Overexpression of OTX2 in human neural cells links depression risk genes.

Genome wide association studies (GWAS) have implicated the OTX2 (Orthodenticle homeobox 2) gene locus in major depressive disorders (MDD) as well as genetically correlated traits. Of the genes identified by MDD GWAS, the gene for the transcription factor OTX2 stands out as it is responsible for both opening and closing of critical and sensitive brain periods. These are developmental periods where the brain is more sensitive to environmental input and are critical for normal brain development. Evidence suggests that the brain may also be more sensitive to negative environmental impact during sensitive periods. Critically, human and animal models both specifically implicate OTX2 gene expression in the response to stress and risk for depression. Based on the genetic findings, and the potential role of OTX2 as a mediator of environmental risk for depression, we identified genes regulated by OTX2 in human neural precursor cells (NPCs) using CRISPR activation (CRISPRa) to increase expression. We identified 17 significantly differentially expressed genes, including OTX2 which was increased 4-fold. In addition to OTX2, 4 genes of the 17 have been directly implicated in depression/depressive behaviours from human and animal studies (GPER1, VGF, TAFA5, P3H2). Additional differentially expressed genes are involved in processes implicated in depression (e.g. neurogenesis, neuroplasticity, response to stress). These novel findings link OTX2 expression with genes previously implicated in depression from human and animal studies, suggesting OTX2 as a master regulator of depression risk.