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 protein–protein 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, \(\hbox {G}\upalpha \) signalling and cGMP-PKG signalling pathways that are not known to be specific to SZ aetiology.
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Acknowledgements
SKB is a recipient of the J. C. Bose National Fellowship. ACS thanks Mohandas Pai foundation for providing fellowship support through Centre for Open Innovation, IndianCST. We thank Raja Seevan, Sri Kumar and the IndianCST team for the infrastructure support. We thank NIMHANS for providing institutional support to SJ. We thank N. Balakrishnan for providing access to the computational facility at the Supercomputer Education and Research Centre, Indian Institute of Science. We also thank Vinod Scaria for providing access to the allele frequencies from his centenarian genome data and Beena Pillai for inputs on gene expression data analysis. We finally thank Meera Purushottam, Ramakrishnan Kannan, Biju Viswanath and Ravi Kumar Nadella for critical reading of this manuscript.
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SKB conceptualized and designed the project. ACS and AKJ performed the gene expression data analysis. AKP performed the meta-analysis of variants and PS constructed the spatio-temporal network. ACS and SKB wrote the manuscript. SJ provided intellectual support in interpreting the results and editing the manuscript.
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Chellappa, S.A., Pathak, A.K., Sinha, P. et al. Meta-analysis of genomic variants and gene expression data in schizophrenia suggests the potential need for adjunctive therapeutic interventions for neuropsychiatric disorders. J Genet 98, 60 (2019). https://doi.org/10.1007/s12041-019-1101-6
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DOI: https://doi.org/10.1007/s12041-019-1101-6