Shared neuroimaging and molecular profiles in type 2 diabetes mellitus and major depressive disorder: an integrative analysis of genetic, transcriptomic, and neuroimaging data

Type 2 diabetes mellitus (T2DM) and major depressive disorder (MDD) are prevalent chronic conditions that frequently co-occur, suggesting potential shared mechanisms. Neuroimaging meta-analyses were conducted to identify gray matter volume (GMV) alterations in T2DM and MDD, with further identification of the overlapping regions between the two diseases. Large-scale genome-wide association study (GWAS) summary statistics were utilized, and conjunctional false discovery rate (conjFDR) analysis was applied to identify shared genes. Transcriptome-neuroimaging association and expression-trait association analyses were performed to identify and prioritize shared genes contributing to these structural brain changes. Knockout mouse models were employed to investigate the functional roles of the prioritized genes. Neuroimaging meta-analysis revealed significant GMV reductions in T2DM and MDD patients compared to controls, with overlapping decreases, such as the bilateral median cingulate gyri, right insula and superior temporal gyrus. ConjFDR analysis identified 664 genes shared between T2DM and MDD, with nine prioritized genes linked to GMV alterations. Knockout models of these genes revealed neural and metabolic abnormalities, highlighting their potential roles in shared neurobiological and metabolic pathways underlying both disorders. This integrative analysis identifies shared neuroimaging and molecular mechanisms between T2DM and MDD, offering novel insights into their comorbidity and underlying biological pathways.