Epigenetic biomarkers of inflammation in studies on mental health: Current applications, limitations, and future directions

BACKGROUND: Inflammation has emerged as a potentially modifiable risk factor for mental illness, warranting further research. Epidemiological studies have primarily relied on measuring blood levels of single inflammatory proteins, but these have proven limited in detecting robust long-term associations with mental health. DNA methylation (DNAm)-based epigenetic biomarkers of inflammation have demonstrated greater predictive performance than protein markers for several physical health outcomes and hold potential to increase understanding of the immune-mental health link.

METHODS: We conducted a comprehensive literature review of mental health studies using DNAm markers of inflammation. First, PubMed and EMBASE were searched for epigenome-wide association studies (EWAS) of inflammation, providing source data for deriving DNAm biomarkers. Second, we identified studies that used DNAm markers of inflammation to study mental health-related outcomes. We address technical considerations, biological implications, and future research directions.

RESULTS: We identified 29 EWAS studies of circulating inflammatory proteins, of which C-reactive protein (CRP) was the most frequently studied. In addition, 14 studies examined epigenetic biomarkers of inflammation in relation to mental health, cognition or neuroimaging outcomes, where higher levels of DNA methylation (DNAm) markers of CRP and interleukin-6 (IL-6) were consistently associated with reduced cognitive function, lower brain volumes, and reduced white matter integrity. In contrast, findings for mental health (mostly depression) were less conclusive, with studies reporting either positive or null associations.

CONCLUSION: Epigenetic biomarkers of inflammation are emerging as valuable tools in mental health research. Further study on the value of these markers for mental health prediction is warranted, evaluating shared and distinct relations across mental illnesses. Advances may also come from developing novel epigenetic biomarkers that capture inflammatory processes with greater resolution, and from examining altered inflammatory states in relation to mental health risk exposures across the lifecourse.