Abstract
An enigma in studies of neuropsychiatric disorders is how to translate polygenic risk into disease biology. For schizophrenia, where > 145 significant GWAS loci have been identified and only a few genes directly implicated, addressing this issue is a particular challenge. We used a combined cellomics and proteomics approach to show that polygenic risk can be disentangled by searching for shared neuronal morphology and cellular pathway phenotypes of candidate schizophrenia risk genes. We first performed an automated high-content cellular screen to characterize neuronal morphology phenotypes of 41 candidate schizophrenia risk genes. The transcription factors Tcf4 and Tbr1 and the RNA topoisomerase Top3b shared a neuronal phenotype marked by an early and progressive reduction in synapse numbers upon knockdown in mouse primary neuronal cultures. Proteomics analysis subsequently showed that these three genes converge onto the syntaxin-mediated neurotransmitter release pathway, which was previously implicated in schizophrenia, but for which genetic evidence was weak. We show that dysregulation of multiple proteins in this pathway may be due to the combined effects of schizophrenia risk genes Tcf4, Tbr1, and Top3b. Together, our data provide new biological functions for schizophrenia risk genes and support the idea that polygenic risk is the result of multiple small impacts on common neuronal signaling pathways.
Highlights
Schizophrenia (SCZ) is a severe neuropsychiatric disorder characterized by persistent delusions and hallucination and abnormal social behavior
Are there many different cellular and molecular pathways that lead to disease, or do risk genes converge onto a small number of shared pathways underlying SCZ? We addressed this issue by performing a combination of cellular phenotyping and proteomics analysis
Most genes (25) are genetically associated with SCZ, others are associated with autism spectrum disorder (ASD; 19 genes) or bipolar disorder (BPD; 10 genes) and have been implicated in SCZ otherwise
Summary
Schizophrenia (SCZ) is a severe neuropsychiatric disorder characterized by persistent delusions and hallucination and abnormal social behavior. Whole-exome sequencing led to the identification of SETD1A [3] and RBM12 [4] and three rare copy number variants (CNVs) have been identified that impact single genes (i.e., NRXN1 [5], TOP3B [6], and VIPR2 [7]). Common variation in the genome seems to have a large impact on the development of SCZ [2]. More than 145 independent genomic risk loci have been associated with SCZ or in genome-wide association studies (GWAS) [12, 13]. Some of these loci include associated gene variants that can modify the expression of large
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
