Journal Article

The methylome in females with adolescent Conduct Disorder: Neural pathomechanisms and environmental risk factors

Haslinger, Denise, Rotter, Björn, Fernández-Rivas, Aranzazu, Chiocchetti, Andreas G., Waltes, Regina, Kohls, Gregor, Krezdorn, Nico, Hervas, Amaia, Bernhard, Anka, Martinelli, Anne, Yousaf, Afsheen, Ackermann, Katharina, Konrad, Kerstin, Freitag, Christine M., Vetro, Agnes

2022

Overview

Conduct Disorder (CD) is an impairing psychiatric disorder of childhood and adolescence characterized by aggressive and dissocial behavior. Environmental factors such as maternal smoking during pregnancy, socio-economic status, trauma, or early life stress are associated with CD. Although the number of females with CD is rising in Western societies, CD is under-researched in female cohorts. We aimed at exploring the epigenetic signature of females with CD and its relation to psychosocial and environmental risk factors. We performed HpaII sensitive genome-wide methylation sequencing of 49 CD girls and 50 matched typically developing controls and linear regression models to identify differentially methylated CpG loci (tags) and regions. Significant tags and regions were mapped to the respective genes and tested for enrichment in pathways and brain developmental processes. Finally, epigenetic signatures were tested as mediators for CD-associated risk factors. We identified a 12% increased methylation 5’ of the neurite modulator SLITRK5 ( FDR = 0.0046) in cases within a glucocorticoid receptor binding site. Functionally, methylation positively correlated with gene expression in lymphoblastoid cell lines. At systems-level, genes (uncorr. P < 0.01) were associated with development of neurons, neurite outgrowth or neuronal developmental processes. At gene expression level, the associated gene-networks are activated perinatally and during early childhood in neocortical regions, thalamus and striatum, and expressed in amygdala and hippocampus. Specifically, the epigenetic signatures of the gene network activated in the thalamus during early childhood correlated with the effect of parental education on CD status possibly mediating its protective effect. The differential methylation patterns identified in females with CD are likely to affect genes that are expressed in brain regions previously indicated in CD. We provide suggestive evidence that protective effects are likely mediated by epigenetic mechanisms impairing specific brain developmental networks and therefore exerting a long-term effect on neural functions in CD. Our results are exploratory and thus, further replication is needed.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Adolescence / Adolescent / Adolescents / Aggressive behavior / Aggressiveness / Amygdala / Axonogenesis / Binding sites / Biology and life sciences / Brain / Cell Line / Child & adolescent psychiatry / Children / Computer and Information Sciences / Conduct disorder / Conduct Disorder - genetics / Conduct Disorder - metabolism / Conduct Disorder - psychology / CpG islands / Development and progression / DNA Methylation / Ecology and Environmental Sciences / Environmental factors / Environmental risk / Epigenesis, Genetic / Epigenetic inheritance / Epigenetics / Epigenome / Female / Females / Gene expression / Gene Regulatory Networks / Gene sequencing / Genes / Genetic aspects / Genome-Wide Association Study / Genomes / Glucocorticoids / Health aspects / Hippocampus - metabolism / Humans / Intelligence tests / Kinases / Lymphoblastoid cell lines / Males / Medicine and Health Sciences / Methylation / Neostriatum / Neuropsychology / Neurosciences / Pediatric research / Pediatrics / Physical Sciences / Psychological aspects / Psychotherapy / Puberty / Regression analysis / Regression models / Risk analysis / Risk Factors / Signatures / Social Sciences / Socioeconomics / Tags / Teenage girls / Teenagers / Thalamus / Trauma / Twins