Summary: Researchers at Umeå University and collaborating institutions report that stress-related epigenetic changes in the CRH gene are associated with increased suicidal behavior in adults and higher psychiatric risk in adolescents.
Source: Umeå University
New research identifies epigenetic alterations in the corticotropin-releasing hormone (CRH) gene—part of the body’s stress-regulation system—as linked to severe suicide attempts in adults and to elevated psychiatric risk in teenagers.
A collaborative study from Umeå University, Karolinska Institutet and Uppsala University examined DNA methylation patterns in genes that govern the hypothalamic-pituitary-adrenal (HPA) axis, the hormonal system that controls our physiological response to stress. The findings, published in EBioMedicine, connect specific epigenetic marks in the CRH gene with both the severity of suicide attempts among adults and an increased psychiatric risk score in adolescent groups.
Previous research has reported that an overactive stress system correlates with higher suicide risk. Building on that evidence, the present study focused on epigenetic changes—chemical modifications that alter gene activity without changing the DNA sequence—particularly DNA methylation at CpG sites near HPA-axis genes. The research team sought to determine whether methylation shifts in these regulatory regions were linked to suicidal behavior severity and whether the same marks could be detected in adolescents at elevated psychiatric risk.
The primary adult sample consisted of 88 individuals who had attempted suicide. Participants were classified into high- and low-risk groups according to the severity of their suicidal behavior. Researchers analyzed whole-blood DNA using the Illumina Infinium Methylation EPIC BeadChip to measure genome-wide methylation, focusing on CpG sites located within 2,000 base pairs of transcription start sites for HPA-axis genes including CRH, CRHBP, CRHR1, CRHR2, FKBP5 and NR3C1.
Two CRH-associated CpG sites (identified as cg19035496 and cg23409074 in the array data) were significantly hypomethylated in the adult high-risk group compared with lower-risk attempters (p < 0.001). The investigators then tested whether these same epigenetic signals were detectable in adolescents using two independent cohort samples.
The adolescent analysis included two cohorts of 129 and 93 participants aged 14–17, each stratified into high-risk and low-risk groups based on a composite psychiatric risk score derived from standardized assessments. In one adolescent cohort, the CRH-associated site cg19035496 showed increased methylation among subjects with a high general psychiatric risk score, indicating that epigenetic variation at CRH is relevant across age groups and types of psychiatric vulnerability.
Lead author Jussi Jokinen, professor of psychiatry at Umeå University, emphasizes the public health importance of these findings: “Psychiatric disorders and suicidal behavior are rising among young people. Detecting early biological changes related to stress regulation can help inform prevention strategies and improve clinical attention to those most at risk.”
The study highlights the dynamic interplay between environment and gene expression: environmental stressors can leave epigenetic marks that modify how stress-related genes operate. While the current results do not prove causation and replication in larger samples is needed, they point to the CRH gene as a molecular target worthy of further investigation in suicide prevention and adolescent mental health research.
Source: Anna Lawrence, Umeå University
Publisher summary: NeuroscienceNews.com summary of research published in EBioMedicine
Original research: “Epigenetic Changes in the CRH Gene are Related to Severity of Suicide Attempt and a General Psychiatric Risk Score in Adolescents,” by Jussi Jokinen, Adrian E. Boström, Ali Dadfar, Diana M. Ciuculete, Andreas Chatzittofis, Marie Åsberg, and Helgi B. Schiöth. Published online December 18, 2017 in EBioMedicine.
Abstract (condensed)
The study aimed to identify HPA-axis-associated CpG sites showing methylation differences related to the severity of suicide attempts. Genome-wide methylation in whole blood was measured in 88 suicide attempters stratified into high- and low-risk groups. CpG sites near HPA-axis genes were assessed, and two CRH-associated sites were significantly hypomethylated in the high-risk attempters. These candidate loci were then evaluated in two adolescent cohorts (129 and 93 subjects) stratified by a general psychiatric risk score. One CRH site was hypermethylated in adolescents with high psychiatric risk. The results indicate epigenetic variation in the CRH gene associated with suicide attempt severity in adults and with psychiatric risk in adolescents.
These findings underline the potential role of stress-system epigenetics in both suicidal behavior and adolescent psychiatric vulnerability. Further research should explore replication in larger, diverse populations and investigate whether these epigenetic marks are stable over time or responsive to intervention.