Psychiatric disorders are the leading cause of disability worldwide while the pathogenesis remains unclear. Genome-wide association studies (GWASs) have made great achievements in detecting disease-related genetic variants. However, functional information on the underlying biological processes is often lacking. Current reports propose the use of metabolic traits as functional intermediate phenotypes (the so-called genetically determined metabotypes or GDMs) to reveal the biological mechanisms of genetics in human diseases. Here we conducted a two-sample Mendelian randomization analysis that uses GDMs to assess the causal effects of 486 human serum metabolites on 5 major psychiatric disorders, which respectively were schizophrenia (SCZ), major depression (MDD), bipolar disorder (BIP), autism spectrum disorder (ASD), and attention-deficit/hyperactivity disorder (ADHD). Using genetic variants as proxies, our study has identified 137 metabolites linked to the risk of psychiatric disorders, including 2-methoxyacetaminophen sulfate, which affects SCZ (P = 1.7 × 10^–5) and 1-docosahexaenoylglycerophosphocholine, which affects ADHD (P = 5.6 × 10^–5). Fourteen significant metabolic pathways involved in the 5 psychiatric disorders assessed were also detected, such as glycine, serine, and threonine metabolism for SCZ (P = .0238), Aminoacyl-tRNA biosynthesis for both MDD (P = .0144) and ADHD (P = .0029). Our study provided novel insights into integrating metabolomics with genomics in order to understand the mechanisms underlying the pathogenesis of human diseases.

中文翻译：

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评估人体血清代谢物对5种主要精神疾病的因果关系。

精神疾病是全球范围内致残的主要原因，而发病机理仍不清楚。全基因组关联研究（GWAS）在检测与疾病相关的遗传变异中取得了巨大成就。但是，通常缺少有关基础生物学过程的功能信息。当前的报告提出使用代谢性状作为功能性中间表型（所谓的遗传确定的代谢型或GDM）来揭示人类疾病遗传学的生物学机制。在这里，我们进行了两次样本孟德尔随机分析，该研究使用GDM评估了486种人类血清代谢物对5种主要精神疾病的因果关系，这些疾病分别是精神分裂症（SCZ），主要抑郁症（MDD），双相情感障碍（BIP），自闭症频谱障碍（ASD）和注意力缺乏/多动症（ADHD）。使用遗传变异作为代理，我们的研究确定了137种与精神疾病风险相关的代谢物，包括影响SCZ的2-甲氧基对乙酰氨基酚硫酸盐（P  = 1.7×10 ^–5）和1-十二碳六烯酰基甘油磷酸胆碱，会影响ADHD（P =  5.6×10 ^–5）。还发现了与评估的5种精神疾病有关的14条重要的代谢途径，例如SCZ的甘氨酸，丝氨酸和苏氨酸代谢（P  = .0238），MDD（P =  .0144）和ADHD（P的氨酰基-tRNA生物合成）=  .0029）。我们的研究为将代谢组学与基因组学整合提供了新颖的见解，以了解人类疾病发病机理的潜在机制。