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Childhood adversity DNA methylation and risk for depression A longitudinal study of promoting factors and sensitive periods i

Safe People

Organisation name

Massachusetts General Hospital, Harvard Medical School

Organisation sector

Academic Institute

Applicant name(s)

Erin DunnCaroline ReltonProfessor of Epigenetic EpidemiologyMatthew SudermanAlison Hoffnagle

Safe Projects

Project ID

B3870

Lay summary

Exposure to childhood adversity is one of the strongest risk factors for depression across the life course, increasing risk for both child- and adult-onsets of the disorder by at least twofold and possibly explaining one-third of all mental disorders. Accumulating research suggests epigenetic processes may be a key biological pathway through which adversity creates this long-term mental health vulnerability. Dozens of human and animal studies have shown that adversity can program the epigenome through DNA methylation (DNAm) marks, which do not alter the sequence of the genome, but can influence how genes are expressed. Our interdisciplinary team has been studying the relationship between adversity, DNAm, and depression risk in the ALSPAC. Our work to date has revealed three main novel findings. First, not only does adversity shape these DNAm marks in both childhood (at age 7) and adolescence (at age 15), but there is a replicated sensitive period between 3-5 years when children’s epigenomes are especially vulnerable to the effects of adversity. Second, these adversity-induced DNAm differences are temporally dynamic, having discernable patterns of stability and change across childhood and adolescence that reflect latent, and transitory effects of adversity on the epigenome. Third, these DNAm marks are not only a molecular record of adversity exposure, but also appear to mediate, meaning explain in part, how adversity influences both risk for – and protection against – subsequent depressive symptoms.

Public benefit statement

By testing our central hypothesis, we can identify molecular mechanisms driving risk for internalizing symptoms and determine when in early life public health resources can be optimally deployed to reduce the negative sequelae of adversity. Successful completion of these aims will change how research questions in epigenetics are pursued, providing a new paradigm (chrono-epigenetics) that can bring greater specificity to conceptualizing, characterizing, and measuring DNAm across time. When the aims are achieved, we will identify a set of laboratory-validated DNAm-based biomarkers that are influenced by adversity and predict onset of internalizing symptoms. We will also determine the ages when adversity is most likely to affect these DNAm marks. Our work will differentiate loci that change with aging vs. remain stable, which will enable researchers in multiple disciplines to further prune the methylome search space to only loci showing temporal variation. The proposed work has the potential to transform clinical care options for youth with mental illness, revealing molecular targets that are temporally and environmentally plastic and could one day be used in formulating new treatment options. The potential significance of this research is exceptional in that these results could identify windows of vulnerability when adversity and DNAm changes are most harmful and highlight windows of opportunity when enriching exposures may be more impactful. Results could allow scientists to differentiate epigenomic responses to adversity, separating out patterns that are adaptive in the short term from those that are irreversible/risk-conferring in the long term, and identify children likely to benefit most from different types of early interventions (i.e., if DNAm markers of inflammation were implicated, that would support the use of interventions with anti-inflammatory properties, including exercise or mindfulness).

Latest approval date

13/09/2021