于 RA，甘氨酸和花生四烯酸 (20:4n6) 用于 CD。进一步进行综合敏感分析以验证关联的稳健性。我们还观察到不同 AD 之间代谢物的一些重叠，这意味着在这些致病过程中存在相似或共享的潜在机制。然后进行多变量MR分析以避免其他复杂性状的潜在多效性影响。在控制了几个共同特征后，多变量 MR 分析排除了大多数潜在的多效性效应，并验证了已识别代谢物的独立性。最后，分别根据每个 AD 的提示代谢物进行代谢途径分析，共鉴定出 7 条代谢途径。综上所述，