Decoding anxiety: Plasma lipids and proteins as causal agents

Area of Science:

• Psychiatry
• Genetics
• Biochemistry

Background:

• Anxiety disorders are a significant public health concern with unclear molecular causes.
• Observational studies suggest links between blood lipids/proteins and mental health, but establishing causality is challenging due to confounding factors.

Purpose of the Study:

• To investigate the causal relationships between plasma lipid species, plasma proteins, and anxiety disorders.
• To identify specific molecular targets for anxiety disorders using genetic evidence.

Main Methods:

• Employed two-sample Mendelian randomization (MR) with large genome-wide association study (GWAS) datasets.
• Utilized inverse variance weighted, Bayesian Weighted MR, and MR Robust Adjusted Profile Score methods for robust causal inference.
• Conducted sensitivity and reverse MR analyses to assess robustness and directionality, and mediation analyses to explore pathways.

Main Results:

• Identified three lipids with significant causal effects on anxiety disorders, including a protective role for sterol ester (27:1/20:5).
• Found 31 proteins causally associated with anxiety disorders.
• Demonstrated that the protective effect of sterol ester (27:1/20:5) is partially mediated by SERPINA4 and ICT1 proteins.

Conclusions:

• Provides strong genetic evidence for the causal involvement of plasma lipids and proteins in anxiety disorders.
• Unveiled a novel lipid-protein-anxiety pathway, suggesting potential biomarkers and therapeutic targets.
• Highlights the utility of multi-omic Mendelian randomization in understanding complex psychiatric conditions.