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

Abstract

Schizophrenia (SZ) is a debilitating mental illness with multigenic etiology and high heritability. Despite extensive genetic studies the molecular etiology stays enigmatic. A systems biology study had suggested a protein-protein interaction (PPI) network for SZ with 504 novel PPIs amongst which several genes happen to be drug targets of existing FDA approved drugs. Although the PPI network presented all possible pairs of interactions (known and novel), it lacks a spatio-temporal information. The onset of psychiatric disorders is predominantly in adolescent and young adult stages, often accompanied by subtle structural abnormalities in multiple regions of the brain. Hence, there is a need to redefine the generic PPI network as a function of time (developmental stages) and space (brain regions). The availability of BrainSpan atlas data allowed us to redefine the SZ interactome as a function of space and time. The absence of non-synonymous variants in centenarians and non-psychiatric ExAC database allowed us to identify the variants of criticality. The expression of candidate genes in different brain regions and during developmental stages, responsible for cognitive processes as well as the onset of disease were studied. A subset of novel interactors detected in the network was further validated using gene-expression data of psychiatric postmortem brains. From the long list of drug targets proposed from the interactome study and based on the microarray gene-expression results, we have shortlisted a probable subset of 10 drug targets (targeted by 34 FDA approved drugs) coalescing into 81 biological pathways, that could be potentially repurposed for neuropsychiatric disorders.