Busca por potenciais marcadores genéticos nas fases iniciais da esquizofrenia

• Ano de defesa: 2016
• Autor(a) principal: Santoro, Marcos Leite [UNIFESP]
• Tipo de documento: Tese
• Tipo de acesso: Acesso aberto
• Idioma: por
• Instituição de defesa: Universidade Federal de São Paulo (UNIFESP)
• Palavras-chave em Português: Schizophrenia; First psychotic episode; Mental state of risk for psychosis; Gene expression; Methylation of dna; And; Polygenic risk score; Esquizofrenia; Primeiro episódio psicótico; Estado mental de risco para psicose; Expressão gênica; Metilação de dna; Escore poligênico de risco
• Link de acesso: https://sucupira.capes.gov.br/sucupira/public/consultas/coleta/trabalhoConclusao/viewTrabalhoConclusao.jsf?popup=true&id_trabalho=4336522; http://repositorio.unifesp.br/handle/11600/47753

Schizophrenia is a severe and disabling psychiatric disorder that affects about 1% of the population. It is a complex disease characterized by the change in multiple genes of susceptibility. Once schizophrenia has been diagnosed, most patients have a poor prognosis, with few returning to normal executive functions after the first psychotic episode (PEP). Thus, the study of individuals at ultra-high risk to develop psychosis (EMR) is of great importance for the understanding of the pathophysiology of schizophrenia, before the establishment of the disease, as well as to find biomarkers related to the transition to schizophrenia. Equally important, the investigation of individuals in their PEP, antipsychotic-naive and before disease progression, is extremely useful for understanding the complexity of schizophrenia and its treatment. Considering that schizophrenia is a chronic disease, its progression and antipsychotic use may be confusing factors in the interpretation of the results of gene expression and DNA methylation. Our main objective was to identify genetic markers of risk, progression and response to treatment in the early stages of schizophrenia by different approaches (genomic, transcriptomic and epigenomic analyses). We investigated 22 subjects at EMR, 66 PEP patients before and after 2 months of treatment with risperidone (PEP-2M), and 67 healthy controls (with no family history or progression of severe psychiatric illness). To better understand the results, we divided this thesis into two studies. In study 1 we evaluated the expression of 12 candidate genes by the TLDA (Taqman Low Density Array) technique in EMR, PEP before treatment and controls. In study 2 we used three large-scale measures (polygenic risk score for schizophrenia, transcriptome and DNA methylome) in controls (N = 60) and in PEP patients before and after risperidone treatment (N = 60). In study 1, we found two differentially expressed genes (UFD1L and MBP), and the UFD1L gene showed an increased expression in the EMR group in relation to the PEP and the controls, suggesting a specific alteration of the individuals at EMR. In study 2, we validated the polygenic risk score (PRS) and demonstrated that this is a measure that can be used effectively in the Brazilian population. In addition, we found positive associations in PEP between PRS and clinical variables, so that the higher the PRS, higher was the impairment. However, these associations are not observed after two months of treatment with risperidone, reinforcing the importance of working with individuals in treatment-free PEP. Finally, we identified some differentially expressed genes and differentially methylated regions related to the disease (when comparing individuals in PEP and controls) and related to the response to treatment (when we followed individuals in PEP before and after risperidone treatment). Using genomic, transcriptomic and epigenomic techniques, we were able to identify genetic markers related to progression and the early stages of schizophrenia in peripheral blood.