Neuroimaging-genetic integration reveals shared structural and functional brain alterations in major depressive...

Major depressive disorder (MDD) is linked to widespread disruptions in brain structure and function. Nevertheless, the extent to which structural and functional abnormalities overlap in MDD, and whether they share a common genetic basis, remains largely unclear.

We performed voxel-wise meta-analyses to identify structural alterations in gray matter volume (GMV) and functional changes using regional homogeneity (ReHo) and amplitude of low-frequency fluctuations (ALFF). MDD-associated genes were prioritized using the H-MAGMA framework with large-scale genome-wide association study data (170,756 MDD cases; 329,443 controls), followed by transcriptome-neuroimaging association analyses to examine gene expression patterns linked to these brain alterations. Finally, enrichment analyses were conducted to reveal the biological processes associated with the shared genes.

The structural meta-analysis included 39 studies (Ncase = 3114, Ncontrol = 3242), and the functional meta-analysis included 50 studies (Ncase = 2489, Ncontrol = 2108). Multimodal analysis revealed overlapping abnormalities mainly in the median cingulate cortex, insula, and superior temporal gyrus, all exhibiting reductions in GMV and ReHo/ALFF. Additionally, decreased GMV and increased ReHo/ALFF were observed primarily in the anterior cingulate corte and temporal pole. We identified 1604 MDD-associated genes, of which 279 were linked to both structural and functional alterations. Enrichment analyses highlighted their roles in neurodevelopmental processes and synaptic signaling, with distinct spatial and temporal expression patterns across key brain regions and developmental stages.

This study identifies overlapping structural and functional alterations in MDD and reveals their shared genetic basis, offering novel insights into its pathology through an integrative neuroimaging-genetic framework.