Abstract
Multiple genetic loci in the dopamine (DA) pathway have been associated with depression symptoms in patients with major depressive disorder (MDD). However, the neural mechanisms underlying the polygenic effects of the DA pathway on depression remain unclear. We used an imaging genetic approach to investigate the polygenic effects of the DA pathway on the reward network in MDD. Fifty-three patients and 37 cognitively normal (CN) subjects were recruited and underwent resting-state functional magnetic resonance imaging (R-fMRI) scans. Multivariate linear regression analysis was employed to measure the effects of disease and multilocus genetic profile scores (MGPS) on the reward network, which was constructed using the nucleus accumbens (NAc) functional connectivity (NAFC) network. DA-MGPS was widely associated within the NAFC network, mainly in the inferior frontal cortex, insula, hypothalamus, superior temporal gyrus, and occipital cortex. The pattern of DA-MGPS effects on the fronto-striatal pathway differed in MDD patients compared with CN subjects. More importantly, NAc-putamen connectivity mediates the association between DA MGPS and anxious depression traits in MDD patients. Our findings suggest that the DA multilocus genetic profile makes a considerable contribution to the reward network and anxious depression in MDD patients. These results expand our understanding of the pathophysiology of polygenic effects underlying brain network abnormalities in MDD.
Highlights
Major depressive disorder (MDD) is a serious disease that poses major risks to human physical and mental health and will become the world’s most common and economically burdensome illness by 2030 (Mathers and Loncar, 2006)
We aimed to investigate the neural mechanism underlying the polygenic effects of the DA pathway on the reward network [constructed using the nucleus accumbens (NAc) functional connectivity (NAFC) network] in MDD patients
Our findings demonstrate the cumulative effects of multiple gene polymorphisms in the dopaminergic pathway on both behavior and the intrinsic reward network in MDD patients
Summary
Major depressive disorder (MDD) is a serious disease that poses major risks to human physical and mental health and will become the world’s most common and economically burdensome illness by 2030 (Mathers and Loncar, 2006). The Gly variant of the DRD3 gene polymorphism (rs6280) has 4–5 times greater affinity for DA compared to the Ser variant, and subjects with this form exhibit increased striatal reward-related DA release during a gambling task (Jeanneteau et al, 2006; Savitz et al, 2013). These findings suggest that the multiple genetic effects of the DA pathway play a critical role in the pathophysiology of depression
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