Elsevier

Schizophrenia Research

Volume 195, May 2018, Pages 298-305
Schizophrenia Research

Integrated analysis supports ATXN1 as a schizophrenia risk gene

https://doi.org/10.1016/j.schres.2017.10.010Get rights and content

Abstract

Protein-protein interaction (PPI) is informative in identifying hidden disease risk genes that tend to interact with known risk genes usually working together in the same disease module. With the use of an integrated approach combining PPI information with pathway and expression analysis as well as genome-wide association study (GWAS), we intended to find new risk genes for schizophrenia (SCZ). We showed that ATXN1 was the only direct PPI partner of the know SCZ risk gene ZNF804A, and it also had direct PPIs with other 18 known SCZ risk genes. ATXN1 serves as one of the hub genes in the PPI network containing many known SCZ risk genes, and this network is significantly enriched for the MAPK signaling pathway. Further gene expression analysis indicated that ATXN1 is highly expressed in prefrontal cortex, and SCZ patients had significantly decreased expression compared with healthy controls. Finally, the published GWAS data supports an association of ATXN1 with SCZ as well as other psychiatric disorders though not reaching genome-wide significance. These convergent evidences support ATXN1 as a promising risk gene for SCZ, and the integrated approach serves as a useful tool for dissecting the genetic basis of psychiatric disorders.

Introduction

Schizophrenia (SCZ) is one of the severe mental disorders with high heritability (Sullivan et al., 2003). Although many SCZ risk genes have been identified by the commonly used methods including genome-wide association studies (GWASs) (Hamshere et al., 2013, Ikeda et al., 2013, Lencz et al., 2013, Li et al., 2011, O'Donovan et al., 2008, Purcell et al., 2009, Rietschel et al., 2012, Ripke et al., 2013, Schizophrenia Psychiatric Genome-Wide Association Study Consortium, 2011, Schizophrenia Working Group of the Psychiatric Genomics Consortium, 2014, Shi et al., 2011, Stefansson et al., 2009, Steinberg et al., 2011, Wong et al., 2014, Yue et al., 2011), linkage and association analysis of candidate genes (Allen et al., 2008, Lewis et al., 2003, Ng et al., 2009, Sun et al., 2008), exon sequencing (Fromer et al., 2014, Purcell et al., 2014) and so on, our knowledge about genetic risk factors of SCZ is still extending. Protein-protein interactions (PPIs) are binary relationships of proteins in cells. Proteins interacting with each other tend to take part in the same cellular process. According to the disease module hypothesis, proteins involved in the same disease process tend to interact with each other to form disease modules (Feldman et al., 2008, Goh et al., 2007). Such properties make PPIs highly informative for identifying hidden disease risk genes (Kohler et al., 2008, Oti et al., 2006).

ZNF804A (zinc finger protein 804A) was the first risk gene identified by GWAS (O'Donovan et al., 2008), and follow-up studies had confirmed its involvement in SCZ in many aspects (Hess and Glatt, 2014). We therefore speculate that any proteins directly interacting with ZNF804A may also serve as risk genes for SCZ. With the use of multiple PPI databases (HRRD, HINT and IntAct) (Keshava Prasad et al., 2009) (Das and Yu, 2012, Orchard et al., 2014), we found that the ATXN1 gene (Ataxin-1) served as the only PPI partner of ZNF804A, suggesting its potential involvement in SCZ susceptibility.

ATXN1 is responsible for the neurodegenerative diseasesingle bondspinocerebellar ataxia type 1 (SCA1, MIM164400). Patients have difficulties with coordination, balance, speech, swallowing, muscle and cognitive performance such as processing, learning and remembering information (https://ghr.nlm.nih.gov/condition/spinocerebellar-ataxia-type-1). A mutational mechanism in ATXN1 with expansion of CAG repeat unit near the amino terminus has been characterized in SCA1 patients. The normal allele contains 6–39 CAG repeats while a defective version contains 40–81 repeats (Zoghbi and Orr, 1995). Several small sample studies had investigated the association between ATXN1 and SCZ (http://www.szgene.org/geneoverview.asp?geneid=354), and the results however remained inconclusive. There were five reported case-control studies of ATXN1 in populations of European ancestry (Culjkovic et al., 2000, Joo et al., 1999, Li et al., 1999, Morris-Rosendahl et al., 1997, Pujana et al., 1997). Two studies showed positive results while the other three were negative. In addition, four family-based association studies of ATXN1 also showed inconsistent results (one positive and three negative) (Fallin et al., 2005, Li et al., 1999, Lin et al., 2009, Pujana et al., 1997). The inconsistency of the reported data was possibly due to the limited sample sizes of these studies (the numbers of cases were less than 350).

The direct PPI network of a set of genes may imply their involvement in a specific disease process. We thus hypothesize that ATXN1 may participate in SCZ etiology through direct interaction(s) with known SCZ risk genes such as ZNF804A. We utilized an integrated approach by combining analyses of PPI network, molecular pathway, gene expression and genetic association, we showed that ATXN1 directly interacts with many known SCZ risk genes including ZNF804A, and it significantly participated in the SCZ disease network.

Section snippets

Protein-protein interaction analysis

We firstly extracted PPI pairs of ZNF804A from the HPRD database (Keshava Prasad et al., 2009). For validation, we also extracted PPI information of ZNF804A from HINT (Das and Yu, 2012) and IntAct (Orchard et al., 2014). It turned out that ATXN1 is the only PPI partner of ZNF804A and this result is consistent among all three databases. We next constructed PPI information of ATXN1 using the HPRD database. We excluded the PPI pairs with missing protein information. The PPI network was visualized

ATXN1 has PPIs with ZNF804A and other known SCZ risk genes

As ATXN1 was the sole PPI partner of ZNF804A based on the search of three PPI databases including HPRD, HINT and IntAct, we next tested if ATXN1 has PPIs with other SCZ risk genes. We obtained 154 PPI partners of ATXN1 from the HPRD database (Keshava Prasad et al., 2009), among which 19 genes including ZNF804A are known SCZ risk genes (Fig. 1, Table S1 and Table S2). In particular, four genes (R3HDM2, SREBF1, ZNF804A and TBC1D5) reached genome-wide significance in the published GWAS studies (

Discussion

SCZ is a complex neuropsychiatric disorder with high heritability. GWASs, linkage analysis, exon sequencing together with other methods have greatly expanded our knowledge about SCZ risk genes though more genes are yet to be identified. In this study, with an integrated approach, we identified ATXN1 as a sole PPI partner of ZNF804A and it is likely involved in SCZ susceptibility.

ATXN1 has 19 direct PPIs with known SCZ risk genes, which is significantly higher than the average number among these

Conflict of interest

The authors report no biomedical financial interests or potential conflicts of interest.

Contributors

J.L and B.S designed the study, J.L performed data analysis, J.L and B.S wrote the manuscript.

Role of the funding source

This work was supported by grants from the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB13010100), the National Natural Science Foundation of China (U1202225 and 31130051).

Acknowledgements

We would like to thank Dr. Xiongjian Luo for his kind help during manuscript preparation.

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