Abstract
Despite advances in pharmacogenetics, the majority of heritability for treatment response cannot be explained by common variation, suggesting that factors such as epigenetics may play a key role. Regulatory genes, such as those involved in DNA methylation and transcriptional repression, are therefore excellent candidates for investigating antipsychotic treatment response. This study explored the differential expression of regulatory genes between patients with schizophrenia (chronic and antipsychotic-naïve first-episode patients) and healthy controls in order to identify candidate genes for association with antipsychotic treatment response. Seven candidate differentially expressed genes were identified, and four variants within these genes were found to be significantly associated with treatment response (DNMT3A rs2304429, HDAC5 rs11079983, and HDAC9 rs1178119 and rs11764843). Further analyses revealed that two of these variants (rs2304429 and rs11079983) are predicted to alter the expression of specific genes (DNMT3A, ASB16, and ASB16-AS1) in brain regions previously implicated in schizophrenia and treatment response. These results may aid in the development of biomarkers for antipsychotic treatment response, as well as novel drug targets.
Highlights
The onset of schizophrenia is marked by a first psychotic episode, typically followed by subsequent relapse episodes, separated by intervals of remission (Lieberman et al, 2001)
The B2M, DNMT3A, HDAC5, HDAC9, MBD2, MBD3, and RPLP0 genes were selected since the expression levels of these genes were significantly different between the chronic patients (CHR) and CON groups and CHR and first-episode patients (FES) groups, respectively (Table 1, Figure 2)
We identified a number of DNA methylation and transcriptional repression genes to be significantly over-expressed in patients with SCZ, in first-episode and CHR, when compared to healthy controls (Table 1)
Summary
The onset of schizophrenia is marked by a first psychotic episode, typically followed by subsequent relapse episodes, separated by intervals of remission (Lieberman et al, 2001). Treatment strategies are not optimal (Brandl et al, 2014), and it is estimated that approximately half of all patients with schizophrenia will not respond satisfactorily to antipsychotics (Lohoff and Ferraro, 2010), which are the mainstay of treatment and, as such, widely used. They are effective for positive symptoms (such as delusions and hallucinations); their efficacy for negative symptoms (such as apathy, anhedonia, and social withdrawal) is limited (Leucht and Davis, 2017). Considering the high rate of nonresponders to treatment and the potential severe side effects of treatment, there is a clear need to improve our understanding of antipsychotic treatment response
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