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

Esther Walton; Vilte Baltramonaityte; Vince Calhoun; Bastiaan T. Heijmans; Paul M. Thompson; Charlotte A. M. Cecil

doi:10.1038/s41380-023-02067-2

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

Esther Walton, Vilte Baltramonaityte, Vince Calhoun, Bastiaan T. Heijmans, Paul M. Thompson, Charlotte A. M. Cecil

Research output: Contribution to journal › Review article › peer-review

8 Citations (SciVal)

Abstract

Epigenetic mechanisms, such as DNA methylation (DNAm), have gained increasing attention as potential biomarkers and mechanisms underlying risk for neurodevelopmental, psychiatric and other brain-based disorders. Yet, surprisingly little is known about the extent to which DNAm is linked to individual differences in the brain itself, and how these associations may unfold across development - a time of life when many of these disorders emerge. Here, we systematically review evidence from the nascent field of Neuroimaging Epigenetics, combining structural or functional neuroimaging measures with DNAm, and the extent to which the developmental period (birth to adolescence) is represented in these studies. We identified 111 articles published between 2011-2021, out of which only a minority (21%) included samples under 18 years of age. Most studies were cross-sectional (85%), employed a candidate-gene approach (67%), and examined DNAm-brain associations in the context of health and behavioral outcomes (75%). Nearly half incorporated genetic data, and a fourth investigated environmental influences. Overall, studies support a link between peripheral DNAm and brain imaging measures, but there is little consistency in specific findings and it remains unclear whether DNAm markers present a cause, correlate or consequence of brain alterations. Overall, there is large heterogeneity in sample characteristics, peripheral tissue and brain outcome examined as well as the methods used. Sample sizes were generally low to moderate (median n all = 98, n developmental = 80), and attempts at replication or meta-analysis were rare. Based on the strengths and weaknesses of existing studies, we propose three recommendations on how advance the field of Neuroimaging Epigenetics. We advocate for: (1) a greater focus on developmentally oriented research (i.e. pre-birth to adolescence); (2) the analysis of large, prospective, pediatric cohorts with repeated measures of DNAm and imaging to assess directionality; and (3) collaborative, interdisciplinary science to identify robust signals, triangulate findings and enhance translational potential.

Original language	English
Pages (from-to)	2839-2847
Number of pages	9
Journal	Molecular Psychiatry
Volume	28
Issue number	7
Early online date	25 Apr 2023
DOIs	https://doi.org/10.1038/s41380-023-02067-2
Publication status	Published - 31 Jul 2023

Funding

PMT received grant support from Biogen, Inc. (Boston, USA) for research unrelated to the topic of this manuscript. This work was funded from the European Union’s Horizon 2020 research and innovation program under the European Research Council grant agreement No 101039672 (TEMPO) to CC and grant agreement No. 848158 (EarlyCause) to EW and CC. EW was also supported by CLOSER, whose mission is to maximize the use, value and impact of longitudinal studies. CLOSER was funded by the Economic and Social Research Council (ESRC) and the Medical Research Council (MRC) between 2012 and 2017. Its initial five-year grant was extended to March 2021 by the ESRC (grant reference: ES/K000357/1). EW also received funding from the National Institute of Mental Health of the National Institutes of Health (award number R01MH113930). The work of CC is also supported by European Union’s HorizonEurope Research and Innovation Programme (FAMILY, grant agreement No 101057529; HappyMums, grant agreement No. 101057390). PMT is funded in part by NIH grants U54 EB020403, R01 MH116147, R56 AG058854, P41 EB015922, R01 MH111671 and a Zenith Grant from the Alzheimer’s Association. VDC is funded in part by NSF grant #2112455 and NIH grant R01MH118695. This work was funded from the European Union’s Horizon 2020 research and innovation program under the European Research Council grant agreement No 101039672 (TEMPO) to CC and grant agreement No. 848158 (EarlyCause) to EW and CC. EW was also supported by CLOSER, whose mission is to maximize the use, value and impact of longitudinal studies. CLOSER was funded by the Economic and Social Research Council (ESRC) and the Medical Research Council (MRC) between 2012 and 2017. Its initial five-year grant was extended to March 2021 by the ESRC (grant reference: ES/K000357/1). EW also received funding from the National Institute of Mental Health of the National Institutes of Health (award number R01MH113930). The work of CC is also supported by European Union’s HorizonEurope Research and Innovation Programme (FAMILY, grant agreement No 101057529; HappyMums, grant agreement No. 101057390). PMT is funded in part by NIH grants U54 EB020403, R01 MH116147, R56 AG058854, P41 EB015922, R01 MH111671 and a Zenith Grant from the Alzheimer’s Association. VDC is funded in part by NSF grant #2112455 and NIH grant R01MH118695.

