Evaluating the Challenges and Reproducibility of Studies Investigating DNA Methylation Signatures of Psychological Stress

Abstract

Psychological stress can increase the risk of a wide range of negative health outcomes. Studies have been completed to determine if DNA methylation changes occur in the human brain because of stress and are associated with long-term effects and disease, but results have been inconsistent. Human candidate gene studies (150) and epigenome-wide association studies (67) were systematically evaluated to assess how DNA methylation is impacted by stress during the prenatal period, early childhood and adulthood. The association between DNA methylation of NR3C1 exon 1F and child maltreatment and early life adversity was well demonstrated, but other genes did not exhibit a clear association. The reproducibility of individual CpG sites in epigenome-wide association studies was also poor. However, biological pathways, including stress response, brain development and immunity, have been consistently identified across different stressors throughout the life span. Future studies would benefit from the increased sample size, longitudinal design, standardized methodology, optimal quality control, and improved statistical procedures.

Plain language summary

Mental stress can increase the risk of a wide range of negative health results. Previous studies have been carried out to explore the epigenetic (related to changes in genes) effect of different types of mental stress. The authors reviewed the literature to look at consistencies in the results of these studies. With the exception of the first exon of NR3C1, the authors found few consistent findings in epigenetic changes related to stress with regard to DNA methylation at individual CpG islands but identified some important biological systems (stress response, brain development and immunity) related to psychological stress. Bioinformatics analysis showed that different types of psychological stress affect different biological systems. The epigenetic mechanism of these systems may control the effects of mental stress on health.

Keywords::

• adulthood
• chronic
• DNA methylation
• early life
• prenatal
• psychological stress
• reproducibility
• specificity

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.tandfonline.com/doi/suppl/10.2217/epi-2021-0190

Acknowledgments

The authors thank RF Kopp for editorial review of the manuscript, Y Chen for critical reading of the manuscript and CH Xia for advice regarding statistical analysis methods.

Financial & competing interests disclosure

This work was supported by NIH grants U01MH122591, 1U01MH116489 and 1R01MH110920 and the SUNY Empire Innovation Program (C Liu); grant 21JR1RA216 from the Science and Technology Department of Gansu Province, China (Y Zhang); and grant 31920170040 from the Central University Program of Northwest University for Nationalities, China (Y Zhang). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Additional information

Funding

This work was supported by NIH grants U01MH122591, 1U01MH116489 and 1R01MH110920 and the SUNY Empire Innovation Program (C Liu); grant 21JR1RA216 from the Science and Technology Department of Gansu Province, China (Y Zhang); and grant 31920170040 from the Central University Program of Northwest University for Nationalities, China (Y Zhang). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.