Depression polygenic risk-linked multimodal MRI network and associated cognitive dysfunction

Major depressive disorder (MDD) involves complex genetic and neurobiological factors. This study integrated polygenic risk scores (PRS), neurocognitive assessments, and multimodal neuroimaging to examine relationships among genetic liability, brain alterations, and cognitive performance in MDD. A total of 74 patients with MDD and 70 healthy controls (HCs) underwent cognitive testing and MRI scans, with gray matter volume (GMV) and amplitude of low-frequency fluctuations (ALFF) extracted as neuroimaging features. PRS were calculated using PRSice based on GWAS summary statistics of depression in East Asian populations, with quality control including MAF filtering, LD pruning, and removal of related individuals. Using multimodal canonical correlation analysis with reference combined with joint independent component analysis (MCCAR + jICA), we identified a PRS-related multimodal brain component involving occipital, frontal, parietal and temporal regions. The identified component exhibited significantly lower ALFF loadings, but not GMV loadings, suggesting greater sensitivity to functional than structural alterations in MDD compared with HCs. PRS scores were negatively associated with performance in pattern recognition memory tasks. These exploratory findings provide preliminary evidence linking genetic susceptibility, multimodal brain alterations, and cognitive dysfunction in MDD, and highlight the potential value of multimodal fusion approaches for investigating genetically informed brain-cognition pathways.