A systematic review of neuroimaging epigenetic research: Calling for an increased focus on development

Abstract

Epigenetic mechanisms, such as DNA methylation (DNAm), have gained increasing attention in the field of neuroimaging as a potential biomarker of -or mechanism mediating -genetic and environmental influences on the brain. Yet, the extent to which DNAm associates with individual differences in the brain -the most relevant organ for the study of psychiatric disorders -is currently unclear.We systematically reviewed research combining structural or functional neuroimaging measures with DNAm to provide an overview of the current state-of-the-art in this new field of research and discuss current challenges.We identified 78 articles, published between 2011 -2019. Most studies investigated DNAm-brain associations in the context of psychiatric and behavioural outcomes (76%), often based on adult (77%) or clinical samples (46%). Only a few studies focussed on risk exposures (21%), developmental periods other than adulthood (23%) or analyzed repeated measures of DNAm or neuroimaging (5%). Studies were highly heterogeneous in design (longitudinal versus cross-sectional), sample characteristics and methods used (candidate-driven versus genome-wide) with relatively few shared practices and common standards. Sample sizes were generally low to moderate (median n=99).On the basis of the strength and weaknesses of existing studies, we recommend how best to address current challenges, including the need for collaborative science to increase comparability across studies. We also advocate for the use of large, prospective, paediatric cohorts with repeated measures of methylation and imaging to draw conclusions about the directionality of associations between these measures.

An epigenetic proxy of chronic inflammation outperforms serum levels as a biomarker of brain ageing

“…To disentangle directionality of effects, there is demand for studies that collect repeated measures of DNAm, cognitive and neuroimaging data over time. A few cohorts, including LBC1936, are suited to this type of longitudinal study as highlighted in a recent systematic review 59 ; to further strengthen causal inference or in cases where no such data is available, a two-sample Mendelian Randomisation approach may be best suited.…”

Epigenetics and ADHD: Reflections on Current Knowledge, Research Priorities and Translational Potential

“…The long-term goal would be to discover whether and how identified peripheral DNAm patterns relate to the brain itself—the most relevant organ for ADHD and other mental disorders. Several models have been proposed for this [ 98 ]. For example, DNAm patterns in blood or saliva may correlate with those in the brain (e.g., in response to common factors, such as prenatal exposures or genetic effects), even though changes in these tissues are not functionally linked to one another (i.e., ‘mirror’ model).…”

“…In humans, studies could begin by examining how the identified epigenetic signals in blood relate to individual differences in brain structure, function, and connectivity associated with ADHD. This could be achieved by leveraging recent collaborative initiatives within the emerging field of neuroimaging epigenetics, which are opening exciting opportunities to test in vivo associations between peripheral DNAm and the brain at different developmental stages [ 98 ] (e.g. consortia: MIND , ENIGMA-Epigenetics ).…”

Epigenetics applied to child and adolescent mental health: Progress, challenges and opportunities

“…While many associations have been reported in the literature, these typically show much smaller effects, are derived from single datasets of modest sample size and mostly await replication. Reproducibility in mental health research has been particularly hampered by heterogeneity in study characteristics, choice of assessments and methodology, adjustment for important confounders (e.g., medication use), the temporally dynamic (and often episodic) nature of many mental health phenotypes, as well as uneven uptake of open science practices, although standards are constantly improving (Walton et al., 2020).…”