ABSTRACT
Background 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 towards depression-like gene expression patterns. We then mapped this T-PRS onto CLC function and related depressive symptoms in a non-clinical sample of young adults.
Methods Genetic, self-report, and neuroimaging data were available in 482 Duke Neurogenetics Study participants (226 men; age 19.78+/-1.23). T-PRS was generated based on common functional SNPs shifting gene expression in the brain towards a depression-like state. 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). Posthoc univariate analyses followed up on the link between T-PRS and amygdala reactivity to neutral and threatening faces. For comparison, we generated a PRS summarizing depression risk variants identified by the Psychiatric Genomics Consortium (PGC-PRS). Sex was modeled as moderating factor.
Results T-PRS was associated with male-specific reductions in neural response to neutral faces in a widespread network of cortical and subcortical regions (multivariate p=0.03) including the amygdala (beta=-0.14, p=0.04). These results mirrored patterns associated with PGC-PRS independently of sex (ps<0.01). Reduced reactivity to neutral faces was further associated with increased self-reported anhedonia.
Conclusions We demonstrate for the first time that in men functional SNPs mimicking the postmortem transcriptomic signature of depression are associated with blunted neural activity to social stimuli, which may be expressed as increased anhedonia.