Protein tyrosine phosphatase receptor type D - A convergent risk gene for MDD, BPD, and ADHD and regulator of dopaminergic neuroplasticity in reward associated circuits; A multivariate GWAS, brain tissue and cell type enrichment, and gene finemapping

Abstract

Major depressive disorder (MDD), bipolar disorder (BPD), and attention-deficit hyperactivity disorder (ADHD), are prevalent, highly heritable psychiatric disorders with significant degrees of genetic overlap. Using open-sourced summary statistics from the Psychiatric Genomics Consortium and 1000 Genomes European reference panel, we utilize a plethora of statistical frameworks to estimate shared genetic liability across MDD, BPD, and ADHD. We observed significant enrichment of latent genetic variables in dopamine neurons, and identify protein tyrosine phosphatase receptor delta (PTPRD), as a candidate gene. Literature review and gene fine-mapping suggest that PTPRD indirectly regulates DAT transporter surface trafficking and neuronal excitability. We propose that the loss of PTPRDs D1 phosphatase domain results in hyperactivated tropomyosin receptor kinase B (TrkB) and rearranged during transfection proto-oncogene tyrosine-protein kinase receptor (RET) signaling in dopamine neurons, potentiating excessive downstream phosphorylation and activation of VAV2, ERK1/2, and PKC. We hypothesize that these mechanisms contribute to the significantly altered reward-related behaviors such as cocaine-conditioned place preference, cocaine self-administration, motivation for cocaine, and goal oriented behavior that are consistently observed across PTPRD KO/inhibition mice studies. With the inclusion of literature review, we present the first integrated multivariate genetic and mechanistic analysis aimed to identify pleiotropic, cell type-specific mechanisms driving psychiatric comorbidity at the biochemical level.