title: Gene expression in blood of children and adolescents: Mediation between childhood maltreatment and major depressive disorder.
abstract: Investigating major depressive disorder (MDD) in childhood and adolescence can help reveal the relative contributions of genetic and environmental factors to MDD, since early stages of disease have less influence of illness exposure. Thus, we investigated the mRNA expression of 12 genes related to the hypothalamic-pituitary-adrenal (HPA) axis, inflammation, neurodevelopment and neurotransmission in the blood of children and adolescents with MDD and tested whether a history of childhood maltreatment (CM) affects MDD through gene expression. Whole-blood mRNA levels of 12 genes were compared among 20 children and adolescents with MDD diagnosis (MDD group), 49 participants without MDD diagnosis but with high levels of depressive symptoms (DS group), and 61 healthy controls (HC group). The differentially expressed genes were inserted in a mediation model in which CM, MDD, and gene expression were, respectively, the independent variable, outcome, and intermediary variable. NR3C1, TNF, TNFR1 and IL1B were expressed at significantly lower levels in the MDD group than in the other groups. CM history did not exert a significant direct effect on MDD. However, an indirect effect of the aggregate expression of the 4 genes mediated the relationship between CM and MDD. In the largest study investigating gene expression in children with MDD, we demonstrated that NR3C1, TNF, TNFR1 and IL1B expression levels are related to MDD and conjunctly mediate the effect of CM history on the risk of developing MDD. This supports a role of glucocorticoids and inflammation as potential effectors of environmental stress in MDD.
authors.affiliation: Genetics Division, Department of Morphology and Genetics, Universidade Federal de Sao Paulo (UNIFESP), Brazil; LiNC - Interdisciplinary Laboratory of Clinical Neurosciences, UNIFESP, Brazil; National Institute of Developmental Psychiatry for Children and Adolescents (INPD), Brazil; Department of Psychiatry, UNIFESP, Brazil.
authors.forename: Leticia Maria
authors.initials: LM
authors.lastname: Spindola
authors.affiliation: LiNC - Interdisciplinary Laboratory of Clinical Neurosciences, UNIFESP, Brazil; National Institute of Developmental Psychiatry for Children and Adolescents (INPD), Brazil; Department of Psychiatry, UNIFESP, Brazil.
authors.forename: Pedro Mario
authors.initials: PM
authors.lastname: Pan
authors.affiliation: Genetics Division, Department of Morphology and Genetics, Universidade Federal de Sao Paulo (UNIFESP), Brazil; LiNC - Interdisciplinary Laboratory of Clinical Neurosciences, UNIFESP, Brazil; National Institute of Developmental Psychiatry for Children and Adolescents (INPD), Brazil; Department of Psychiatry, UNIFESP, Brazil.
authors.forename: Patricia Natalia
authors.initials: PN
authors.lastname: Moretti
authors.affiliation: Genetics Division, Department of Morphology and Genetics, Universidade Federal de Sao Paulo (UNIFESP), Brazil; LiNC - Interdisciplinary Laboratory of Clinical Neurosciences, UNIFESP, Brazil; National Institute of Developmental Psychiatry for Children and Adolescents (INPD), Brazil; Department of Psychiatry, UNIFESP, Brazil.
authors.forename: Vanessa Kiyomi
authors.initials: VK
authors.lastname: Ota
authors.affiliation: Genetics Division, Department of Morphology and Genetics, Universidade Federal de Sao Paulo (UNIFESP), Brazil; LiNC - Interdisciplinary Laboratory of Clinical Neurosciences, UNIFESP, Brazil; National Institute of Developmental Psychiatry for Children and Adolescents (INPD), Brazil.
authors.forename: Marcos Leite
authors.initials: ML
authors.lastname: Santoro
authors.affiliation: LiNC - Interdisciplinary Laboratory of Clinical Neurosciences, UNIFESP, Brazil; National Institute of Developmental Psychiatry for Children and Adolescents (INPD), Brazil; Department of Psychiatry, UNIFESP, Brazil.
