Abstract
The increased vulnerability to alcohol dependence (AD) seen in individuals with childhood adversity (CA) may result in part from CA-induced epigenetic changes. To examine CA-associated DNA methylation changes in AD patients, we examined peripheral blood DNA methylation levels of 384 CpGs in promoter regions of 82 candidate genes in 279 African Americans [AAs; 88 with CA (70.5% with AD) and 191 without CA (38.2% with AD)] and 239 European Americans [EAs; 61 with CA (86.9% with AD) and 178 without CA (46.6% with AD)] using Illumina GoldenGate Methylation Array assays. The effect of CA on methylation of individual CpGs and overall methylation in promoter regions of genes was evaluated using a linear regression analysis (with consideration of sex, age, and ancestry proportion of subjects) and a principal components-based analysis, respectively. In EAs, hypermethylation of 10 CpGs in seven genes (ALDH1A1, CART, CHRNA5, HTR1B, OPRL1, PENK, and RGS19) were cross validated in AD patients and healthy controls who were exposed to CA. P values of two CpGs survived Bonferroni correction when all EA samples were analyzed together to increase statistical power [CHRNA5_cg17108064: Padjust = 2.54×10−5; HTR1B_cg06031989: Padjust = 8.98×10−5]. Moreover, overall methylation levels in the promoter regions of three genes (ALDH1A1, OPRL1 and RGS19) were elevated in both EA case and control subjects who were exposed to CA. However, in AAs, CA-associated DNA methylation changes in AD patients were not validated in healthy controls. Our findings suggest that CA could induce population-specific methylation alterations in the promoter regions of specific genes, thus leading to changes in gene transcription and an increased risk for AD and other disorders.
Highlights
Childhood adversity (CA) may lead to impaired mental and physical health that can persist into adulthood
CA-induced epigenetic changes may partially represent the molecular mechanism whereby CA predisposes to complex disorders such as alcohol dependence (AD)
Studies have shown that alcohol consumption may lead to widespread changes in DNA methylation in the genome [45]
Summary
Childhood adversity (CA) may lead to impaired mental and physical health that can persist into adulthood. Excessive and persistent adversity in early childhood produces sustained elevations of stress hormones (e.g., cortisol) [15], which may damage the development of the basic neural circuitry in the brain. Epigenetic changes resulting from environmental factors such as CA may alter biological activities in the brain, leading to increased risk for diseases. A seminal study by Weaver et al [20] showed that early life stress (i.e., postnatal maternal separation) in rats led to higher methylation levels at specific CpG sites in the exon 17 promoter of the glucocorticoid receptor (GR) gene (GR), decreased GR expression in the hippocampus, and increased hypothalamic-pituitary-adrenal (HPA) responses to stress.
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