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

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Abstract

Adverse experiences in childhood are associated with altered hypothalamic–pituitary–adrenal (HPA) axis function and negative health outcomes throughout life. It is now commonly accepted that abuse and neglect can alter epigenetic regulation of HPA genes. Accumulated evidence suggests harsh parenting practices such as spanking are also strong predictors of negative health outcomes. We predicted harsh parenting at 2.5 years old would predict HPA gene DNA methylation similarly to abuse and neglect, and cortisol output at 8.5 years old. Saliva samples were collected three times a day across 3 days to estimate cortisol diurnal slopes. Methylation was quantified using the Illumina Infinium MethylationEPIC array BeadChip (850 K) with DNA collected from buccal cells. We used principal components analysis to compute a summary statistic for CpG sites across candidate genes. The first and second components were used as outcome variables in mixed linear regression analyses with harsh parenting as a predictor variable. We found harsh parenting significantly predicted methylation of several HPA axis genes, including novel gene associations with AVPRB1, CRHR1, CRHR2, and MC2R (FDR corrected p < 0.05). Further, we found NR3C1 methylation predicted a steeper diurnal cortisol slope. Our results extend the current literature by demonstrating harsh parenting may influence DNA methylation similarly to more extreme early life experiences such as abuse and neglect. Further, we show NR3C1 methylation is associated with diurnal HPA function. Elucidating the molecular consequences of harsh parenting on health can inform best parenting practices and provide potential treatment targets for common complex disorders.

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Acknowledgements

The authors have no acknowledgements.

Funding

This work was financially supported by Grants from R01 HD079520, R01 HD086085, and Science Foundation Arizona. The funding sources played no role in the design of the study or the collection, analysis, and interpretation of data, or the writing of the manuscript.

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Authors

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CL designed the study, performed the microarrays, analyses, and was the primary writer of the manuscript. RB collected participant data and samples. AH assisted in microarrays and data preparation. HS ran analyses and assisted in manuscript preparation. IP assisted in data analysis and manuscript preparation. MH provided genomic and methodological expertise. LD was in charge of cortisol collection, measurement, and analysis. KL was in charge of collection and maintenance of longitudinal behavioral data, and provided assistance in writing the manuscript.

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Correspondence to Candace R. Lewis.

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The authors have no conflicts of interest to declare.

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The Arizona State University IRB and the Western Institutional Review Board (WIRB) approved this study.

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Lewis, C.R., Breitenstein, R.S., Henderson, A. et al. Harsh Parenting Predicts Novel HPA Receptor Gene Methylation and NR3C1 Methylation Predicts Cortisol Daily Slope in Middle Childhood. Cell Mol Neurobiol 41, 783–793 (2021). https://doi.org/10.1007/s10571-020-00885-4

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  • DOI: https://doi.org/10.1007/s10571-020-00885-4

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