authors.forename: Hugo
authors.initials: H
authors.lastname: Cogo-Moreira
authors.affiliation: LiNC - Interdisciplinary Laboratory of Clinical Neurosciences, UNIFESP, Brazil; National Institute of Developmental Psychiatry for Children and Adolescents (INPD), Brazil; Department of Psychiatry, UNIFESP, Brazil.
authors.forename: Ary
authors.initials: A
authors.lastname: Gadelha
authors.affiliation: National Institute of Developmental Psychiatry for Children and Adolescents (INPD), Brazil; Department of Psychiatry, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Brazil.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Salum
authors.affiliation: National Institute of Developmental Psychiatry for Children and Adolescents (INPD), Brazil; Department of Psychiatry, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Brazil.
authors.forename: Gisele Gus
authors.initials: GG
authors.lastname: Manfro
authors.affiliation: LiNC - Interdisciplinary Laboratory of Clinical Neurosciences, UNIFESP, Brazil; National Institute of Developmental Psychiatry for Children and Adolescents (INPD), Brazil; Department of Psychiatry, UNIFESP, Brazil.
authors.forename: Jair Jesus
authors.initials: JJ
authors.lastname: Mari
authors.affiliation: National Institute of Developmental Psychiatry for Children and Adolescents (INPD), Brazil; Department & Institute of Psychiatry, Faculdade de Medicina da Universidade de São Paulo, Brazil.
authors.forename: Helena
authors.initials: H
authors.lastname: Brentani
authors.affiliation: Post-Graduation Program in Psychology, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Brazil; Developmental Cognitive Neuroscience Lab, PUCRS, Brazil.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Grassi-Oliveira
authors.affiliation: Department of Psychiatry, UNIFESP, Brazil.
authors.forename: Elisa
authors.initials: E
authors.lastname: Brietzke
authors.affiliation: National Institute of Developmental Psychiatry for Children and Adolescents (INPD), Brazil; Department & Institute of Psychiatry, Faculdade de Medicina da Universidade de São Paulo, Brazil.
authors.forename: Euripedes Constantino
authors.initials: EC
authors.lastname: Miguel
authors.affiliation: National Institute of Developmental Psychiatry for Children and Adolescents (INPD), Brazil; Department of Psychiatry, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Brazil.
authors.forename: Luis Augusto
authors.initials: LA
authors.lastname: Rohde
authors.affiliation: National Institute of Developmental Psychiatry for Children and Adolescents (INPD), Brazil; Center of Mathematics, Computation and Cognition, Universidade Federal do ABC, Brazil.
authors.forename: João Ricardo
authors.initials: JR
authors.lastname: Sato
authors.affiliation: LiNC - Interdisciplinary Laboratory of Clinical Neurosciences, UNIFESP, Brazil; National Institute of Developmental Psychiatry for Children and Adolescents (INPD), Brazil; Department of Psychiatry, UNIFESP, Brazil.
authors.forename: Rodrigo Affonseca
authors.initials: RA
authors.lastname: Bressan
authors.affiliation: Genetics Division, Department of Morphology and Genetics, Universidade Federal de Sao Paulo (UNIFESP), Brazil; LiNC - Interdisciplinary Laboratory of Clinical Neurosciences, UNIFESP, Brazil; National Institute of Developmental Psychiatry for Children and Adolescents (INPD), Brazil; Department of Psychiatry, UNIFESP, Brazil. Electronic address: sinbelangero@gmail.com.
authors.forename: Sintia Iole
authors.initials: SI
authors.lastname: Belangero
mesh_terms: D000293:Adolescent; D002648:Child; D002649:Child Abuse / Q000523:psychology*; D015331:Cohort Studies; D003865:Major Depressive Disorder / Q000097:blood* / Q000503:physiopathology; D005260:Female; D015870:Gene Expression / Q000502:physiology*; D005820:Genetic Testing; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism*; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D008297:Male; D008954:Models, Biological; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism; D010913:Pituitary-Adrenal System / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000378:metabolism; D012111:Residence Characteristics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D053583:Interleukin-1beta; C497713:NR3C1 protein, human; D010446:Peptide Fragments; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; C052994:interleukin-1beta (163-171)
keywords: Child; Childhood maltreatment; Gene expression; Glucocorticoids; Inflammation; Major depressive disorder