Identification of genetic variants influencing methylation in brain with pleiotropic effects on psychiatric disorders

Pineda-Cirera, Laura; Cabana‐Domínguez, Judit; Lee, Phil H.; Fernàndez‐Castillo, Noèlia; Cormand, Bru

doi:10.1016/j.pnpbp.2021.110454

Cited by 13 publications

(7 citation statements)

References 61 publications

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“…SNP in ZSCAN31 (rs7759855) had the strongest association with the phenotypes for schizophrenia in the Japanese population ( Saito et al, 2014 ). Methylation in promoter regions of ZSCAN31 in the brain had an effect on schizophrenia ( Pineda-Cirera et al, 2022 ). ZKSCAN3 plays a role in the transcriptional regulation of autophagy ( Pan et al, 2017 ; Barthez et al, 2020 ; Cho et al, 2021 ).…”

Section: Resultsmentioning

confidence: 99%

Association of NKAPL rs1635 With Cognitive Function in Early-Onset Schizophrenia

Yang

Su²,

Wei³

et al. 2022

Front. Genet.

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BACKGROUND: Schizophrenia is a severe mental disorder with high heritability, and cognitive dysfunction is one of the core features. Growing evidence suggests the genetic risk of schizophrenia may contribute to cognitive impairments. The variant rs1635 (nucleotide sequence: c.455C>A; amino acid sequence: T152N) located on the (NFKB activating protein like) NKAPL gene confers risk for schizophrenia and might play a role in the neurodevelopmental process, which is particularly relevant to cognitive function. However, the relationship between rs1635 and cognitive function remains unclear.METHODS: A total of 130 patients with early-onset schizophrenia (EOS) and 300 patients with adult-onset schizophrenia (AOS) of Han Chinese were recruited and underwent neurocognitive tests by using the MATRICS Consensus Cognitive Battery (MCCB). The NKAPL rs1635 was genotyped by using DNA sequencing. The peripheral blood NKAPL mRNA expression level was examined in 152T or 152N carriers (n = 20) in EOS patients, by using the qRT-PCR. The phosphorylation level of NAKPL T152N polymorphism was detected by cell experiments. In utero electroporation of mouse embryos was examined to explore the effect of Nkapl on neuronal migration.RESULTS: Compared with rs1635 AA and AC carriers, CC (the CC genotype encodes the protein NKAPL-152T) carriers of EOS patients performed better in cognitive domain of speed of processing (t = 2.644, p = 0.009), trail making test (t = 2.221, p = 0.028) and category fluency (t = 2.578, p = 0.011). However, patients with AOS exhibited no significant differences in seven domains among the three genotype groups. There were no significant differences in cognitive performance between EOS and AOS. In EOS patients, NKAPL mRNA level in NKAPL-152N carriers is significantly lower than that of NKAPL-152T carriers. The phosphorylation level of NKAPL-152N is significantly decreased compared to NKAPL-152T. In utero electroporation showed that Nkapl deletion impairs the embryonic radial migration process.CONCLUSION: The present study found that NKAPL rs1635 was associated with cognitive impairments and peripheral blood mRNA expression level in EOS patients. The NKAPL full-length protein is required for embryonic cortical neuronal migration. The phosphorylation level of NKAPL-152N is significantly decreased. The NKAPL T152N may affect the NAKPL mRNA expression level and embryonic cortical neuronal migration by regulating the NAKPL protein phosphorylation. These data suggest that NKAPL rs1635 affects cognitive function by regulating early brain development in early-onset schizophrenia.

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Section: Resultsmentioning

confidence: 99%

Association of NKAPL rs1635 With Cognitive Function in Early-Onset Schizophrenia

Yang

Su²,

Wei³

et al. 2022

Front. Genet.

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“…The pathogenesis of depression remains unclear; a previous study showed that nearly 40% of patients administered antidepressants did not recover, and 20% of patients did not respond to any form of intervention ( Brown et al, 2019 ). Epigenetic studies demonstrated a common genetic basis for psychiatric disorders, but the underlying molecular mechanisms remain largely unknown ( Pineda-Cirera et al, 2022 ). Recently, m6A epigenetic modifications have gained attention.…”

Section: Discussionmentioning

confidence: 99%

m6A Regulator-Mediated RNA Methylation Modification Patterns are Involved in the Pathogenesis and Immune Microenvironment of Depression

Wang

Yang

et al. 2022

Front. Genet.

