Multi-omics Analysis of Energy Metabolism Pathways Across Major Psychiatric Disorders

Area of Science:

• Neuroscience
• Genetics
• Metabolic Disorders

Background:

• Brain energy demands are high, relying on glucose metabolism.
• Dysfunctional glucose metabolism is observed in neuropsychiatric disorders.
• Genetic factors contribute to the complexity of these conditions.

Purpose of the Study:

• To investigate the association between glucose metabolism-related genes and major psychiatric disorders.
• To identify potential genetic targets for therapeutic interventions.

Main Methods:

• Secondary analysis of genome-wide association study (GWAS) data for major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SCZ).
• Utilized multi-marker analysis of genomic annotation (MAGMA), transcriptome-wide association studies (TWAS) with joint-tissue imputation (JTI), and summary-based Mendelian randomization (SMR).
• Explored gene expression, druggability, and gene network interactions.

Main Results:

• MAGMA identified significant genes for MDD (1), BD (19), and SCZ (32), with RBKS shared across all three.
• TWAS-JTI found significant genes for BD (17) and SCZ (35).
• SMR prioritized 2 and 9 putatively causal genes for BD and SCZ, respectively. No convergent evidence for MDD.
• Integrated analysis highlighted NDUFS2, NDUFS7, and NDUFC2 in oxidative phosphorylation as potential targets.
• Gene network analysis revealed enrichment in mitochondrial respiratory chain complex I, NADH dehydrogenase complex assembly, and ATP synthesis.

Conclusions:

• Energy metabolic disturbance is implicated in psychiatric disorders, especially BD and SCZ.
• Specific genes within the oxidative phosphorylation pathway present potential therapeutic targets.
• Findings support further research into targeted interventions for these conditions.