By age 16, close to 2 children in 3 have suffered at least one adverse experience such as parental death, life-threatening illness, or family violence. Adversities have been robustly linked to an array of psychiatric and other medical conditions where the consequences can persist far into adulthood. The medical costs, mental health utilization, societal cost, and the psychological toll on its victims are tremendous. It is not wel understood how early adverse experiences are biologically embedded and what processes might be set into effect that would sustain long term health risks. To address these key questions we need prospective, longitudinal studies that begin in childhood and continue into adulthood and where data on adverse experiences can be linked to biosamples collected before and after adverse experiences as well as in adulthood. We propose just such a study, using already available samples from the Great Smoky Mountains Study (GSMS) and DNA methylation as the biological mechanism of interest. Methylation involves the addition of a methyl group to DNA and, in human non-embryonic cells, occurs mainly at CpGs. Animal and human research have shown that adverse events can result in persistent methylation changes with long-term phenotypic consequences. Capitalizing on these observations we propose a comprehensive study in a real life setting. First, we will use next-generation sequencing (NGS) to assay all >28 million CpGs in the human genome to study adversity-induced methylation changes and their persistence over time. To avoid false positive findings caused by pre-existing case-control differences (e.g. personality related or environmental factors such as poverty) we use a design that considers within-subject changes before and after DSM-IV extreme stressor events. Random assignment to trauma being impossible, this natural experiment is arguably the next best option this topic in children. Consistent with a model assuming a mediator role of methylation, we will select only the methylation sites that changed as a result of adversity for association testing with health risks. For the substantive and methodological reasons, we propose to treat maltreated children as a separate group in these analyses. Finally, we will replicate the 175 top findings in independent samples using a different and targeted technology to minimize the risk of false positives due to sampling and/or possibly technical errors. Successful completion of this project implies that we gained insight into how childhood adversities alters the methylome and what changes persist over time. We will also have identified processes associated with health risks in childhood/adulthood and found replicable methylation biomarkers associated with these risks. Methylation markers are stable and can be measured cost-effectively in blood, which is relatively easy to collect. Our findings therefore als have considerable translational potential as, for example, diagnostic biomarkers of health risk that could guide intervention strategies.

Public Health Relevance

Adverse childhood experiences are common and their repercussions in terms of medical costs, societal cost, and psychological toll on its victims are tremendous. The goal of this project are to characterize how these experiences become 'embedded' in the methylome and to identify the biologically processes that affect the long term health risks. Successful completion of this project also implies that we will have found replicable methylation biomarker signatures that could, for example, serve as diagnostic 'biomarkers of damage' to guide intervention strategies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH104576-02
Application #
8884675
Study Section
Behavioral Genetics and Epidemiology Study Section (BGES)
Program Officer
Koester, Susan E
Project Start
2014-08-01
Project End
2019-04-30
Budget Start
2015-08-01
Budget End
2016-04-30
Support Year
2
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Virginia Commonwealth University
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
105300446
City
Richmond
State
VA
Country
United States
Zip Code
23298
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Chan, Robin F; Shabalin, Andrey A; Xie, Lin Y et al. (2017) Enrichment methods provide a feasible approach to comprehensive and adequately powered investigations of the brain methylome. Nucleic Acids Res 45:e97
Aberg, Karolina A; Chan, Robin F; Shabalin, Andrey A et al. (2017) A MBD-seq protocol for large-scale methylome-wide studies with (very) low amounts of DNA. Epigenetics 12:743-750
Hattab, Mohammad W; Shabalin, Andrey A; Clark, Shaunna L et al. (2017) Correcting for cell-type effects in DNA methylation studies: reference-based method outperforms latent variable approaches in empirical studies. Genome Biol 18:24
Copeland, William E; Wolke, Dieter; Shanahan, Lilly et al. (2015) Adult Functional Outcomes of Common Childhood Psychiatric Problems: A Prospective, Longitudinal Study. JAMA Psychiatry 72:892-9
Shabalin, Andrey A; Aberg, Karolina A; van den Oord, Edwin J C G (2015) Candidate gene methylation studies are at high risk of erroneous conclusions. Epigenomics 7:13-5