Estrogen Receptor Alpha Gene (ESR1): Genetics, Epigenetics, Early Life Abuse and Depression in Women Open Access

Malone, Madison Elizabeth (2015)

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The current study investigates the association between the environment and underlying genetics on selective epigenetic methylation and adult depression outcomes. The specific aims of this study were to examine (1) whether early-life abuse associates with methylation of CpG sites across the Estrogen Receptor Alpha gene (ESR1), (2) the association between ESR1 single nucleotide polymorphisms (SNPs) and ESR1 CpG methylation, (3) whether CpG methylation may serve as a mediator between early-life abuse and adulthood depression, and (4) how early-life abuse may interact with CpG methylation to be associated with adult depression. The study focuses exclusively on a female sample, with 301 adult females drawn from the Grady Trauma Project, a large cross-sectional research study in Atlanta, focused on genetic and environmental predictors of Post Traumatic Stress Disorder. Linear regressions were used to test the study aims, and correction for multiple testing was accomplished with Bonferroni and False Discovery Rate calculations. We found that (a) exposure to early-life abuse associated with methylation of several ESR1 CpG sites, with two surviving correction. While ESR1 methylation (b) did not serve as a mediator between early-life abuse and adult depression (p>0.05), (c) methylation may moderate the association between early-life abuse and adult depression (p<0.05), though no moderator analyses survived correction for multiple tesing. We also found that (d) several ESR1 SNPs may associate with nearby CpG site methylation, with one SNP-CpG pair surviving stringent correction, suggesting that genetic and epigenetic variability is not independent. This research further extends the scientific work exploring the interplay between our environment and our biology in the development of adult outcomes. In context, understanding the biological implications of early-life adversity would give credence to intervention for those living in adverse enviroments and provide an outcome (methylation) that may be more proximally measured to assess the impact of adversity and/or intervention. This study is an initial step in extending animal literature assessing the role of ESR1 regulation in the link between early adversity and adult outcomes.

Table of Contents

  1. Introduction
  2. Background
  3. Method
    1. Participants
    2. Measures
  4. Statistical Analysis
    1. Covariates
    2. Statistical tests
  5. Results
    1. Study cohort
    2. Early life abuse associates with methylation of 7 CpG sites
    3. Genetic and epigenetic association
    4. CpG methylation does not mediate between abuse and depression
    5. CpG methylation moderates abuse and depression
  6. Discussion
    1. Interpretation of findings
      1. Early life abuse and methylation
      2. Genetic and Epigenetic Association
      3. CpG methylation moderates the relationship between early life abuse and adult depression
    2. Translatability of rodent studies
      1. ESR1 in humans, rats, and mice
      2. Neglect and Abuse
    3. Limitations
      1. Using peripheral blood tissue as a source of methylation data
      2. Dynamic vs stable changes in the epigenome
    4. d. Future directions
      1. Estrogen receptor types
      2. Critical windows and canalization
  7. Conclusion
  8. References
  9. Tables and Figures
    1. Table 1. Study Variables among those with None to Mild, Moderate, or Severe Abuse
    2. Table 2. Descriptive statistics for CpGs
    3. Table 3. Abuse predicting CpG site
    4. Table 4. Association between SNPs and methylation of specific CpG sites
    5. Table 5. Association between Childhood abuse and depression symptoms: Potential moderating role of ESR1 CpG site and methylation
    6. Table 6. CpG correlations
    7. Figure 1. ESR1 diagram with CpG sites and SNPs
    8. Figure 2. cg07059469 interaction with abuse and depression

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