Análises de metilação do DNA e de expressão gênica associados a sintomas psiquiátricos e a fatores ambientais em adolescentes

• Ano de defesa: 2019
• Autor(a) principal: Spindola, Leticia Maria Nery [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: Psychiatric Symptoms; Adolescents; DNA Methylation; Gene Expression; Environmental Factors; Sintomas Psiquiátricos; Adolescentes; Metilação do DNA; Expressão gênica; Fatores ambientais
• Link de acesso: https://sucupira.capes.gov.br/sucupira/public/consultas/coleta/trabalhoConclusao/viewTrabalhoConclusao.jsf?popup=true&id_trabalho=7642035; https://repositorio.unifesp.br/handle/11600/59567

Psychiatric disorders are complex phenotypes influenced by genetics and environmental factors and by the interaction between them. Studies suggest that early adverse life events can lead to changes in gene expression through epigenetic mechanisms (such as DNA methylation) that, in turn, alter stress reactivity, brain function, and at last the behavior. One way of measuring altered behavior is to assess the levels of psychopathology, i.e., the presence or frequency of psychiatric symptoms. The main aim of this doctoral thesis was to investigate the relationship among early adverse life events, changes in DNA methylation, changes in gene expression and the emergence of dimensional psychopathology in adolescents over a 3-year follow-up. For this purpose, we performed two studies investigating adolescents (n=24) who presented a significant increase in psychopathology after 3 years of follow-up and who had biological samples collected before and after this follow-up. In the study 1, we explored the relationship among psychopathology, DNA methylation and gene expression by an initial screening analysis to identify differentially methylated positions (DMPs) and differentially methylated regions (DMRs) associated with the emergence of psychopathology. We identified 663 DMPs and 90 DMRs associated with the emergence of psychopathology. We observed that 15 DMPs were mapped to genes that were differentially expressed in the blood. Of the DMRs, three genes were differentially expressed: ASCL2, HLA-E and RPS6KB1. In the study 2, we aimed to find a link between life adversities and the emergence of psychopathology, with the hypothesis that life adversities may dysregulate blood gene expression associated with psychopathology through DNA methylation. Life adversity variables were generated using a latent modelling approach with a bifactor structure, considering general and specifics life experiences. We found that adversity factors related to school or health/loss events were associated with changes in DNA methylation of EST1, FYTTD1 e FAM117B genes. These changes in DNA methylation, in turn, were associated with changes in the expression of these genes. Finally, the expression of these genes was associated with the xxiii emergence of psychopathology. Overall, the results of these two studies showed that the emergence of psychopathology in adolescents along a 3-year follow-up appeared concurrently with changes in the patterns of DNA methylation and gene expression patterns, and that these changes were related. Moreover, we have shown that life adversities that occurred over the 3 years evaluated may have influenced DNA methylation patterns, which in turn may have changed the expression patterns of the genes associated with the emergence of psychopathology. This study highlight the influence of gene expression and DNA methylation in the development of psychopathology in adolescents.