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

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Autor(es):
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Spindola, Leticia M. [1, 2, 3] ; Santoro, Marcos L. [1, 2, 3] ; Pan, Pedro M. [1, 3] ; Ota, Vanessa K. [2, 3] ; Xavier, Gabriela [2, 3] ; Carvalho, Carolina M. [1, 2, 3] ; Talarico, Fernanda [2, 3] ; Sleiman, Patrick [4] ; March, Michael [4] ; Pellegrino, Renata [4] ; Brietzke, Elisa [1] ; Grassi-Oliveira, Rodrigo [5] ; Mari, Jair J. [1, 3] ; Gadelha, Ary [1, 3] ; Miguel, Euripedes C. [6] ; Rohde, Luis A. [7] ; Bressan, Rodrigo A. [1, 3] ; Mazzotti, Diego R. [8] ; Sato, Joao R. [9] ; Salum, Giovanni A. [7] ; Hakonarson, Hakon [4] ; Belangero, I, Sintia
Número total de Autores: 22
Afiliação do(s) autor(es):
[1] I, Univ Fed Sao Paulo, Dept Psychiat, Sao Paulo - Brazil
[2] I, Univ Fed Sao Paulo UNIFESP, Dept Morphol & Genet, Genet Div, Rua Botucatu 740, Sao Paulo, SP - Brazil
[3] I, Univ Fed Sao Paulo, LiNC Lab Integrat Neurosci, Sao Paulo - Brazil
[4] Childrens Hosp Philadelphia, Ctr Appl Genom, Philadelphia, PA 19104 - USA
[5] Pontificia Univ Catolica Rio Grande do Sul PUCRS, Brain Inst, Porto Alegre, RS - Brazil
[6] Univ Sao Paulo, Fac Med, Dept Psychiat, Sao Paulo - Brazil
[7] Univ Fed Rio Grande do Sul, Hosp Clin Porto Alegre, Dept Psychiat, Porto Alegre, RS - Brazil
[8] Univ Penn, Ctr Sleep & Circadian Neurobiol, Philadelphia, PA 19104 - USA
[9] Univ Fed ABC, Ctr Math Comp & Cognit, Santo Andre - Brazil
Número total de Afiliações: 9
Tipo de documento: Artigo Científico
Fonte: CLINICAL EPIGENETICS; v. 11, n. 1 OCT 21 2019.
Citações Web of Science: 0
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: 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
Linha de fomento: 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
Linha de fomento: Auxílio à Pesquisa - Temático
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
Linha de fomento: Bolsas no Brasil - Doutorado
Processo FAPESP: 16/25374-9 - Alterações de metilação do DNA durante o desenvolvimento de transtornos psiquiátricos
Beneficiário:Leticia Maria Nery Spindola
Linha de fomento: Bolsas no Exterior - Estágio de Pesquisa - 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
Linha de fomento: Auxílio à Pesquisa - Regular
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
Linha de fomento: Auxílio à Pesquisa - Regular