Integrated analysis supports ATXN1 as a schizophrenia risk gene

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.

Keywords: ATXN1; MAPK signaling pathway; Prefrontal cortex; Protein-protein interaction; Schizophrenia; ZNF804A.