Meta-analysis of genomic variants and gene expression data in schizophrenia suggests the potential need for adjunctive therapeutic interventions for neuropsychiatric disorders

Abstract

Schizophrenia (SZ) is a debilitating mental illness with a multigenic aetiology and significant heritability. Despite extensive genetic studies, the molecular aetiology has remained enigmatic. A recent systems biology study suggested a proteinprotein interaction network for SZ with 504 novel interactions. The onset of psychiatric disorders is predominant 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 the SZ interactome as a function of space and time. The availability of genomes of healthy centenarians and nonpsychiatric Exome Aggregation Consortium database allowed us to identify the variants of criticality. The expression of the SZ candidate genes responsible for cognition and disease onset was 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 Food and Drug Administration-approved drugs that have distinct potential for the treatment of neuropsychiatric disorders. We also report the possibility of targeting key genes belonging to celecoxib pharmacodynamics, G α signalling and cGMP-PKG signalling pathways that are not known to be specific to SZ aetiology.

Potentially repurposable drugs for schizophrenia identified from its interactome

“…Danazol and miconazole target ESR1 and NOS3, both associated with Alzheimer’s disease. NOS3 was also identified as a potential target for schizophrenia based on its druggability, membership in schizophrenia-related biological pathways and differential expression in schizophrenia 60 .…”

Interactome of SARS-CoV-2 / nCoV19 modulated host proteins with computationally predicted PPIs

“… 26 ) (2) computational systems biologists may investigate it in conjunction with transcriptomic/proteomic data (e.g.). 30 , 33 – 35 To facilitate ‘(1)’, we are making these results available over an interactive webserver, and to facilitate ‘(2)’, we are releasing the data as downloadable files in various formats.…”