Harsh Parenting Predicts Novel HPA Receptor Gene Methylation and NR3C1 Methylation Predicts Cortisol Daily Slope in Middle Childhood

Lewis, Candace R.; Breitenstein, Reagan S.; Henderson, Adrienne; Sowards, Hayley A.; Piras, Ignazio S.; Huentelman, Matthew J.; Doane, Leah D.; Lemery‐Chalfant, Kathryn

doi:10.1007/s10571-020-00885-4

Cited by 31 publications

(30 citation statements)

References 97 publications

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“…In fact, childhood adversity as well as psychiatric disorders such as depression, anxiety and substance-use disorders were related with reduced methylation of NR3C1 40 . A recent study, reported also that the methylation of specific CG sites within the NR3C1 exon 1F predicted a steeper diurnal cortisol slope instead of cortisol levels in the morning, afternoon or bedtime 41 .…”

Section: Discussionmentioning

confidence: 92%

HPA axis dysregulation is associated with differential methylation of CpG-sites in related genes

Chatzittofis

Boström

Ciuculete

et al. 2021

Sci Rep

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DNA methylation shifts in Hypothalamic–pituitary–adrenal (HPA) axis related genes is reported in psychiatric disorders including hypersexual disorder. This study, comprising 20 dexamethasone suppression test (DST) non-suppressors and 73 controls, examined the association between the HPA axis dysregulation, shifts in DNA methylation of HPA axis related genes and importantly, gene expression. Individuals with cortisol level ≥ 138 nmol/l, after the low dose (0.5 mg) dexamethasone suppression test (DST) were classified as non-suppressors. Genome-wide methylation pattern, measured in whole blood using the EPIC BeadChip, investigated CpG sites located within 2000 bp of the transcriptional start site of key HPA axis genes, i.e.: CRH, CRHBP, CRHR-1, CRHR-2, FKBP5 and NR3C1. Regression models including DNA methylation M-values and the binary outcome (DST non-suppression status) were performed. Gene transcripts with an abundance of differentially methylated CpG sites were identified with binomial tests. Pearson correlations and robust linear regressions were performed between CpG methylation and gene expression in two independent cohorts. Six of 76 CpG sites were significantly hypermethylated in DST non-suppressors (nominal P < 0.05), associated with genes CRH, CRHR1, CRHR2, FKBP5 and NR3C1. NR3C1 transcript AJ877169 showed statistically significant abundance of probes differentially methylated by DST non-suppression status and correlated with DST cortisol levels. Further, methylation levels of cg07733851 and cg27122725 were positively correlated with gene expression levels of the NR3C1 gene. Methylation levels of cg08636224 (FKBP5) correlated with baseline cortisol and gene expression. Our findings revealed that DNA methylation shifts are involved in the altered mechanism of the HPA axis suggesting that new epigenetic targets should be considered behind psychiatric disorders.

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Section: Discussionmentioning

confidence: 92%

HPA axis dysregulation is associated with differential methylation of CpG-sites in related genes

Chatzittofis

Boström

Ciuculete

et al. 2021

Sci Rep

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“…Importantly, the use of DNA samples from individuals with no lifetime history of substance use, makes our findings unlikely to be explained by reverse causality [46,47]. Moreover, since previous studies had found associations between NR3C1 methylation and cortisol stress responses [15,17,[20][21][22], we also examined the correlations between the five CpGs under investigation and salivary cortisol levels available from a subset of individuals. We found that DNA methylation at CpG 3 was associated with higher morning cortisol levels.…”

Section: Discussionmentioning

confidence: 99%

“…A number of human studies have also found that NR3C1 hypermethylation at the equivalent human locus (i.e., exon 1 F) is associated with exposure to early life stress, including childhood maltreatment, parental loss, or parental disease, and being the victim of bullying [12][13][14][15][16][17][18][19]. Moreover, several human studies have linked NR3C1 methylation levels with changes in HPA functioning, e.g., as reflected by aberrant cortisol stress responses [15,17,[20][21][22].…”

