Abstract
Convergent data from imaging and postmortem brain transcriptome studies implicate corticolimbic circuit (CLC) dysregulation in the pathophysiology of depression. To more directly bridge these lines of work, we generated a novel transcriptome-based polygenic risk score (T-PRS), capturing subtle shifts toward depression-like gene expression patterns in key CLC regions, and mapped this T-PRS onto brain function and related depressive symptoms in a nonclinical sample of 478 young adults (225 men; age 19.79 +/− 1.24) from the Duke Neurogenetics Study. First, T-PRS was generated based on common functional SNPs shifting CLC gene expression toward a depression-like state. Next, we used multivariate partial least squares regression to map T-PRS onto whole-brain activity patterns during perceptual processing of social stimuli (i.e., human faces). For validation, we conducted a comparative analysis with a PRS summarizing depression risk variants identified by the Psychiatric Genomics Consortium (PGC-PRS). Sex was modeled as moderating factor. We showed that T-PRS was associated with widespread reductions in neural response to neutral faces in women and increases in neural response to emotional faces and shapes in men (multivariate p < 0.01). This female-specific reductions in neural response to neutral faces was also associated with PGC-PRS (multivariate p < 0.03). Reduced reactivity to neutral faces was further associated with increased self-reported anhedonia. We conclude that women with functional alleles mimicking the postmortem transcriptomic CLC signature of depression have blunted neural activity to social stimuli, which may be expressed as higher anhedonia.
Highlights
Major depressive disorder (MDD or depression) is the leading cause of disability worldwide[1], with lifetime prevalence up to 17%2
Activity in all clusters was negatively correlated with the Neutral faces condition in women, indicating that, across this network, higher transcriptome-based polygenic risk score (T-PRS) was associated with female-specific blunting of activity driven by the neutral faces condition
Here, we provide novel evidence that a polygenic score comprised of functional variants mimicking the postmortem transcriptomic signature of depression in key corticolimbic brain regions (T-PRS) is associated with female-specific widespread reductions in activity across cortex, subcortex, and cerebellum to neutral faces, and indirectly, with increased anhedonia, in a nonclinical sample of young adults
Summary
Major depressive disorder (MDD or depression) is the leading cause of disability worldwide[1], with lifetime prevalence up to 17%2. Functional neuroimaging studies of the CLC in depression have typically focused on the amygdala as a primary region of interest, because this structure serves as a processing hub through which associative learning of threat and related physiological and behavioral responses are coordinated[3,5,6]. These studies associate depression with increased amygdala reactivity to threat[3], which may predate the development of depressive symptoms[4] and Mareckova et al Translational Psychiatry (2020)10:410 persist after remission[3,5,6]. Functional connectivity studies using both hypothesisand data-driven approaches have reported reduced coupling between amygdala and prefrontal regulatory regions[13,14], as well as broader dysconnectivity within and beyond the CLC15–20
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