Xiao Xiao, Luo Xiaolei, Wang Yanyun, Pan Xinmin, Gao Linbo, Liu Shanling, Zhang Lin
Department of Medical Genetics, West China Second University Hospital, Sichuan University, No. 20, Section 3, Renmin Nan Road, Chengdu, 610041, Sichuan, China.
Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, No. 20, Section 3, Renmin Nan Road, Chengdu, 610041, Sichuan, China.
Mol Neurobiol. 2025 Jun 3. doi: 10.1007/s12035-025-05105-y.
Lipid metabolism disruptions are implicated in nervous and mental disorders; plasma lipidomics show promise as diagnostic and therapeutic targets. However, clarification of causal relationships between plasma lipids and neuropsychiatric disorders (NPDs) remains unclear. We employed bidirectional Mendelian randomization (MR) to examine causal links between 179 plasma lipids and 17 NPDs. Significant associations in the forward MR were further investigated using linkage disequilibrium score regression (LDSC), Bayesian colocalization (COLOC) analysis, and mediation analysis. Forward MR revealed sterol ester (27:1/16:1) and diacylglycerol (16:0_18:2) elevations may increase anorexia nervosa (AN) risk, while sphingomyelin (d36:2) elevation potentially lowers it. LDSC analysis showed no substantial genetic link between the three lipids and AN, while low posterior probability of hypothesis 4 from COLOC test disputed the presence of shared variants. Besides, AN risk elevated by sterol ester's (27:1/16:1) was suggested to mediate through C-X-C chemokine 10 downregulation. In the reverse MR, we uncovered varied causal ties: ADHD increased sterol ester (27:1/20:3), phosphatidylcholines (18:0_20:3, 18:1_20:3); Alzheimer's disease lowered phosphatidylcholine (O - 18:1_20:3); Ischemic stroke tied to less phosphatidylcholine (16:0_0:0); Obsessive-compulsive disorder exhibited a dual effect, upregulating phosphatidylcholine (16:1_18:0) and downregulating sterol ester (27:1/22:6); Parkinson's disease linked to less diacylglycerol (18:1_18:3); Schizophrenia tied to more triacylglycerols (48:0,51:1); Migraine reduced sterol ester (27:1/20:2). These insights reveal causal dynamics between plasma lipids and neuropsychiatric conditions. Our findings extend the causal landscape linking the plasma lipidome to NPDs, offering insights for the discovery of novel biomarkers and therapeutic targets in these diseases.
脂质代谢紊乱与神经和精神疾病有关；血浆脂质组学有望成为诊断和治疗靶点。然而，血浆脂质与神经精神疾病（NPDs）之间因果关系的阐明仍不明确。我们采用双向孟德尔随机化（MR）来研究179种血浆脂质与17种NPDs之间的因果联系。使用连锁不平衡评分回归（LDSC）、贝叶斯共定位（COLOC）分析和中介分析对正向MR中的显著关联进行了进一步研究。正向MR显示，甾醇酯（27:1/16:1）和二酰基甘油（16:0_18:2）升高可能会增加神经性厌食症（AN）的风险，而鞘磷脂（d36:2）升高则可能降低其风险。LDSC分析表明这三种脂质与AN之间不存在实质性的遗传联系，而COLOC检验中假设4的后验概率较低，对共享变异体的存在提出了质疑。此外，甾醇酯（27:1/16:1）升高导致的AN风险增加被认为是通过C-X-C趋化因子10的下调介导的。在反向MR中，我们发现了不同的因果关系：注意力缺陷多动障碍（ADHD）会增加甾醇酯（27:1/20:3）、磷脂酰胆碱（18:0_20:3、18:1_20:3）的水平；阿尔茨海默病会降低磷脂酰胆碱（O - 18:1_20:3）的水平；缺血性中风与较少的磷脂酰胆碱（16:0_0:0）有关；强迫症表现出双重作用，上调磷脂酰胆碱（16:1_18:0）并下调甾醇酯（27:1/22:6）；帕金森病与较少的二酰基甘油（18:1_18:3）有关；精神分裂症与较多的三酰基甘油（48:0,51:1）有关；偏头痛会降低甾醇酯（27:1/20:2）的水平。这些见解揭示了血浆脂质与神经精神疾病之间的因果动态关系。我们的研究结果扩展了将血浆脂质组与NPDs联系起来的因果关系图景，为这些疾病中新型生物标志物和治疗靶点的发现提供见解。
