Bidirectional Mendelian randomization analysis of plasma lipidome and psychiatric disorders.

Background: 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.

Methods: 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.

Results: 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.

Limitations: 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.

Conclusion: 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.