Alterations in microRNA of extracellular vesicles associated with major depression, attention-deficit/hyperactivity and anxiety disorders in adolescents

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Honorato-Mauer, Jessica ; Xavier, Gabriela ; Ota, Vanessa Kiyomi ; Chehimi, Samar Nasser ; Mafra, Fernanda ; Cuoco, Cassia ; Ito, Lucas Toshio ; Ormond, Rafaella ; Asprino, Paula Fontes ; Oliveira, Adrielle ; Bugiga, Amanda Victoria Gomes ; Torrecilhas, Ana Claudia ; Bressan, Rodrigo ; Manfro, Gisele Gus ; Miguel, Euripedes Constantino ; Rohde, Luis Augusto ; Pan, Pedro Mario ; Salum, Giovanni Abrahao ; Pellegrino, Renata ; Belangero, Sintia ; Santoro, Marcos Leite

• Document type: Journal article
• Source: TRANSLATIONAL PSYCHIATRY; v. 13, n. 1, p. 9-pg., 2023-02-06.

Abstract

Extracellular vesicles (EVs) are present in numerous peripheral bodily fluids and function in critical biological processes, including cell-to-cell communication. Most relevant to the present study, EVs contain microRNAs (miRNAs), and initial evidence from the field indicates that miRNAs detected in circulating EVs have been previously associated with mental health disorders. Here, we conducted an exploratory longitudinal and cross-sectional analysis of miRNA expression in serum EVs from adolescent participants. We analyzed data from a larger ongoing cohort study, evaluating 116 adolescent participants at two time points (wave 1 and wave 2) separated by three years. Two separate data analyses were employed: A cross-sectional analysis compared individuals diagnosed with Major Depressive Disorder (MDD), Anxiety disorders (ANX) and Attention deficit/Hyperactivity disorder (ADHD) with individuals without psychiatric diagnosis at each time point. A longitudinal analysis assessed changes in miRNA expression over time between four groups showing different diagnostic trajectories (persistent diagnosis, first incidence, remitted and typically developing/control). Total EVs were isolated, characterized by size distribution and membrane proteins, and miRNAs were isolated and sequenced. We then selected differentially expressed miRNAs for target prediction and pathway enrichment analysis. In the longitudinal analysis, we did not observe any statistically significant results. In the cross-sectional analysis: in the ADHD group, we observed an upregulation of miR-328-3p at wave 1 only; in the MDD group, we observed a downregulation of miR-4433b-5p, miR-584-5p, miR-625-3p, miR-432-5p and miR-409-3p at wave 2 only; and in the ANX group, we observed a downregulation of miR-432-5p, miR-151a-5p and miR-584-5p in ANX cases at wave 2 only. Our results identified previously observed and novel differentially expressed miRNAs and their relationship with three mental health disorders. These data are consistent with the notion that these miRNAs might regulate the expression of genes associated with these traits in genome-wide association studies. The findings support the promise of continued identification of miRNAs contained within peripheral EVs as biomarkers for mental health disorders. (AU)

• FAPESP's process: 17/25016-8 - Investigation of the treatment response of schizophrenia with risperidone: a pharmacogenetics study in a cohort of first episode of psychosis patients
• Grantee: Síntia Iole Nogueira Belangero
• Support Opportunities: Regular Research Grants
• FAPESP's process: 17/05339-7 - Characterization of gene expression profiles in children and adolescents at risk for mental disorders
• Grantee: Vanessa Kiyomi Ota Kuniyoshi
• Support Opportunities: Regular Research Grants
• FAPESP's process: 21/09584-1 - Integration of microRNA sequencing and genotyping data: local ancestry inference adjustment for eQTL analysis in the Brazilian High Risk Cohort
• Grantee: Jessica Honorato Mauer
• Support Opportunities: Scholarships abroad - Research Internship - Master's degree
• FAPESP's process: 08/57896-8 - National Institute for Developmental Psychiatry
• Grantee: Eurípedes Constantino Miguel Filho
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 20/02247-7 - Evaluation of differential extracellular vesicule miRNA expression associated with the emergence of psychiatric symptoms in adolescents
• Grantee: Jessica Honorato Mauer
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 14/50917-0 - INCT 2014: developmental psychiatry for children and adolescents
• Grantee: Eurípedes Constantino Miguel Filho
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 21/05332-8 - Brazilian high-risk cohort for psychiatric disorders: 10 years follow-up
• Grantee: Rodrigo Affonseca Bressan
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 16/19462-2 - MiRNA role in schizophrenia: from genome until protein
• Grantee: Gabriela Xavier
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)