Abstract
Background: Schizophrenia is a complex psychiatric disorder with a lifetime morbidity rate of 0.5–1.0%. The pathophysiology of schizophrenia still remains obscure. Accumulating evidence indicates that DNA methylation, which is the addition of a methyl group to the cytosine in a CpG dinucleotide, might play an important role in the pathogenesis of schizophrenia.Methods: To gain further insight into the molecular mechanisms underlying schizophrenia, a genome-wide DNA methylation profiling (27,578 CpG dinucleotides spanning 14,495 genes) of the human dorsolateral prefrontal cortex (DLPFC) was conducted in a large cohort (n = 216) of well characterized specimens from individuals with schizophrenia and non-psychiatric controls, combined with an analysis of genetic variance at ~880,000 SNPs.Results: Aberrant DNA methylation in schizophrenia was identified at 107 CpG sites at 5% Bonferroni correction (p < 1.99 × 10−6). Of these significantly altered sites, hyper-DNA methylation was observed at 79 sites (73.8%), mostly in the CpG islands (CGIs) and in the regions flanking CGIs (CGI: 31 sites; CGI shore: 35 sites; CGI shelf: 3 sites). Furthermore, a large number of cis-methylation quantitative trait loci (mQTL) were identified, including associations with risk SNPs implicated in schizophrenia.Conclusions: These results suggest that altered DNA methylation might be involved in the pathophysiology and/or treatment of schizophrenia, and that a combination of epigenetic and genetic approaches will be useful to understanding the molecular mechanism of this complex disorder.
Highlights
Schizophrenia is a complex psychiatric disorder with a lifetime morbidity rate of 0.5–1.0%
Accumulating evidence indicates that DNA methylation, which is the addition of a methyl group to the cytosine in a CpG dinucleotide, might play an important role in the pathogenesis of schizophrenia
Aberrant DNA methylation in schizophrenia was identified at 107 CpG sites at 5% Bonferroni correction (p < 1.99 × 10−6)
Summary
Schizophrenia is a complex psychiatric disorder with a lifetime morbidity rate of 0.5–1.0%. L-methionine-treated mice exhibited increased DNA methylation that was accompanied by decreased mRNA levels of specific genes, and by behavioral changes similar to those seen in schizophrenia (Tremolizzo et al, 2002, 2005). An increased mRNA expression of DNA methyl-transferases (DNMT1 and DNMT3a) has been observed in schizophrenia (Veldic et al, 2004, 2005; Ruzicka et al, 2007; Zhubi et al, 2009). Accumulating evidence indicates that DNA methylation, which is the addition of a methyl group to the cytosine in a CpG dinucleotide, might play an important role in the pathogenesis of schizophrenia
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