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. 2016 Apr 27:2:16012.
doi: 10.1038/npjschz.2016.12. eCollection 2016.

Schizophrenia interactome with 504 novel protein-protein interactions

Madhavi K Ganapathiraju  1 , Mohamed Thahir  1 , Adam Handen  2 , Saumendra N Sarkar  3 , Robert A Sweet  4 , Vishwajit L Nimgaonkar  5 , Christine E Loscher  6 , Eileen M Bauer  7 , Srilakshmi Chaparala  2
Affiliations

Schizophrenia interactome with 504 novel protein-protein interactions

Madhavi K Ganapathiraju et al. NPJ Schizophr. .

Abstract

Genome-wide association studies of schizophrenia (GWAS) have revealed the role of rare and common genetic variants, but the functional effects of the risk variants remain to be understood. Protein interactome-based studies can facilitate the study of molecular mechanisms by which the risk genes relate to schizophrenia (SZ) genesis, but protein-protein interactions (PPIs) are unknown for many of the liability genes. We developed a computational model to discover PPIs, which is found to be highly accurate according to computational evaluations and experimental validations of selected PPIs. We present here, 365 novel PPIs of liability genes identified by the SZ Working Group of the Psychiatric Genomics Consortium (PGC). Seventeen genes that had no previously known interactions have 57 novel interactions by our method. Among the new interactors are 19 drug targets that are targeted by 130 drugs. In addition, we computed 147 novel PPIs of 25 candidate genes investigated in the pre-GWAS era. While there is little overlap between the GWAS genes and the pre-GWAS genes, the interactomes reveal that they largely belong to the same pathways, thus reconciling the apparent disparities between the GWAS and prior gene association studies. The interactome including 504 novel PPIs overall, could motivate other systems biology studies and trials with repurposed drugs. The PPIs are made available on a webserver, called Schizo-Pi at http://severus.dbmi.pitt.edu/schizo-pi with advanced search capabilities.

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Figures

Figure 1
Figure 1
Computational evaluation of predicted protein–protein interactions on hub proteins: (a) precision recall curve. (b) True positive versus false positives in ranked lists of hub type membrane receptors for our method and that by Qi et al. True positives versus false positives are shown for individual membrane receptors by our method in (c) and by Qi et al. in (d). Thick line is the average, which is also the same as shown in (b). Note: x-axis is recall in (a), whereas it is number of false positives in (b–d). The range of y-axis is observed by varying the threshold from 1.0–0 in (a), and to 0.5 in (b–d).
Figure 2
Figure 2
Schizophrenia interactome: network view of the schizophrenia interactome is shown as a graph, where genes are shown as nodes and PPIs as edges connecting the nodes. Schizophrenia-associated genes are shown as dark blue nodes, novel interactors as red color nodes and known interactors as blue color nodes. The source of the schizophrenia genes is indicated by its label font, where Historic genes are shown italicized, GWAS genes are shown in bold, and the one gene that is common to both is shown in italicized and bold. For clarity, the source is also indicated by the shape of the node (triangular for GWAS and square for Historic and hexagonal for both). Symbols are shown only for the schizophrenia-associated genes; actual interactions may be accessed on the web. Red edges are the novel interactions, whereas blue edges are known interactions. GWAS, genome-wide association studies of schizophrenia; PPI, protein–protein interaction.
Figure 3
Figure 3
Number of novel and known PPIs of GWAS genes. For each gene, the number of known PPIs is shown in light blue color and novel PPIs is red color. GWAS, genome-wide association studies of schizophrenia; PPI, protein–protein interaction.
Figure 4
Figure 4
Overlap of significant pathways from GWAS interactome and Historic gene interactome. Pathway associations are computed with Ingenuity Pathway Analysis. Pathways shown are the top 30 pathways in the GWAS interactome, and additionally, some of the pathways that are known to be associated with SZ. Number of genes associated with GWAS interactome is shown in green, with Historic gene interactome in blue and common to both in yellow. GWAS, genome-wide association studies of schizophrenia; PPI, protein–protein interaction.
Figure 5
Figure 5
Number of drugs that target the genes in the GWAS interactome: the numbers are shown separated by the anatomic category of the drugs (Anatomic, Therapeutic and Chemical classification) and also separated by whether they target known interactors (blue) or novel interactors (red) or both (green). GWAS, genome-wide association studies of schizophrenia.
Figure 6
Figure 6
Gene–drug interactome. The network shows the drugs that target genes from the schizophrenia interactome. Drugs are shown as round nodes colored in green and genes as square nodes colored in dark blue (schizophrenia genes), light blue (known interactors), and red (novel interactors). Nervous system drugs (based on Anatomic category of ATC classification) are shown as larger size green colored nodes compared with other drugs. Drugs that are in clinical trials for schizophrenia are labeled purple. ATC, anatomic, therapeutic and chemical classification.
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