Linking individual variability in functional brain connectivity to polygenic risk in major depressive disorder

Major depressive disorder (MDD) is a highly heterogeneous disease, which brings great difficulties to clinical diagnosis and therapy. Its mechanism is still unknown. Prior neuroimaging studies mainly focused on mean differences between patients and healthy controls (HC), largely ignoring individual differences between patients. This study included 112 MDD patients and 93 HC subjects. Resting-state functional MRI data were obtained to examine the patterns of individual variability of brain functional connectivity (IVFC). The genetic risk of pathways including dopamine, 5-hydroxytryptamine (5-HT), norepinephrine (NE), hypothalamic-pituitary-adrenal (HPA) axis, and synaptic plasticity was assessed by multilocus genetic profile scores (MGPS), respectively. The IVFC pattern of the MDD group was similar but higher than that in HCs. The inter-network functional connectivity in the default mode network contributed to altered IVFC in MDD. 5-HT, NE, and HPA pathway genes affected IVFC in MDD patients. The age of onset, duration, severity, and treatment response, were correlated with IVFC. IVFC in the left ventromedial prefrontal cortex had a mediating effect between MGPS of the 5-HT pathway and baseline depression severity. Environmental factors and differences in locations of functional areas across individuals were not taken into account. This study found MDD patients had significantly different inter-individual functional connectivity variations than healthy people, and genetic risk might affect clinical manifestations through brain function heterogeneity.