Prefrontal interneuron genes underlie neurobiological processes shared between psychiatric disorders.

The use of bulk tissue in gene expression analyses underplays the diversity of cell populations and cellular components involved in single-cell preparations. On the other hand, single-cell RNA sequencing provides a finer-grained resolution when interrogating brain cell types, dynamic states, and functional processes. To identify cell-type specific co-expression patterns relevant to major depressive disorder (MDD) etiopathogenesis, we analyzed single-nucleus transcriptomes from the prefrontal cortex of male patients with MDD who died by suicide. We report distinct co-expression patterns in PV- and SST-expressing interneurons, which correlated with genetic risk for MDD and schizophrenia (SCZ) and differed between patients and controls. We found similar co-expression patterns in an independent tissue homogenate cohort analyzed including both patients with MDD and SCZ. These results suggest a molecular pathway in these neurons that might clarify how the shared genetic risk of these disorders influences specific gene activity in the prefrontal cortex neural circuit.