Genome-wide DNA methylation levels and altered cortisol stress reactivity following childhood trauma in humans

Abstract

DNA methylation likely plays a role in the regulation of human stress reactivity. Here we show that in a genome-wide analysis of blood DNA methylation in 85 healthy individuals, a locus in the Kit ligand gene (KITLG; cg27512205) showed the strongest association with cortisol stress reactivity (P=5.8 × 10−6). Replication was obtained in two independent samples using either blood (N=45, P=0.001) or buccal cells (N=255, P=0.004). KITLG methylation strongly mediates the relationship between childhood trauma and cortisol stress reactivity in the discovery sample (32% mediation). Its genomic location, a CpG island shore within an H3K27ac enhancer mark, and the correlation between methylation in the blood and prefrontal cortex provide further evidence that KITLG methylation is functionally relevant for the programming of stress reactivity in the human brain. Our results extend preclinical evidence for epigenetic regulation of stress reactivity to humans and provide leads to enhance our understanding of the neurobiological pathways underlying stress vulnerability.

Discovery and replication of a peripheral tissue DNA methylation biosignature to augment a suicide prediction model

“…Similar adverse effects have been observed in humans with exposure to early life stress [25, 26]. This link was further bolstered by an overrepresentation analysis that showed an enrichment of AUC weekday cortisol-associated genes in GenRED Offspring blood and saliva with suicide-associated genes in prefrontal neurons as well as previously identified genes associated with cortisol stress reactivity in blood [20], indicating that there are consistent cross-tissue DNA methylation changes with cortisol dysregulation and a behavioral outcome such as suicide. Our results are consistent with a model whereby suicide-associated HPA axis dysregulation causes an overproduction of circulating cortisol, which causes DNA methylation changes in various tissues, resulting in behavioral changes through the actions of DNA methylation in the brain, while leaving measurable marks in the periphery that enable the biomarker-based prediction of suicidal ideation and behaviors.…”

“…Given the importance of dysregulated cortisol biology to suicidal behaviors, cortisol-associated methylation probes in peripheral blood ( N  = 18) and saliva ( N  = 20) from the GenRED Offspring cohorts were assessed for an overrepresentation with those probes significantly associated with completed suicide separately in postmortem prefrontal cortical neurons and non-neurons ( N  = 45). Cortisol-associated probes within genes or gene regulatory sites were significantly overrepresented among prefrontal neuron suicide-associated genes and genes previously identified as associated with cortisol stress reactivity (Table 2) [20]. These findings indicate that there may be common pathways between cortisol biology and suicidal behavior and that the epigenetic marks of suicide-associated hormonal changes may be detectable in peripheral tissues.…”

“…[20]CortisolNeuron, suicide0.050.4700.5782.01 × 10 −105 0.010.1190.1936.02 × 10 −32 0.0010.0110.0293.15 × 10 −3 Combined GenRED OffspringBlood and saliva, cortisolHoutepen et al . [20]Cortisol0.050.5220.6036.70 × 10 −60 0.010.1870.2641.08 × 10 −25 0.0010.0320.0614.96 × 10 −3 Overrepresentation analysis of genes significantly associated with AUC weekday cortisol measures in GenRED Offspring blood and saliva samples, genes significantly associated with suicide in postmortem prefrontal cortex neurons, and genes associated with AUC cortisol in blood from Houtepen et al . [20]…”

Childhood and Adolescent Adversity and Cardiometabolic Outcomes: A Scientific Statement From the American Heart Association

“…113,114 Preliminary data suggest that epigenetic changes may form part of the biological linkage between subjective experience of adversity and objective cardiometabolic derangement. [115][116][117][118] Methylation of genes regulating pathways to obesity and metabolic disorders in adults exposed to child abuse also has been identified. 119 However, research on DNA methylation is still an emerging field of study.…”

Psychiatric Disorders, Morbidity, and Mortality: Tracing Mechanistic Pathways to Accelerated Aging

“…Stressors can provoke persistent changes in DNA methylation (32, 33). For example, cumulative lifetime stress in an urban, African American cohort predicted accelerated epigenetic aging (34).…”