Increased individual variability in functional connectivity of the default mode network and its genetic correlates in major depressive disorder

Major depressive disorder (MDD) is a highly heterogeneous psychiatric disorder characterized with considerable individual variability in clinical manifestations which may correspond to brain alterations including the default mode network (DMN). This study analyzed resting-state functional magnetic resonance imaging (rs-fMRI) data from 796 MDD patients and 823 healthy controls (HC) to investigate individual variability in functional connectivity (IVFC) between the DMN and 108 non-DMN regions. We aimed to identify MDD-related IVFC abnormalities and their clinical relevance, alongside exploring gene expression correlations. The results revealed similar spatial patterns of IVFC within the DMN in both groups, yet significantly increased IVFC values in MDD patients were observed in regions such as the ventromedial prefrontal cortex, anterior cingulate cortex, posterior cingulate cortex, fusiform gyrus, and occipital cortex. Notably, the mean IVFC in the DMN and fusiform gyrus was positively correlated with Hamilton Rating Scale for Depression (HAMD) scores in MDD patients. Gene expression analyses explained 47.0% of the variance in MDD-related IVFC alterations, with the most associated genes enriched in processes including membrane potential regulation, head development, synaptic transmission, and dopaminergic synapse. These findings highlight the clinical importance of IVFC variability in the DMN and suggest its potential role as a biomarker in MDD.