Effects of the Social Environment and Stress on Glucocorticoid Receptor Gene Methylation: A Systematic Review

Abstract

The early-life social environment can induce stable changes that influence neurodevelopment and mental health. Research focused on early-life adversity revealed that early-life experiences have a persistent impact on gene expression and behavior through epigenetic mechanisms. The hypothalamus-pituitary-adrenal axis is sensitive to changes in the early-life environment that associate with DNA methylation of a neuron-specific exon 17 promoter of the glucocorticoid receptor (GR) (Nr3c1). Since initial findings were published in 2004, numerous reports have investigated GR gene methylation in relationship to early-life experience, parental stress, and psychopathology. We conducted a systematic review of this growing literature, which identified 40 articles (13 animal and 27 human studies) published since 2004. The majority of these examined the GR exon variant 1F in humans or the GR17 in rats, and 89% of human studies and 70% of animal studies of early-life adversity reported increased methylation at this exon variant. All the studies investigating exon 1F/17 methylation in conditions of parental stress (one animal study and seven human studies) also reported increased methylation. Studies examining psychosocial stress and psychopathology had less consistent results, with 67% of animal studies reporting increased exon 17 methylation and 17% of human studies reporting increased exon 1F methylation. We found great consistency among studies investigating early-life adversity and the effect of parental stress, even if the precise phenotype and measures of social environment adversity varied among studies. These results are encouraging and warrant further investigation to better understand correlates and characteristics of these associations.

Keywords: DNA methylation; Early-life adversity; Epigenetics; Glucocorticoid receptor; Social environment; Systematic review.

Figure 1. Early-life adversity findings in animal and human studies

Significant findings reported from animal and human studies examining the effects of early-life adversity according to the NR3C1 first exon variant investigated. Publications are numbered according to their position in the reference list. Upward arrow indicates increased methylation while downward arrow indicates decreased methylation. Results were reported as mean methylation of the region investigated unless otherwise indicated by the footnotes. a. GR gene CpG methylation undetectable in all conditions. b. Hippocampus only at CpG 1 and 2, NGFI-A site; ↑ methylation correlated to decreased nursing frequency. c. CpG 35 (NGFI-A site is CpG 37 & 38). d. For 6 promoter-associated CpGs. e. CpG 6 & 8, ↑ methylation of both abused and non-abused compared to controls; CpG11, ↓ methylation of both abused and non-abused compared to controls; hippocampus only. f. CpGs 8, 9, 12 & 13; hippocampus only. g. hippocampus only. h. Cerebellum; CpGs −127 & −10; single sex males and mixed-litter females compared to mixed-sex males. i. CpG 13,14, 17, DBA/2J only. j. C57BL/6J, hippocampus and males only. k. CpG 1 & 3 only (NGFI-A site is CpG 3 & 4). l. Repeated exposure to non-physical, non-sexual abuse. m. Single exposure to sexual abuse only. n. ↓ CpG 2 in subset of subjects only; ↑ CpGs 3, 6 and 7 whole sample, 3, 5 & 6 in subset; NGFI-A site at CpG 3 & 4. o. CpGs at −99 & −57 for all females in hippocampus; CpGs −118, −116, −114 in single-sex females in nucleus accumbens; CpG −57 in males vs. females in nucleus accumbens. p. Reached significance with physical abuse, trend with emotional neglect.

Figure 2. Parental stress findings in animal and human studies

Significant findings reported from animal and human studies examining the effects of parental stress according to the NR3C1 first exon variant investigated. Publications are numbered according to their position in the reference list. Upward arrow indicates increased methylation while downward arrow indicates decreased methylation. Results were reported as mean methylation of the region investigated unless otherwise indicated by the footnotes. a. CpG 1–3, NFGI-A site. b. indicates a sampling downstream of region 1H, within the gene body. c. CpG2, depression only. d. Early gestation group only; CpGs −523 & −496. e. CpG 12 & 13 with fear of delivery all trimesters; CpG 25 & 28 with fear of integrity of the baby T1. f. CpG 6 with fear of delivery. g. Site- and parameter-specific: CpG 38/39 (near NGFI-A site) ↓ with fear of changes T1 & 2; CpG 36 ↑ with fear of integrity T1 & 2; CpG 36 ↑ with fear of delivery T3. h. Total region for children; CpGs 1, 5 & 8 for mothers. i. ↑ methylation with paternal PTSD only in the absence of maternal PTSD.

Figure 3. Psychological stress/psychopathology findings in animal and human studies

Significant findings reported from animal and human studies examining the effects of psychological stress/psychopathology according to the NR3C1 first exon variant investigated. Publications are numbered according to their position in the reference list. Upward arrow indicates increased methylation while downward arrow indicates decreased methylation. Results were reported as mean methylation of the region investigated unless otherwise indicated by the footnotes. a. CpGs 10 & 21; BN vs. no eating disorder. b. In BN+BPD vs. BN no BPD/no eating disorder. c. no detectable methylation on NR3C1 CpGs. d. Acute stress group – ↑ methylation at several CpG sites in hippocampus only; Chronic stress group – ↑ methylation in response to psychosocial stress in adrenal and pituitary, ↑ methylation in adrenal and ↓ methylation in the pituitary in response to restraint stress. e. No change over time and no difference between responders and non-responders. f. CpGs 3 & 4.