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

Translational Psychiatry, November 2020

Authors: Klara Mareckova, Colin Hawco, Fernanda C. Dos Santos, Arin Bakht, Navona Calarco, Amy E. Miles, Aristotle N. Voineskos, Etienne Sibille, Ahmad R. Hariri & Yuliya S. Nikolova

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. Here we show that T-PRS was associated with widespread reductions in neural response to neutral faces in women and to emotional faces and shapes in men. We also demonstrate links between female-specific reductions in neural response to neutral faces and increased self-reported anhedonia and a PRS summarizing depression risk variants identified by the Psychiatric Genomics Consortium. 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.