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Depression is a genetical disease characterized by neuroinflammatory symptoms and is difficult to diagnose and treat effectively. Recently, modification of N6-methyladenosine (m6A) at the gene level was shown to be closely related to immune regulation. This study was conducted to explore the effect of m6A modifications on the occurrence of depression and composition of the immune microenvironment. We downloaded gene expression profile data of healthy and depressed rats from the Gene Expression Omnibus. We described the overall expression of m6A regulators in animal models of depression and constructed risk and clinical prediction models using training and validation sets. Bioinformatics analysis was performed using gene ontology functions, gene set enrichment analysis, gene set variation analysis, weighted gene co-expression network analysis, and protein-protein interaction networks. We used CIBERSORT to identify immune-infiltrating cells in depression and perform correlation analysis. We then constructed two molecular subtypes of depression and assessed the correlation between the key genes and molecular subtypes. Through differential gene analysis of m6A regulators in depressed rats, we identified seven m6A regulators that were significantly upregulated in depressed rats and successfully constructed a clinical prediction model. Gene Ontology functional annotation showed that the m6A regulators enriched differentially expressed genes in biological processes, such as the regulation of mRNA metabolic processes. Further, 12 hub genes were selected from the protein-protein interaction network. Immune cell infiltration analysis showed that levels of inflammatory cells, such as CD4 T cells, were significantly increased in depressed rats and were significantly correlated with the depression hub genes. Depression was divided into two subtypes, and the correlation between hub genes and these two subtypes was clarified. We described the effect of m6A modification on the pathogenesis of depression, focusing on the role of inflammatory infiltration.

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“…In line, normal DDAH1 expression levels have previously been shown in chronic schizophrenic patients, while DDAH1 upregulation was found in patients with short-term schizophrenia [ 33 ]. For DDAH2 expression, upregulation is reported in association with schizophrenia patient-specific methylations and promoter region SNPs [ 36 ]. Other studies have also shown that DDAH2 mRNA levels were significantly elevated in brain tissue in schizophrenia, although the brain region was not specified in this study [ 37 ].…”

Section: Discussionmentioning

confidence: 99%

“…DDAH2 gene variants are associated with schizophrenia and bipolar disorder susceptibility [ 36 ]. In schizophrenia patients, the DDAH2 gene is aberrantly methylated in both the prefrontal cortex and blood, and DDAH2 brain mRNA levels are significantly increased [ 37 ].…”

Section: Introductionmentioning

confidence: 99%

Assessment of DDAH1 and DDAH2 Contributions to Psychiatric Disorders via In Silico Methods

Kozlova

Vaganova

Rodionov

et al. 2022

IJMS

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The contribution of nitric oxide synthases (NOSs) to the pathophysiology of several neuropsychiatric disorders is recognized, but the role of their regulators, dimethylarginine dimethylaminohydrolases (DDAHs), is less understood. This study’s objective was to estimate DDAH1 and DDAH2 associations with biological processes implicated in major psychiatric disorders using publicly accessible expression databases. Since co-expressed genes are more likely to be involved in the same biologic processes, we investigated co-expression patterns with DDAH1 and DDAH2 in the dorsolateral prefrontal cortex in psychiatric patients and control subjects. There were no significant differences in DDAH1 and DDAH2 expression levels in schizophrenia or bipolar disorder patients compared to controls. Meanwhile, the data suggest that in patients, DDAH1 and DDHA2 undergo a functional shift mirrored in changes in co-expressed gene patterns. This disarrangement appears in the loss of expression level correlations between DDAH1 or DDAH2 and genes associated with psychiatric disorders and reduced functional similarity of DDAH1 or DDAH2 co-expressed genes in the patient groups. Our findings evidence the possible involvement of DDAH1 and DDAH2 in neuropsychiatric disorder development, but the underlying mechanisms need experimental validation.

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Identification of genetic variants influencing methylation in brain with pleiotropic effects on psychiatric disorders

Cited by 13 publications

References 61 publications

Association of NKAPL rs1635 With Cognitive Function in Early-Onset Schizophrenia

Association of NKAPL rs1635 With Cognitive Function in Early-Onset Schizophrenia

m6A Regulator-Mediated RNA Methylation Modification Patterns are Involved in the Pathogenesis and Immune Microenvironment of Depression

Assessment of DDAH1 and DDAH2 Contributions to Psychiatric Disorders via In Silico Methods

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