Funders	Funder number
CLOSER
European Union’s HorizonEurope Research and Innovation Programme
FAMILY	101057390, 101057529
National Institutes of Health	R01 MH111671, P41 EB015922, R01MH113930, R56 AG058854, U54 EB020403, R01 MH116147
National Institute of Mental Health
Alzheimer's Association
Biogen, Cambridge, MA, USA.
Horizon 2020 Framework Programme
Medical Research Council	ES/K000357/1
Economic and Social Research Council
European Research Council	101039672, 848158
Neurosciences Foundation	2112455, R01MH118695

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title = "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 as potential biomarkers and mechanisms underlying risk for neurodevelopmental, psychiatric and other brain-based disorders. Yet, surprisingly little is known about the extent to which DNAm is linked to individual differences in the brain itself, and how these associations may unfold across development - a time of life when many of these disorders emerge. Here, we systematically review evidence from the nascent field of Neuroimaging Epigenetics, combining structural or functional neuroimaging measures with DNAm, and the extent to which the developmental period (birth to adolescence) is represented in these studies. We identified 111 articles published between 2011-2021, out of which only a minority (21%) included samples under 18 years of age. Most studies were cross-sectional (85%), employed a candidate-gene approach (67%), and examined DNAm-brain associations in the context of health and behavioral outcomes (75%). Nearly half incorporated genetic data, and a fourth investigated environmental influences. Overall, studies support a link between peripheral DNAm and brain imaging measures, but there is little consistency in specific findings and it remains unclear whether DNAm markers present a cause, correlate or consequence of brain alterations. Overall, there is large heterogeneity in sample characteristics, peripheral tissue and brain outcome examined as well as the methods used. Sample sizes were generally low to moderate (median n all = 98, n developmental = 80), and attempts at replication or meta-analysis were rare. Based on the strengths and weaknesses of existing studies, we propose three recommendations on how advance the field of Neuroimaging Epigenetics. We advocate for: (1) a greater focus on developmentally oriented research (i.e. pre-birth to adolescence); (2) the analysis of large, prospective, pediatric cohorts with repeated measures of DNAm and imaging to assess directionality; and (3) collaborative, interdisciplinary science to identify robust signals, triangulate findings and enhance translational potential. ",

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AU - Walton, Esther

AU - Baltramonaityte, Vilte

AU - Calhoun, Vince

AU - Heijmans, Bastiaan T.

AU - Thompson, Paul M.

AU - Cecil, Charlotte A. M.

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AB - Epigenetic mechanisms, such as DNA methylation (DNAm), have gained increasing attention as potential biomarkers and mechanisms underlying risk for neurodevelopmental, psychiatric and other brain-based disorders. Yet, surprisingly little is known about the extent to which DNAm is linked to individual differences in the brain itself, and how these associations may unfold across development - a time of life when many of these disorders emerge. Here, we systematically review evidence from the nascent field of Neuroimaging Epigenetics, combining structural or functional neuroimaging measures with DNAm, and the extent to which the developmental period (birth to adolescence) is represented in these studies. We identified 111 articles published between 2011-2021, out of which only a minority (21%) included samples under 18 years of age. Most studies were cross-sectional (85%), employed a candidate-gene approach (67%), and examined DNAm-brain associations in the context of health and behavioral outcomes (75%). Nearly half incorporated genetic data, and a fourth investigated environmental influences. Overall, studies support a link between peripheral DNAm and brain imaging measures, but there is little consistency in specific findings and it remains unclear whether DNAm markers present a cause, correlate or consequence of brain alterations. Overall, there is large heterogeneity in sample characteristics, peripheral tissue and brain outcome examined as well as the methods used. Sample sizes were generally low to moderate (median n all = 98, n developmental = 80), and attempts at replication or meta-analysis were rare. Based on the strengths and weaknesses of existing studies, we propose three recommendations on how advance the field of Neuroimaging Epigenetics. We advocate for: (1) a greater focus on developmentally oriented research (i.e. pre-birth to adolescence); (2) the analysis of large, prospective, pediatric cohorts with repeated measures of DNAm and imaging to assess directionality; and (3) collaborative, interdisciplinary science to identify robust signals, triangulate findings and enhance translational potential.

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

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