An Imaging Genetic Study Of Individual Variability Patterns Of Brain Functional Connectivity In Major Depressive Disorder

Background: Major depressive disorder(MDD)is a highly heterogeneous disease,which brings great difficulties to for clinical diagnosis and therapy.Its mechanism is still not fully characterized.Prior neuroimaging studies of MDD have mainly focused on determining group mean differences in brain connectivity between patients and healthy controls(HC),largely ignoring individual differences between patients.Objective: This study will explore the changes of individual variability patterns of brain functional connectivity(IVFC)in patients with MDD at both level of regions and networks,and explore the effects of common genetic risks of MDD on brain IVFC patterns in patients with MDD.Subjects and methods: The present study included 112 MDD patients and 93 HC patients.Whole-brain resting state functional MRI data were obtained,and IVFC were examined in MDD patients and HC patients.The genetic risks of dopamine pathway,serotonin pathway,norepinephrine pathway,hypothalamic-pituitary-adrenal axis and synaptic plasticity were assessed by multilocus genetic profile scores(MGPS),respectively.Permutation tests were used to identify the brain regions where differences of IVFC existed between groups and the critical connections that contributed to the differences.Secondly,multiple linear regression and partial correlation analysis were used to examine the relationship between IVFC and genetic risks and clinical variables.Finally,mediation analysis was used to further determine whether changes in IVFC could mediate the associations between genetic risks and clinical characteristics in MDD.Results: The whole-brain IVFC pattern in the MDD group was generally similar to that in HCs.,but showed show a widespread increase in the brain.The critical connections that contributed to alterations of IVFC in MDD were inter-network functional connectivities between the default mode network and sensorimotor network,salience network and cerebellar network.Serotonin,norepinephrine and hypothalamicpituitary-adrenal axis pathway genes affect IVFC in MDD patients.The interaction of MDD,HPA pathway genes and NE pathway genes affect the auxiliary motor area.As disease course and onset age increased,the IVFC of several regions showed an increasing trend.The IVFC value of MDD showed a negative correlation with the severity of MDD.With the increase of the severity of depression,the IVFC of the left ventromedial prefrontal lobe and the left posterior parietal lobe were lager in MDD patients.MDD patients with higher IVFC had better 2-week curative effects,but higher IVFC in left basal ganglia predicted poor curative effect at 8 weeks.IVFC in the left ventromedial prefrontal lobe had a mediating effect between 5-HT-MGPS and baseline depression severity.Conclusions: In this study,we found that MDD patients have significantly different interindividual functional connectivity variations than healthy people,and genetic risk may affect clinical manifestations through brain function heterogeneity.Changes of IVFC patterns in MDD have potential implications for understanding the high clinical heterogeneity of MDD and might be helpful in individualized clinical diagnosis and treatment of the disease in the future.