TY  - JOUR
A1  - Geburtig-Chiocchetti, Andreas
A1  - Yousaf, Afsheen
A1  - Waltes, Regina
A1  - Bernhard, Anka
A1  - Martinelli, Anne
A1  - Ackermann, Katharina
A1  - Haslinger, Denise
A1  - Rotter, Björn
A1  - Krezdorn, Nico
A1  - Konrad, Kerstin
A1  - Kohls, Gregor
A1  - Vetro, Agnes
A1  - Hervás, Amaia
A1  - Fernández-Rivas, Aranzazu
A1  - Freitag, Christine M.
T1  - The methylome in females with adolescent Conduct Disorder: Neural pathomechanisms and environmental risk factors
T2  - PLOS ONE
N2  - 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.
KW  - DNA methylation
KW  - Epigenetics
KW  - Methylation
KW  - Environmental impacts
KW  - Gene expression
KW  - Aggression
KW  - Genetic loci
KW  - Genetic networks
Y1  - 2022
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/62714
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-627142
SN  - 1932-6203
N1  - Data Availability: All data needed to replicate the findings is available here: https://osf.io/erqwp/ This includes the anonymized phenotypic data of probands, the epigenetics data (reads per proband matrix) and any additional files used. The code used in the analytical pipeline is available here: https://github.com/achiocch/femNATCD_MethSeq. The full outcomes of the analysis are available as git-hub page https://achiocch.github.io/femNATCD_MethSeq/ Due to ethical restrictions in the informed consent given by the study participants, raw genetic or epigenetic data (FASTQ) cannot be made publicly available. The reason is that genetic data cannot be anonymized, and is thus considered special sensitive data. However, the FASTQ dataset is not part of the minimal data set and not needed to replicated the analyses and conclusions made.
N1  - Funding: This project has been funded by the European FP7 Framework, grant agreement no: 602407, FemNAT-CD (coordinator CM Freitag). The funder provided support in the form of salaries for authors [AGC, AB, AM, KA] as well as for the methylation analysis at geneXpro and other consumables.
VL  - 17
IS  - 1, art. e0261691
SP  - 1
EP  - 17
PB  - PLOS
CY  - San Francisco, California, US
ER  -