Research articleChild Abuse and Epigenetic Mechanisms of Disease Risk
Introduction
Child abuse occurs at epidemic rates, with nearly 700,000 substantiated reports of child maltreatment each year,1 many reported cases of actual abuse referred to protective services that are not verified,2 and countless other cases that never come to the attention of authorities.2, 3, 4 Child maltreatment and other adverse childhood experiences are nonspecific risk factors for multiple psychiatric disorders5, 6, 7 and several health risk behaviors including smoking, overeating, and excessive alcohol and drug use.8, 9, 10 Above and beyond the effect of these risk behaviors, however, adverse childhood experiences predict ischemic heart disease,9, 11, 12 stroke,9 respiratory problems,13, 14 diabetes,9, 12 and cancer.9, 15
How do experiences of early adversity confer risk for later psychiatric and medical problems? Epigenetics has been proposed as one possible mechanism.16, 17, 18 Epigenetics refers to functionally relevant modifications to the genome that do not involve a change in DNA nucleotide sequence.19 These modifications regulate gene activity and play a role in acute regulation of genes in response to changes in the environment.20, 21
DNA methylation is one of the most studied epigenetic mechanisms.22 In mammalian cells, DNA methylation occurs mainly at discrete CpG sites in the genome, regions where cytosine nucleotides occur next to guanine nucleotides.23, 24 Although gene regulation is influenced by DNA methylation in other regions of the genome, the impact of methylation in promoters is best understood; it can lead to gene silencing.
The effect of a history of childhood abuse on methylation has been examined previously in candidate gene studies. In two reports, a history of childhood abuse was associated with increased methylation in lymphoblast DNA in the promoter region of the serotonin transporter (SLC6A4), a gene implicated in several neuropsychiatric disorders.25, 26 A third report found childhood abuse associated with differences in methylation at four CpG sites in nonpromoter regions of SLC6A4, but these did not withstand correction for multiple comparisons.27 Methylation in the glucocorticoid receptor (NR3C1), a gene involved in the stress response and implicated in several neuropsychiatric disorders, also has been examined, and two independent research groups reported that a history of childhood abuse was associated with altered methylation of NR3C1 in hippocampal-derived DNA.28, 29
With the advent of methodologies to complete high-throughput methylation profiling of the entire genome,30 novel epigenetic modifications associated with early adversity also can be identified. Two small-scale studies used the Illumina 27K BeadChip, which assays 27,578 CpG promoter-associated sites across the genome to examine methylation differences associated with early adversity. The first study included 28 children: 14 reared from birth in institutions and 14 reared with their parents.31 The second study included 100 adults: 25 who met criteria for posttraumatic stress disorder (PTSD) secondary to childhood abuse; 25 who met criteria for PTSD secondary to other traumas; 25 adults with histories of childhood abuse without PTSD; and 25 adults without PTSD and without histories of childhood abuse.32 The first study reported methylation differences between institution- and family-reared children in numerous CpG sites in genes involved in immune response and cellular signaling systems.31 These findings were not replicated in the second study with adults in which more-rigorous controls were used for multiple comparison testing and contained adults with PTSD secondary to other traumas in the non-abused control group.32
The present investigation examines methylation profile differences in a sample of maltreated and nontraumatized comparison children using the new Illumina 450K BeadChip, which examines a broader range of CpG sites involved in gene regulation. In addition to examining promoter-associated CpG sites, this array also assays CpG sites involved in gene regulation located on the gene body, 3′-untranslated regions (3′UTR), 5′UTRs, and intergenic regions.30 The goal of the current study is to identify novel pathways and mechanisms by which child abuse and other adverse early experiences may confer risk for a range of health problems later in life.
Section snippets
Methods
Participants included 192 children recruited between 2003 and 2010: of these, 96 were maltreated children removed from their parents' care due to reports of abuse and/or neglect within 6 months of study enrollment, and 96 were controls with no history of maltreatment or exposure to intrafamilial violence. All maltreated children in this investigation also participated in a prior published report of genetic and environmental factors associated with depression33; the cohort of controls was
Group Differences in Methylation
After controlling for demographic factors (e.g., race, gender, age), and multiple comparisons, maltreated and control children had significantly different methylation values at a total of 2868 CpGs sites of the 485K sites included on the array (p<5.0 × 10–7, all sites). On average, methylation values of maltreated and control children differed by 17% (range: 1%–62%). Significant CpG sites were identified on all 23 chromosomes: 2113 (74%) at sites with low methylation values (<0.2); 288 (10%) at
Discussion
Child maltreatment was associated with widespread differences in methylation across the entire genome. After rigorously controlling for demographic factors and multiple comparisons, group differences in methylation values emerged at a total of 2868 CpGs sites of the 485K sites included on the array. A general pattern emerged, such that maltreated children had elevated methylation values at CpG sites with methylation values in the low to mid range, and reduced methylation values at CpG sites
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