Shared genetic underpinnings of gray matter volume alterations and metabolic traits in major depressive disorder

Major depressive disorder (MDD) is linked to extensive gray matter volume (GMV) reductions and frequently co-occurs with metabolic dysfunction. However, the shared genetic basis linking neurostructural abnormalities and metabolic traits remains poorly understood.

Using a coordinate-based meta-analytic framework, we synthesized findings from 57 voxel-based morphometry (VBM) studies to characterize GMV alterations in MDD. Spatial transcriptomic correlation analysis was performed using the Allen Human Brain Atlas to identify genes associated with these alterations. In parallel, conjunctional false discovery rate (conjFDR) analysis was applied to genome-wide association study (GWAS) summary statistics from MDD and five metabolic traits-glucose, hemoglobin A1c (HbA1c), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG)-to identify pleiotropic loci. Functional characterization of the intersecting genes was conducted by applying gene ontology enrichment and protein-protein interaction (PPI) analyses.

We identified consistent GMV reductions in the left superior temporal gyrus, inferior frontal gyrus, and insula. A total of 2,585 genes were spatially correlated with GMV alterations. ConjFDR analysis revealed 20-195 pleiotropic loci across metabolic traits and MDD. Gene-level overlap analysis identified 13-73 shared genes per trait, with FADS2 emerging as a common gene across all five traits. Functional annotation highlighted pathways related to lipid metabolism and synaptic signaling.

This integrative multi-omics study reveals shared genetic mechanisms linking brain structure in MDD with systemic metabolic traits. FADS2 may serve as a molecular hub underlying this convergence, suggesting that targeting FADS2-mediated lipid metabolism could represent a novel therapeutic strategy for mitigating both neurostructural deficits and metabolic dysregulation in MDD.

Clinical trial number: Not applicable.