RESUMO
Psychotic disorders affect ~3% of the general population and are among the most severe forms of mental diseases. In early stages of psychosis, clinical aspects may be difficult to distinguish from one another. Undifferentiated psychopathology at the first-episode of psychosis (FEP) highlights the need for biomarkers that can improve and refine differential diagnosis. We investigated gene expression differences between patients with FEP-schizophrenia spectrum (SCZ; N=53) or FEP-Mania (BD; N=16) and healthy controls (N=73). We also verified whether gene expression was correlated to severity of psychotic, manic, depressive symptoms and/or functional impairment. All participants were antipsychotic-naive. After the psychiatric interview, blood samples were collected and the expression of 12 psychotic-disorder-related genes was evaluated by quantitative PCR. AKT1 and DICER1 expression levels were higher in BD patients compared with that in SCZ patients and healthy controls, suggesting that expression of these genes is associated more specifically to manic features. Furthermore, MBP and NDEL1 expression levels were higher in SCZ and BD patients than in healthy controls, indicating that these genes are psychosis related (independent of diagnosis). No correlation was found between gene expression and severity of symptoms or functional impairment. Our findings suggest that genes related to neurodevelopment are altered in psychotic disorders, and some might support the differential diagnosis between schizophrenia and bipolar disorder, with a potential impact on the treatment of these disorders.
Assuntos
Transtorno Bipolar/genética , Regulação da Expressão Gênica/genética , Transtornos Psicóticos/genética , Esquizofrenia/genética , Psicologia do Esquizofrênico , Adulto , Proteínas de Transporte/genética , Estudos de Casos e Controles , RNA Helicases DEAD-box/genética , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Proteína Básica da Mielina/genética , Proteínas Proto-Oncogênicas c-akt/genética , Escalas de Graduação Psiquiátrica/estatística & dados numéricos , Psicometria , Transtornos Psicóticos/diagnóstico , Transtornos Psicóticos/psicologia , Valores de Referência , Ribonuclease III/genética , Esquizofrenia/diagnóstico , Estatística como Assunto , Adulto JovemRESUMO
Genes implicated in neurodevelopmental disorders (NDDs) important in cognition and behavior may have convergent function and several cellular pathways have been implicated, including protein translational control, chromatin modification, and synapse assembly and maintenance. Here, we test the convergent effects of methyl-CpG binding domain 5 (MBD5) and special AT-rich binding protein 2 (SATB2) reduced dosage in human neural stem cells (NSCs), two genes implicated in 2q23.1 and 2q33.1 deletion syndromes, respectively, to develop a generalized model for NDDs. We used short hairpin RNA stably incorporated into healthy neural stem cells to supress MBD5 and SATB2 expression, and massively parallel RNA sequencing, DNA methylation sequencing and microRNA arrays to test the hypothesis that a primary etiology of NDDs is the disruption of the balance of NSC proliferation and differentiation. We show that reduced dosage of either gene leads to significant overlap of gene-expression patterns, microRNA patterns and DNA methylation states with control NSCs in a differentiating state, suggesting that a unifying feature of 2q23.1 and 2q33.1 deletion syndrome may be a lack of regulation between proliferation and differentiation in NSCs, as we observed previously for TCF4 and EHMT1 suppression following a similar experimental paradigm. We propose a model of NDDs whereby the balance of NSC proliferation and differentiation is affected, but where the molecules that drive this effect are largely specific to disease-causing genetic variation. NDDs are diverse, complex and unique, but the optimal balance of factors that determine when and where neural stem cells differentiate may be a major feature underlying the diverse phenotypic spectrum of NDDs.
Assuntos
Diferenciação Celular/genética , Proliferação de Células/genética , Proteínas de Ligação a DNA/genética , Proteínas de Ligação à Região de Interação com a Matriz/genética , Células-Tronco Neurais/metabolismo , Transtornos do Neurodesenvolvimento/genética , Neurogênese/genética , Fatores de Transcrição/genética , Células Cultivadas , Deleção Cromossômica , Cromossomos Humanos Par 2 , Metilação de DNA , Epigênese Genética , Dosagem de Genes , Regulação da Expressão Gênica no Desenvolvimento , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , MicroRNAs , Modelos Moleculares , Análise de Sequência de RNARESUMO
Apolipoproteins have an important role in lipid metabolism and transport. Polymorphisms in the APOA1/C3/A4/A5 gene cluster have been associated with lipid alterations and cardiovascular diseases. We investigated APOA1 XmnI, APOA5 S19W, and APOA5 -1131T>C polymorphisms in 377 individuals from a cohort of a longitudinal Brazilian elderly study. Allele frequencies, genotype distribution, and association with major morbidities as well as with lipids, creatinine, albumin, urea, glycated hemoglobin, and fasting glucose serum levels were investigated. Linkage disequilibrium and haplotype associations were also analyzed. This is the first time that haplotypes involving these polymorphisms were evaluated. Genotyping was performed by PCR-RFLP. Minor allele frequencies were 0.119, 0.071, and 0.158 for XmnI, S19W, and -1131T>C polymorphisms, respectively. We found a significant association of the -1131C allele with low LDL-C levels. We also observed that XmnI and S19W polymorphisms were in linkage disequilibrium. The C/G haplotype, which is composed of the wild-type allele of XmnI and the minor allele of S19W, was associated with high total cholesterol serum levels in this elderly population. We conclude that the -1131T>C polymorphism and the C/G haplotype, including XmnI and S19W polymorphisms, are associated with alterations in lipid levels and may be risk factors for cardiovascular disease in the Brazilian elderly.
