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. 2022 Nov;26(6):581-606.
doi: 10.1007/s40291-022-00609-y. Epub 2022 Aug 6.

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

Charlotte A M Cecil  1   2   3 , Joel T Nigg  4
Affiliations

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

Charlotte A M Cecil et al. Mol Diagn Ther. 2022 Nov.

Abstract

Attention-deficit/hyperactivity disorder (ADHD) is a common and debilitating neurodevelopmental disorder influenced by both genetic and environmental factors, typically identified in the school-age years but hypothesized to have developmental origins beginning in utero. To improve current strategies for prediction, prevention and treatment, a central challenge is to delineate how, at a molecular level, genetic and environmental influences jointly shape ADHD risk, phenotypic presentation, and developmental course. Epigenetic processes that regulate gene expression, such as DNA methylation, have emerged as a promising molecular system in the search for both biomarkers and mechanisms to address this challenge. In this Current Opinion, we discuss the relevance of epigenetics (specifically DNA methylation) for ADHD research and clinical practice, starting with the current state of knowledge, what challenges we have yet to overcome, and what the future may hold in terms of methylation-based applications for personalized medicine in ADHD. We conclude that the field of epigenetics and ADHD is promising but is still in its infancy, and the potential for transformative translational applications remains a distant goal. Nevertheless, rapid methodological advances, together with the rise of collaborative science and increased availability of high-quality, longitudinal data make this a thriving research area that in future may contribute to the development of new tools for improved prediction, management, and treatment of ADHD.

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Conflict of interest statement

Charlotte A.M. Cecil and Joel T. Nigg declare no conflicts of interest related to this work.

Figures

Fig. 1
Fig. 1
ADHD as a complex, multifactorial entity involving interactions across environmental, biological, and behavioral domains. According to current theoretical models of ADHD, such as the ‘mechanistic-cybernetic model’ [2], multiple extrinsic (e.g., environmental factors, blue), intrinsic (genetic, pink; biological and psychological processes, white) and behavioral (green) domains are thought to interact together to shape risk and resilience in ADHD development. Key findings to date from research on both genetic (left-hand side) and environmental (right-hand side) influences on ADHD are highlighted. While this Current Opinion focuses specifically on the potential relevance of epigenetics in ADHD research and clinical practice, it is important to note that epigenetic processes are likely only one of several interconnected domains implicated in the pathophysiology of ADHD. Note: double-headed blue arrows = bidirectional influence; single-headed blue arrow = directional influence; grey dotted arrow = correlated but not causal association. ADHD attention-deficit/hyperactivity disorder, SNP single nucleotide polymorphism, GWAS genome-wide association study, DNAm DNA methylation, BMI body mass index, PGS polygenic score
Fig. 2
Fig. 2
Key gap 1: Explaining the neonatal epigenetic signal for ADHD risk. a Top panel: General pattern of epigenetic timing effects observed by EWAS studies in population-based birth cohorts [64, 72], indicating that (1) DNAm patterns at birth prospectively associate with ADHD symptoms in childhood; and (2) DNAm patterns in childhood do not associate cross-sectionally with ADHD symptoms in childhood. Bottom panel: EWAS Manhattan plots from the meta-analysis by Neumann et al. [72] showing that differences in signal are evident both in terms of the identification of prospective, but not cross-sectional, genome-wide significant associations (i.e., ‘dots’ above the blue genome-wide correction line), as well as the overall association ‘signal’ detected across the genome at birth versus in childhood (i.e., height of the bars in the Manhattan plot). b Top panel: Future research will be needed to characterize key properties of the epigenetic signal detected at birth, in order to evaluate its potential as a possible biomarker for early risk detection, pre-symptom manifestation, including (1) how much variance in ADHD it explains (quantification); (2) to what extent this signal is specific to ADHD compared with other child mental and physical outcomes (specificity); (3) whether this signal at birth continues to predict ADHD and related outcomes in adulthood (persistence); and (4) what genetic and environmental influences drive this signal in the first place (origins). Bottom panel: In future, studies will also need to clarify why the epigenetic signal identified at birth is no longer detected from DNAm in childhood, for example due to ‘fading’ predictive power (e.g. DNAm at birth may tag genetic or prenatal influences on ADHD, with this signal becoming noisier in time due to the accumulation of postnatal influences on DNAm) or tissue and cell-type differences between time points (e.g., with cord blood containing unique types of multipotent cells that disappear rapidly after birth, potentially explaining why the signal at birth is not detected in peripheral blood later in life). ADHD attention-deficit/hyperactivity disorder, EWAS epigenome-wide association studies, DNAm DNA methylation
Fig. 3
Fig. 3
Key gap 2: Tracking dynamic DNAm/ADHD associations over the life course. (a) Epigenome-wide association studies. Examples of different longitudinal profiles of ADHD based on what has been reported in the literature, illustrating the large individual heterogeneity in the onset, level, and persistence of ADHD symptoms from early life to adulthood. Of note, there is ongoing debate about the existence of an ‘adult-onset’ ADHD trajectory, which necessitates more research going forward. Furthermore, while it is clear from existing research that longitudinal profiles of ADHD are heterogeneous across individuals, the specific developmental pathways remain hypothetical. (b) Research priorities for future research making use of repeated measures of both DNAm and ADHD symptoms. DNAm DNA methylation, ADHD attention-deficit/hyperactivity disorder
Fig. 4
Fig. 4
Key gap 3: Mechanistic insights into the link between peripheral DNAm and ADHD. Plausible hypothetical models explaining observed DNAm/ADHD associations. Note that these models are not mutually exclusive (e.g., DNAm alterations may be a causal factor in, as well as a consequence of, ADHD) and other models are also possible, which may emerge from future research (e.g., DNAm may function as a moderator of genetic and environmental influences on outcomes). Top panel: The (non-causal) biomarker model, whereby DNAm may tag multiple aspects relevant to ADHD, including associated risk factors (e.g. genetic liability or environmental risks such as maternal prenatal inflammation; exposure biomarker), intermediate phenotypes (e.g. neonatal developmental status, motor functioning or brain features; risk prediction biomarker), subclinical symptoms (e.g. hyperactivity and impulsivity symptoms; early detection biomarker), disorder onset (e.g. ADHD diagnosis; diagnostic biomarker), progression (e.g. change in ADHD levels over time, remittance; prognostic biomarker) and treatment response (e.g. stimulant medication or psychosocial intervention; treatment response). This application may be especially well-suited for use in peripheral tissues, which are more readily available in vivo but may not be causal for the phenotype of interest, and effective when DNAm is assessed as an aggregate polyepigenetic score (capturing broader DNAm ‘signatures’) in combination with other markers as part of a multimodal assessment tool. Middle panel: The (simplified) causal ‘mechanism’ model, whereby risk factors (independent variable) are hypothesized to partly influence ADHD and related outcomes (dependent variable) via changes in DNAm (mediator variable). Bottom panel: The (simplified) causal ‘consequence’ model, whereby DNAm patterns may be altered by ADHD and related factors, for example as a consequence of medication use (e.g., psychostimulant medication) or the disease process itself. An important priority for future research will be to test these different models by using more advanced causal inference approaches (e.g., experimental animal and in vitro designs), as well as to characterize how peripheral DNAm patterns associated with ADHD relate to the brain itself—the most relevant organ for ADHD and other mental disorders. DNAm DNA methylation, ADHD attention-deficit/hyperactivity disorder
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