Section: Introductionmentioning

confidence: 99%

DNA methylation of the glucocorticoid receptor gene predicts substance use in adolescence: longitudinal data from over 1000 young individuals

et al. 2021

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Early life stress has been linked to increased methylation of the Nuclear Receptor Subfamily 3 Group C Member 1 (NR3C1) gene, which codes for the glucocorticoid receptor. Moreover, early life stress has been associated with substance use initiation at a younger age, a risk factor for developing substance use disorders. However, no studies to date have investigated whether NR3C1 methylation can predict substance use in young individuals. This study included adolescents 13–14 years of age that reported no history of substance use at baseline, (N = 1041; males = 46%). Participants contributed saliva DNA samples and were followed in middle adolescence as part of KUPOL, a prospective cohort study of 7th-grade students in Sweden. Outcome variables were self-reports of (i) recent use, (ii) lifetime use, and (iii) use duration of (a) alcohol, (b) tobacco products, (c) cannabis, or (d) any substance. Outcomes were measured annually for three consecutive years. The predictor variable was DNA methylation at the exon 1 F locus of NR3C1. Risk and rate ratios were calculated as measures of association, with or without adjustment for internalizing symptoms and parental psychiatric disorders. For a subset of individuals (N = 320), there were also morning and afternoon salivary cortisol measurements available that were analyzed in relation to NR3C1 methylation levels. Baseline NR3C1 hypermethylation associated with future self-reports of recent use and use duration of any substance, before and after adjustment for potential confounders. The overall estimates were attenuated when considering lifetime use. Sex-stratified analyses revealed the strongest association for cigarette use in males. Cortisol analyses revealed associations between NR3C1 methylation and morning cortisol levels. Findings from this study suggest that saliva NR3C1 hypermethylation can predict substance use in middle adolescence. Additional longitudinal studies are warranted to confirm these findings.

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“…In Africa, significant correlations were observed between newborn birth weight/ NR3C1 promoter methylation and culturally relevant measures of maternal prenatal stress [ 21 ]. Adverse childhood experiences also lead to novel methylation of NR3C1 [ 22 ]. Genetic variants modifying epigenetic signatures at NR3C1 could contribute to effects of maternal perinatal and early childhood stress on OM, an interesting hypothesis given the early onset of severe OM in Aboriginal Australians.…”

Section: Discussionmentioning

confidence: 99%

Common and Rare Genetic Variants That Could Contribute to Severe Otitis Media in an Australian Aboriginal Population

Jamieson

Fakiola

Tang

et al. 2021

Clinical Infectious Diseases

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Background Our goal was to identify genetic risk factors for severe otitis media (OM) in Aboriginal Australians. Methods Illumina ® Omni2.5 BeadChip and imputed data were compared between 21 children with severe OM (multiple episodes chronic suppurative OM and/or perforations or tympanic sclerosis) and 370 individuals without this phenotype, followed by FUnctional Mapping and Annotation (FUMA). Exome data filtered for common (EXaC_all≥0.1) putative deleterious variants influencing protein coding (CADD-scaled scores ≥ 15) were used to compare 15 severe OM cases with 9 mild cases (single episode of acute OM recorded over ≥ 3 consecutive years). Rare (ExAC_all≤0.01) such variants were filtered for those present only in severe OM. Enrichr was used to determine enrichment of genes contributing to pathways/processes relevant to OM. Results FUMA analysis identified two plausible genetic risk loci for severe OM: NR3C1 (Pimputed_1000G=3.62x10 -6) encoding the glucocorticoid receptor, and NREP (Pimputed_1000G=3.67x10 -6) encoding neuronal regeneration related protein. Exome analysis showed: (i) association of severe OM with variants influencing protein coding (CADD-scaled ≥ 15) in a gene-set (GRXCR1, CDH23, LRP2, FAT4, ARSA, EYA4) enriched for Mammalian Phenotype Level 4 abnormal hair cell stereociliary bundle morphology and related phenotypes; (ii) rare variants influencing protein coding only seen in severe OM provided gene-sets enriched for “abnormal ear” (LMNA, CDH23, LRP2, MYO7A, FGFR1), integrin interactions, transforming growth factor signalling, and cell projection phenotypes including hair cell stereociliary bundles and cilium assembly. Conclusions This study highlights interacting genes and pathways related to cilium structure and function that may contribute to extreme susceptibility to OM in Aboriginal Australian children.

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Harsh Parenting Predicts Novel HPA Receptor Gene Methylation and NR3C1 Methylation Predicts Cortisol Daily Slope in Middle Childhood

Cited by 31 publications

References 97 publications

HPA axis dysregulation is associated with differential methylation of CpG-sites in related genes

HPA axis dysregulation is associated with differential methylation of CpG-sites in related genes

DNA methylation of the glucocorticoid receptor gene predicts substance use in adolescence: longitudinal data from over 1000 young individuals

Common and Rare Genetic Variants That Could Contribute to Severe Otitis Media in an Australian Aboriginal Population

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