Detecting multiple differentially methylated CpG sites and regions related to dimensional psychopathology in youths

Autor(es):Mostrar menos -

Spindola, Leticia M. ; Santoro, Marcos L. ; Pan, Pedro M. ; Ota, Vanessa K. ; Xavier, Gabriela ; Carvalho, Carolina M. ; Talarico, Fernanda ; Sleiman, Patrick ; March, Michael ; Pellegrino, Renata ; Brietzke, Elisa ; Grassi-Oliveira, Rodrigo ; Mari, Jair J. ; Gadelha, Ary ; Miguel, Euripedes C. ; Rohde, Luis A. ; Bressan, Rodrigo A. ; Mazzotti, Diego R. ; Sato, Joao R. ; Salum, Giovanni A. ; Hakonarson, Hakon ; Belangero, Sintia, I

• Tipo de documento: Artigo Científico
• Fonte: CLINICAL EPIGENETICS; v. 11, n. 1, p. 16-pg., 2019-10-21.

Resumo

Background Psychiatric symptomatology during late childhood and early adolescence tends to persist later in life. In the present longitudinal study, we aimed to identify changes in genome-wide DNA methylation patterns that were associated with the emergence of psychopathology in youths from the Brazilian High-Risk Cohort (HRC) for psychiatric disorders. Moreover, for the differentially methylated genes, we verified whether differences in DNA methylation corresponded to differences in mRNA transcript levels by analyzing the gene expression levels in the blood and by correlating the variation of DNA methylation values with the variation of mRNA levels of the same individuals. Finally, we examined whether the variations in DNA methylation and mRNA levels were correlated with psychopathology measurements over time. Methods We selected 24 youths from the HRC who presented with an increase in dimensional psychopathology at a 3-year follow-up as measured by the Child Behavior Checklist (CBCL). The DNA methylation and gene expression data were compared in peripheral blood samples (n = 48) obtained from the 24 youths before and after developing psychopathology. We implemented a methodological framework to reduce the effect of chronological age on DNA methylation using an independent population of 140 youths and the effect of puberty using data from the literature. Results We identified 663 differentially methylated positions (DMPs) and 90 differentially methylated regions (DMRs) associated with the emergence of psychopathology. We observed that 15 DMPs were mapped to genes that were differentially expressed in the blood; among these, we found a correlation between the DNA methylation and mRNA levels of RB1CC1 and a correlation between the CBCL and mRNA levels of KMT2E. Of the DMRs, three genes were differentially expressed: ASCL2, which is involved in neurogenesis; HLA-E, which is mapped to the MHC loci; and RPS6KB1, the gene expression of which was correlated with an increase in the CBCL between the time points. Conclusions We observed that changes in DNA methylation and, consequently, in gene expression in the peripheral blood occurred concurrently with the emergence of dimensional psychopathology in youths. Therefore, epigenomic modulations might be involved in the regulation of an individual's development of psychopathology. (AU)

• Processo FAPESP: 15/10733-0 - Análise de metilação do DNA em sangue associados à emergência de sintomas psiquiátricos e a fatores de estresses ambientais na adolescência
• Beneficiário: Leticia Maria Nery Spindola
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 17/05339-7 - Caracterização do perfil de expressão gênica em crianças e adolescentes em risco para transtornos mentais
• Beneficiário: Vanessa Kiyomi Ota Kuniyoshi
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 16/04983-7 - Neuroimagem, genômica, transcriptômica e epigenômica: conduzindo análises em larga escala em direção a um modelo integrativo de transtornos mentais
• Beneficiário: Jair de Jesus Mari
• Modalidade de apoio: Auxílio à Pesquisa - Programa eScience e Data Science - Regular
• Processo FAPESP: 14/50917-0 - INCT 2014: psiquiatria do desenvolvimento para crianças e adolescentes
• Beneficiário: Eurípedes Constantino Miguel Filho
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 14/07280-1 - Busca por marcadores genéticos de risco, de progressão e de reposta ao tratamento na esquizofrenia
• Beneficiário: Síntia Iole Nogueira Belangero
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 16/25374-9 - Alterações de metilação do DNA durante o desenvolvimento de transtornos psiquiátricos
• Beneficiário: Leticia Maria Nery Spindola
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Doutorado