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Analysis of DNA methylation in blood associated with emergence of psychiatric symptoms and environmental stressors in adolescence

Grant number: 15/10733-0
Support type:Scholarships in Brazil - Doctorate
Effective date (Start): November 01, 2016
Effective date (End): April 30, 2019
Field of knowledge:Health Sciences - Medicine - Psychiatry
Principal researcher:Síntia Iole Nogueira Belangero
Grantee:Leticia Maria Nery Spindola
Home Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
Associated scholarship(s):16/25374-9 - Methylomic changes during development of psychiatric disorders, BE.EP.DR

Abstract

Psychiatric disorders are complex phenotypes and, despite decades of research, their biological bases are still unclear. The heritability of psychiatric disorders estimated by twin studies is high (from 30 to 80%), however, genetic variants explain less than half of this heritability, suggesting the influence of other biological aspects on the etiology of these disorders. So, the study of epigenetic modifications could help in understanding the biological bases of psychiatric disorders. In addition, the use of psychiatric symptoms, which are less subjective clinical phenotypes than clinical diagnoses, is a strategy to obtain less heterogeneous phenotypes that may aid in the search for epigenetic marks related to psychiatric disorders. In the present study, we intend to identify alterations of DNA methylation in blood associated with the emergence of psychiatric symptoms and exposure to environmental stress factors in adolescence. In addition, for differentially methylated genes, we will check if the expressions of these genes in blood are also altered. In addition, we will correlate the levels of methylation with the expression levels of differentially expressed genes. We investigated individuals from a large prospective community-based, school-based study in Brazil, called the High Risk Cohort (HRC) for psychiatric disorders. The HRC has clinical and genetic measures at two different times (W0: baseline, and W1: 3 years after baseline). At both points, non-specific psychiatric symptoms were assessed using the Child Behavior Checklist (CBCL) instrument. In addition, data on environmental stressors experienced by participants during the follow-up time (between W0 and W1) were collected in W1. For the present study, 24 HRC subjects with a total CBCL score <30 on W0 were selected and who increased this score by more than 16 points (mean = 29, SD = 9) in W1, characterizing a symptom emergence group psychiatric disorders. To create a variable that measures the environmental stress factors, we used structural equation modeling using the data collected in W1. This analysis generated a general environmental stress factor and 5 specific environmental stressors (6 variables in total). The methylation data were generated by means of the methylation microarray technique using the Infinium Methylation EPIC BeadChip. To reduce the influence of chronological age and pubertal transition on methylation data, we excluded microarray probes that were associated with age and pubertal transition in two other independent populations of children and adolescents. The results of this study will identify changes in DNA methylation simultaneously with differential gene expression in blood of differentially methylated genes that occur concurrently with the increase of nonspecific psychiatric symptoms in adolescents. In addition, we will identify levels of DNA methylation correlated with exposure to environmental stress factors in adolescence, which is a critical period for neurodevelopment. These results may contribute in the future to a better understanding of the pathogenesis of psychiatric disorders in general and, more specifically, in children and adolescents.

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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
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, I, SINTIA. Detecting multiple differentially methylated CpG sites and regions related to dimensional psychopathology in youths. CLINICAL EPIGENETICS, v. 11, n. 1 OCT 21 2019. Web of Science Citations: 0.

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