Novel polygenic risk score as a translational tool linking depression-related changes in the corticolimbic transcriptome with neural face processing and anhedonic symptoms

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.

Transcriptome-based polygenic score links depression-related corticolimbic gene expression changes to sex-specific brain morphology and depression risk

“…To address this important gap, our group developed a novel transcriptome-based polygenic risk score (T-PRS) that makes use of common genetic variants to translate molecular changes observed in post-mortem tissue into an in-vivo peripheral proxy measure capturing similarity to the MDD cortical transcriptome. We recently mapped this score onto sex-specific patterns of CLC function in a non-clinical sample of young adults [8]. In this prior study, higher T-PRS was associated with elevated reactivity to emotional faces in men, but blunted reactivity to neutral faces in women.…”

Novel polygenic risk score links depression-related cortical transcriptomic changes to brain morphology and symptom severity

“…These results provide an important initial validation of our approach and suggest a potential clinical relevance of the T-PRS. Of note, although we previously showed partially convergent effects of T-PRS and PRS derived from MDD genome-wide association studies (GWAS) on brain function phenotypes, we also showed that the scores are uncorrelated (4). The genes included in our T-PRS are also distinct from those emerging from transcriptome-wide association studies (TWAS) of depression, which seek to map MDD-associated SNPs onto specific gene expression patterns (24).…”

“…(A)Clusters in which T-PRS was negatively associated (1,2) or positively associated (3,4) with LGI in men.…”

“…By examining each of these brain-based phenotypes, which have unique genetic origins (7) and developmental and aging-related trajectories (8), we sought to capture links between depression-associated changes in gene expression and distinct variations in brain structure that could indicate atypical neurodevelopment (i.e., variations in cortical surface area or local gyrification) or accelerated aging (i.e., variations in cortical thickness or subcortical volume), both of which have been implicated in the pathophysiology of MDD (9, 10). Given consistent evidence of sex differences in depression risk (11, 12) and sex-specificity of T-PRS effects in our prior work (4), we tested associations between T-PRS and brain morphology in men and women separately.…”

“…To address this important gap, our group developed a novel transcriptome-based polygenic risk score (T-PRS) that makes use of common genetic variants to translate these post-mortem molecular changes into an in vivo peripheral proxy measure capturing similarity to the post-mortem depression transcriptome. We recently mapped this score onto corticolimbic function in a sample of healthy young adults, associating higher T-PRS with a female-specific pattern of blunted reactivity to neutral faces further predictive of subclinical anhedonia (4). These findings suggest that molecular shifts towards a depression-like transcriptome may contribute to a functional risk phenotype even in the absence of clinically-significant depression.…”