Vanessa Kiyomi Ota ¹ Adrielle M Oliveira ¹ Amanda Bugiga ¹ Helena B Conceição ² Pedro A F Galante ² Paula Asprino ² Julia Luiza Schäfer ³ Mauricio Hoffmann ⁴ Rodrigo Bressan ¹ Elisa Brietzke ⁵ Gisele G Manfro ³ Rodrigo Grassi-Oliveira ⁶ Ary Gadelha ¹ Luis Augusto Rohde ³ Euripedes Constantino Miguel ⁷ Pedro M Pan ¹ Marcos Leite Santoro ¹ Giovanni Salum ³ Carolina Muniz Carvalho ¹ Sintia I. Belangero ^1*

• ¹ Federal University of São Paulo, São Paulo, Brazil
• ² Hospital Sirio Libanes, São Paulo, São Paulo, Brazil
• ³ Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil
• ⁴ Federal University of Santa Maria, Santa Maria, Rio Grande do Sul, Brazil
• ⁵ Department of Psychiatry, School of Medicine, Faculty of Health Sciences, Queen's University, Kingston, Ontario, Canada
• ⁶ Aarhus University, Aarhus, Central Denmark Region, Denmark
• ⁷ Hospital das Clinicas da FMUSP, SAO PAULO, Brazil

While the influence of both genetic and environmental factors on the development of psychiatric symptoms is well-recognized, the precise nature of their interaction throughout development remains a subject of ongoing debate. This study investigated the association between the expression of 78 candidate genes, previously associated with psychiatric phenotypes, in peripheral blood and both adversity and psychopathology in a sample of 298 young individuals assessed at two time points from the Brazilian High Risk Cohort Study for Mental Conditions (BHRCS). Psychopathology was assessed using the Child Behavior Checklist (CBCL), considering the total CBCL, p-factor (i.e. general factor of psychopathology), and internalizing and externalizing symptoms as clinical variables. The life adversities considered in this study includes four composite variables: child maltreatment, stressful life events, threat and deprivation.Gene expression was measured using next-generation sequencing for target genes and differential gene expression was analyzed with the DESeq2 package. Mixed models revealed six genes associated with internalizing symptoms: NR3C1, HSPBP1, SIN3A, SMAD4, and CRLF3 genes exhibited a negative correlation with these symptoms, while FAR1 gene showed a positive correlation. Additionally, we also found a negative association between USP38 gene expression and externalizing symptoms. Finally, DENND11 and PRRC1 genes were negatively associated with deprivation, a latent factor characterized by neglect, parental absence, and measures of material forms of deprivation. No mediation or moderation effect was observed of gene expression on the association between life adversities and psychiatric symptoms, meaning that they might influence distinct pathways. Among these nine genes, NR3C1, which encodes a glucocorticoid receptor, is by far the most investigated, being associated with depressive symptoms, early life adversity, and stress. While further research is needed to fully understand the complex relationship between gene expression, life adversities, and psychopathology, our findings provide valuable insights into the molecular mechanisms underlying mental disorders.