Schizophrenia is a brain disorder with high heritability. Recent studies have implicated genes involved in the immune response pathway in the pathogenesis of schizophrenia. Interferon regulatory factor 3 (IRF3), a virus-immune-related gene, activates the transcription of several interferon-induced genes, and functionally interacts with several schizophrenia susceptibility genes. To test whether IRF3 is a schizophrenia susceptibility gene, we analyzed the associations of its SNPs with schizophrenia in independent population samples as well as reported data from expression quantitative trait loci (eQTL) in healthy individuals. We observed multiple independent SNPs in IRF3 showing nominally significant associations with schizophrenia (P < 0.05); more intriguingly, a SNP (rs11880923), which is significantly correlated with IRF3 expression in independent samples (P < 0.05), is also consistently associated with schizophrenia across different cohorts and in combined samples (odds ratio = 1.075, Pmeta = 2.08 × 10−5), especially in Caucasians (odds ratio = 1.078, Pmeta = 2.46 × 10−5). These results suggested that IRF3 is likely a risk gene for schizophrenia, at least in Caucasians. Although the clinical associations of IRF3 with diagnosis did not achieve genome-wide level of statistical significance, the observed odds ratio is comparable with other susceptibility loci identified through large-scale genetic association studies on schizophrenia, which could be regarded simply as small but detectable effects.
Schizophrenia is one of the most severe psychiatric disorders with worldwide lifetime prevalence approaching 1%, and characterized by psychotic features (delusions and hallucinations), disorganization, dysfunction in normal affective responses, and altered cognitive functions (Andreasen, 1995). Previous studies have implicated schizophrenia as an illness involved by interactions of one or more environmental insults with predisposing genetic susceptibility (Cannon et al., 2003, Caspi and Moffitt, 2006 and Clarke et al., 2009). Among these environmental hazards, viral infection is one of the most widely accepted factors that could increase risk of future development of schizophrenia.
Viral infections produce considerable gene expression changes as they trigger immune defenses through type I interferons (IFNs) and the mobilization of transcription factors of the signal transducer and activator of transcription (STAT) and interferon regulatory factor (IRF) families (de Veer et al., 2001 and Stark et al., 1998). Altered expressions of IRF genes in brains have been implicated to contribute to disrupted brain circuit development, maturation and function and result in behavioral deficits that overlap with those seen in schizophrenia and major depression (Hurlock, 2001, Schaefer et al., 2002a and Schaefer et al., 2002b). However, sensitivity to environmental stressors like viral infections shows substantial inter-individual variation, and at least part of this variation may be genetically determined and/or involved with gene–environment interactions.
The interferon regulatory factor 3 gene (IRF3), located on chromosome 19q13, a genomic region possibly harbors risk genes for psychiatric disorders, i.e., APOE, a risk gene for schizophrenia and Alzheimer's disease ( Harold et al., 2009, Lambert et al., 2009, Liu et al., 2003 and Seshadri et al., 2010). IRF3 plays an important role in the innate immune system's response to viral infection ( Collins et al., 2004), and the protein encoded by IRF3 is found in an inactive cytoplasmic form that upon serine/threonine phosphorylation forms a complex with CREBBP, which can translocate to the nucleus and activate transcription of interferons alpha and beta, as well as other interferon-induced genes ( Juang et al., 1998, Lee et al., 2014 and Prinarakis et al., 2008).
Thus, IRF3 is likely a susceptibility gene for schizophrenia based on these lines of epidemiologic and etiologic evidence. Interestingly, a known and predicted protein–protein interactions database (STRING, http://string-db.org/) showed that IRF3 interacts with many other schizophrenia susceptibility genes ( Franceschini et al., 2013), such as AKT1, CREB1, ESR1, and TP53 ( Fig. S1). This observation encouraged our speculation because of recent evidence about protein–protein interactions among schizophrenia risk genes ( Luo et al., 2014a and Yu et al., 2014).
Here, we attempt to characterize the genetic contributions of common variants within IRF3 to schizophrenia susceptibility in independent samples as well as to explore the potential effects on gene expression. The discovery stage involved data from a large screening schizophrenia case–control sample and two independent cohorts containing expression quantitative trait loci (eQTL) data; the replication step includes a variety of independent replications on both clinical and eQTL associations. Our results indicated that IRF3 is likely a schizophrenia susceptibility gene.
