Cell type-specific DNA methylation analysis of the prefrontal cortex of patients with schizophrenia.
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ABSTRACT:
SUBMITTER: Ueda J
PROVIDER: S-EPMC8457163 | biostudies-literature | 2021 Sep
REPOSITORIES: biostudies-literature
Publications
Cell type-specific DNA methylation analysis of the prefrontal cortex of patients with schizophrenia.
Ueda Junko J Bundo Miki M Nakachi Yutaka Y Kasai Kiyoto K Kato Tadafumi T Iwamoto Kazuya K
Psychiatry and clinical neurosciences 20210722 9
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Project description:BackgroundSchizophrenia 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.MethodsTo 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.ResultsAberrant 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.ConclusionsThese 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.
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Project description:Genetic variations and adverse environmental events in utero or shortly after birth can lead to abnormal brain development and increased risk of schizophrenia. γ-Aminobutyric acid (GABA), the major inhibitory neurotransmitter in the mammalian brain, plays a vital role in normal brain development. GABA synthesis is controlled by enzymes derived from two glutamic acid decarboxylase (GAD) genes, GAD1 and GAD2, both of which produce transcript isoforms. While the full-length GAD1 transcript (GAD67) has been implicated in the neuropathology of schizophrenia, the transcript structure of GAD1 in the human brain has not been fully characterized. In this study, with the use of RNA sequencing and PCR technologies, we report the discovery of 10 novel transcripts of GAD1 in the human brain. Expression levels of four novel GAD1 transcripts (8A, 8B, I80 and I86) showed a lifespan trajectory expression pattern that is anticorrelated with the expression of the full-length GAD1 transcript. In addition, methylation levels of two CpG loci within the putative GAD1 promoter were significantly associated with the schizophrenia-risk SNP rs3749034 and with the expression of GAD25 in dorsolateral prefrontal cortex (DLPFC). Moreover, schizophrenia patients who had completed suicide and/or were positive for nicotine exposure had significantly higher full-length GAD1 expression in the DLPFC. Alternative splicing of GAD1 and epigenetic state appear to play roles in the developmental profile of GAD1 expression and may contribute to GABA dysfunction in the PFC and hippocampus of patients with schizophrenia.
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Project description:Tremendous work has demonstrated the critical roles of genetics, epigenetics as well as their interplay in brain transcriptional regulations in the pathology of schizophrenia (SZ). There is great success currently in the dissection of the genetic components underlying risk-conferring transcriptomic networks. However, the study of regulating effect of epigenetics in the etiopathogenesis of SZ still faces many challenges. In this work, we investigated DNA methylation and gene expression from the dorsolateral prefrontal cortex (DLPFC) region of schizophrenia patients and healthy controls using weighted correlation network approach. We identified and replicated two expression and two methylation modules significantly associated with SZ. Among them, one pair of expression and methylation modules were significantly overlapped in the module genes which were significantly enriched in astrocyte-associated functional pathways, and specifically expressed in astrocytes. Another two linked expression-methylation module pairs were involved ageing process with module genes mostly related to oligodendrocyte development and myelination, and specifically expressed in oligodendrocytes. Further examination of underlying quantitative trait loci (QTLs) showed significant enrichment in genetic risk of most psychiatric disorders for expression QTLs but not for methylation QTLs. These results support the coherence between methylation and gene expression at the network level, and suggest a combinatorial effect of genetics and epigenetics in regulating gene expression networks specific to glia cells in relation to SZ and ageing process.
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