BACKGROUND From the pathway perspective, metabolites have the potential to improve knowledge about the aetiology of psychiatric diseases. Previous studies suggested a link between specific blood metabolites and mental disorders, but some Mendelian randomisation (MR) studies in particular are insufficient for various reasons. OBJECTIVE This study focused on bias assessment due to interdependencies between metabolites and psychiatric mediation effects. METHODS In a multistep framework containing network and multivariable MR, direct effects of 21 mutually adjusted metabolites on 8 psychiatric disorders were estimated based on summary statistics of genome-wide association studies from multiple resources. Robust inverse-variance weighted models were used in primary analyses. Several sensitivity analyses were performed to assess different patterns of pleiotropy and weak instrument bias. Estimates for the same phenotypes from different resources were pooled using fixed effect meta-analysis models. FINDINGS After adjusting for mediation effects, genetically predicted metabolite levels of six metabolites of lipid, amino acid and cofactors pathways were directly associated with overall six mental disorders (attention-deficit/hyperactivity disorder, bipolar disorder, anorexia nervosa, depression, post-traumatic stress disorder and schizophrenia). Point estimates ranged from -0.45 (95% CI -0.67; -0.24, p=1.0×104) to 1.78 (95% CI 0.85; 2.71, p=0.006). No associations were found with anxiety and suicide attempt. CONCLUSIONS This study provides insights into new metabolic pathways that seems to be causally related to certain mental disorders. CLINICAL IMPLICATIONS Further studies are needed to investigate whether the identified associations are effects of the metabolites itself or the biochemical pathway regulating the metabolites.

中文翻译：

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中介调整多变量孟德尔随机化研究确定了与心理健康相关的新代谢物。


背景从途径的角度来看，代谢物有可能提高对精神疾病病因学的认识。先前的研究表明特定的血液代谢物与精神障碍之间存在联系，但由于各种原因，一些孟德尔随机化（MR）研究尤其不足。目的 这项研究的重点是由于代谢物和精神中介效应之间的相互依赖性而导致的偏差评估。方法 在包含网络和多变量 MR 的多步骤框架中，根据来自多个资源的全基因组关联研究的汇总统计，估计了 21 种相互调整的代谢物对 8 种精神疾病的直接影响。初步分析中使用了稳健的逆方差加权模型。进行了几种敏感性分析来评估不同模式的多效性和弱仪器偏差。使用固定效应荟萃分析模型汇集了来自不同资源的相同表型的估计值。研究结果调整中介效应后，基因预测的脂质、氨基酸和辅因子途径的六种代谢物的代谢水平与总体六种精神障碍（注意力缺陷/多动障碍、双相情感障碍、神经性厌食症、抑郁症、创伤后应激障碍）直接相关。障碍和精神分裂症）。点估计值范围为 -0.45 (95% CI -0.67; -0.24, p=1.0×104) 至 1.78 (95% CI 0.85; 2.71, p=0.006)。没有发现与焦虑和自杀企图有关。结论 这项研究提供了对新代谢途径的见解，这些途径似乎与某些精神障碍存在因果关系。 临床意义 需要进一步研究来调查所确定的关联是否是代谢物本身的影响或调节代谢物的生化途径的影响。