Bidirectional causal associations between plasma metabolites and bipolar disorder

Area of Science:

• Genetics
• Metabolomics
• Psychiatry

Background:

• Altered plasma metabolite levels are linked to bipolar disorder (BD) etiology.
• The causal relationship between metabolites and BD remains unclear.

Purpose of the Study:

• To perform a bidirectional metabolome-wide Mendelian randomization (MR) analysis to assess causal links between 871 plasma metabolites and BD.
• To identify potential therapeutic targets for BD among related metabolites.
• To identify shared genomic loci between BD and metabolites using Bayesian colocalization analysis.

Main Methods:

• Bidirectional metabolome-wide Mendelian randomization (MR) analysis.
• Evaluation of metabolite druggability using DrugBank and ChEMBL.
• Bayesian colocalization analysis to identify shared genomic loci.

Main Results:

• Six metabolites were associated with reduced BD risk (e.g., arachidonate, sphingomyelin).
• Five metabolites were associated with increased BD risk (e.g., 1-palmitoyl-2-linoleoyl-GPE).
• Reverse MR showed no association between BD and metabolite levels; colocalization identified a shared region on chromosome 11q12 involving genes like FADS1, FADS2, FADS3, and SYT7.

Conclusions:

• Plasma metabolites play a causal role in BD susceptibility.
• Identified metabolites represent potential targets for novel BD prevention and treatment strategies.