Multi-scale analysis of schizophrenia risk loci: Integrating centenarian genomes and spatio-temporal expression profiles suggests the need for adjunctive therapeutic interventions for neuropsychiatric disorders

Abstract

AbstractSchizophrenia (SZ) is a debilitating mental illness with multigenic etiology and significant heritability. Despite extensive genetic studies the molecular etiology has remained enigmatic. A recent systems biology study suggested a protein-protein interaction (PPI) network for SZ with 504 novel interactions. The onset of psychiatric disorders is predominantly during adolescence often accompanied by subtle structural abnormalities in multiple regions of the brain. The availability of BrainSpan atlas data allowed us to re-examine the genes present in SZ interactome as a function of space and time. The availability of genomes of healthy centenarians and non-psychiatric ExAC database allowed us to identify the variants of criticality. The expression of SZ candidate genes responsible for cognition and disease onset were studied in different brain regions during particular developmental stages. A subset of novel interactors detected in the network was further validated using gene-expression data of post-mortem brains of patients with psychiatric illness. We have narrowed down the list of drug targets proposed by the previous interactome study to 10 proteins. These proteins belonging to 81 biological pathways, are targeted by 34 known FDA approved drugs that have distinct potential for treatment of neuropsychiatric disorders. We also report the possibility of targeting key genes belonging to Celecoxib pharmacodynamics, Gα signaling and cGMP-PKG signaling pathways, that are non-specific to schizophrenia etiology.