Yu Ling, Long Qing, Zhang Yunqiao, Liu Yilin, Guo Ziyi, Cao Xiang, Qin Fuyi, Xu Yangyang, Qian Qingqing, Gao Biyao, Chen Jian, Liu Jie, Zeng Yong, Teng Zhaowei
Key Laboratory of Neurological and Psychiatric Disease Research of Yunnan Province, The Second Affiliated Hospital of Kunming Medical University, Kunming, China.
Key Laboratory of Neurological and Psychiatric Disease Research of Yunnan Province, The Second Affiliated Hospital of Kunming Medical University, Kunming, China; Department of Psychiatry, the Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan Province, China.
J Affect Disord. 2025 Jun 15;379:871-883. doi: 10.1016/j.jad.2024.10.063. Epub 2024 Oct 21.
Evidence from observational studies and clinical experiments suggests a close association between plasma lipidome and psychiatric disorders. However, the causal relationship between plasma lipidome and psychiatric disorders remains insufficiently determined. Plasma lipidome are relatively easy to measure and regulate clinically, and they play a crucial role in neuronal signal transduction, making them a focus of interest as potential therapeutic targets for psychiatric disorders.
In this study, we utilized the latest Finnish population-based genome-wide association study (GWAS) data on 179 lipid species. We downloaded data on five psychiatric disorders from the IEU database, including schizophrenia, bipolar disorder, depression, autism from the PGC consortium, and anxiety disorder from the Neale lab. Using two-sample bidirectional Mendelian randomization (MR) analysis, we assessed the relationship between these 179 lipid species and the risk of the five psychiatric disorders. To validate the assumptions of Mendelian randomization, we conducted tests for horizontal pleiotropy and heterogeneity.
After applying FDR correction to assess the relationship between 179 lipid species traits and the risk of five psychiatric disorders, our analysis provided evidence of a causal relationship specifically between genetic susceptibility in the plasma lipidome and bipolar disorder. This relationship notably involves eight phosphatidylcholines (PCs) and two sterols, with PCs displaying a dual and complex role in the disorder. Reverse Mendelian randomization (MR) analysis did not reveal a significant causal impact of psychiatric disorders on the plasma lipidome.
Despite using two-sample bidirectional Mendelian randomization analysis, the complex biological pathways and potential confounding factors may still affect the accuracy of the causal relationships. The impact of genetic variations on the lipidome and psychiatric disorders may involve multiple mechanisms, which cannot be fully elucidated in this study.
This study identified a causal relationship between genetic susceptibility in plasma lipidome and bipolar disorder, indicating that plasma lipidome may influence the risk of psychiatric disorders and providing direction for exploring them as potential intervention targets. The findings not only deepen our understanding of the etiology of psychiatric disorders but also provide a critical theoretical foundation for future clinical interventions and prevention strategies, potentially contributing to the development of novel therapeutic approaches.
观察性研究和临床实验的证据表明血浆脂质组与精神疾病之间存在密切关联。然而，血浆脂质组与精神疾病之间的因果关系仍未得到充分确定。血浆脂质组在临床上相对易于测量和调节，并且它们在神经元信号转导中起关键作用，这使得它们成为作为精神疾病潜在治疗靶点的关注焦点。
在本研究中，我们利用了芬兰最新的基于人群的全基因组关联研究（GWAS）数据，涉及179种脂质种类。我们从IEU数据库下载了关于五种精神疾病的数据，包括来自PGC联盟的精神分裂症、双相情感障碍、抑郁症、自闭症，以及来自尼尔实验室的焦虑症。使用两样本双向孟德尔随机化（MR）分析，我们评估了这179种脂质种类与五种精神疾病风险之间的关系。为了验证孟德尔随机化的假设，我们进行了水平多效性和异质性测试。
在应用FDR校正以评估179种脂质种类特征与五种精神疾病风险之间的关系后，我们的分析提供了血浆脂质组中的遗传易感性与双相情感障碍之间存在因果关系的证据。这种关系特别涉及八种磷脂酰胆碱（PCs）和两种固醇，PCs在该疾病中显示出双重且复杂的作用。反向孟德尔随机化（MR）分析未揭示精神疾病对血浆脂质组有显著的因果影响。
尽管使用了两样本双向孟德尔随机化分析，但复杂的生物学途径和潜在的混杂因素仍可能影响因果关系的准确性。基因变异对脂质组和精神疾病的影响可能涉及多种机制，本研究无法完全阐明。
本研究确定了血浆脂质组中的遗传易感性与双相情感障碍之间的因果关系，表明血浆脂质组可能影响精神疾病的风险，并为将其作为潜在干预靶点进行探索提供了方向。这些发现不仅加深了我们对精神疾病病因的理解，还为未来的临床干预和预防策略提供了关键的理论基础，可能有助于新型治疗方法的开发。
