Examining the epigenetic mechanisms of childhood adversity and sensitive periods: a gene set-based approach

Yiwen Zhu; Alexandre A. Lussier; Andrew D.A.C. Smith; Andrew J. Simpkin; Matthew J. Suderman; Esther Walton; Caroline L. Relton; Erin C. Dunn

doi:10.1016/j.psyneuen.2022.105854

Examining the epigenetic mechanisms of childhood adversity and sensitive periods: a gene set-based approach

Yiwen Zhu, Alexandre A. Lussier, Andrew D.A.C. Smith, Andrew J. Simpkin, Matthew J. Suderman, Esther Walton, Caroline L. Relton, Erin C. Dunn

Research output: Contribution to journal › Article › peer-review

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Abstract

Background: Sensitive periods are developmental stages of heightened plasticity when life experiences, including exposure to childhood adversity, have the potential to exert more lasting impacts. Epigenetic mechanisms, including DNA methylation (DNAm), may provide a pathway through which adversity induces long-term biological changes. DNAm shifts may be more likely to occur during sensitive periods, especially within genes that regulate the timing of sensitive periods. Here, we investigated the possibility that childhood adversity during specific life stages is associated with DNAm changes in genes known to regulate the timing and duration of sensitive periods. Methods: Genome-wide DNAm profiles came from the Avon Longitudinal Study of Parents and Children (n = 785). We first used principal component analysis (PCA) to summarize DNAm variation across 530 CpG sites mapped to the promoters of 58 genes previously-identified as regulating sensitive periods. Gene-level DNAm summaries were calculated for genes regulating sensitive period opening (n _genes = 15), closing (n _genes = 36), and expression (n _genes = 8). We then performed linear discriminant analysis (LDA) to test associations between seven types of parent-reported, time-varying measures of exposure to childhood adversity and DNAm principal components. To our knowledge, this is the first time LDA has been applied to analyze functionally grouped DNAm data to characterize associations between an environmental exposure and epigenetic differences. Results: Suggestive evidence emerged for associations between sexual or physical abuse as well as financial hardship during middle childhood, and DNAm of genetic pathways regulating sensitive period opening and expression. However, no statistically significant associations were identified after multiple testing correction. Conclusions: Our gene set-based method combining PCA and LDA complements epigenome-wide approaches. Although our results were largely null, these findings provide a proof-of-concept for studying time-varying exposures and gene- or pathway-level epigenetic modifications.

Original language	English
Article number	105854
Journal	Psychoneuroendocrinology
Volume	144
Early online date	27 Jun 2022
DOIs	https://doi.org/10.1016/j.psyneuen.2022.105854
Publication status	Published - 31 Oct 2022

Bibliographical note

Funding Information:
The UK Medical Research Council and Wellcome (Grant ref: 217065/Z/19/Z ) and the University of Bristol provide core support for ALSPAC. A comprehensive list of grants funding is available on the ALSPAC website ( http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf ). This research was specifically funded by grants from the BBSRC ( BBI025751/1 ; BB/I025263/1 ), IEU ( MC_UU_12013/1 ; MC_UU_12013/2 ; MC_UU_12013/8 , MRC_UU_00011/5 ), National Institute of Child and Human Development ( R01HD068437 ), NIH ( 5RO1AI121226-02 ), and CONTAMED EU ( 212502 ). This publication is the work of the authors, and all authors will serve as guarantors for the contents of this paper.

Funding Information:
Research reported in this publication was supported by the National Institute of Mental Health of the National Institutes of Health [Award Number R01MH113930 ; PI: ECD]. The NIMH had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Funding Information:
Dr. Walton is funded by CLOSER, whose mission is to maximize the use, value and impact of longitudinal studies ( www.closer.ac.uk ). CLOSER was funded by the Economic and Social Research Council (ESRC) and the Medical Research Council (MRC) between 2012 and 2021 (grant reference: ES/K000357/1 ). The funders took no role in the design, execution, analysis or interpretation of the data or in the writing up of the findings. Dr. Walton is also supported by the European Union’s Horizon 2020 research and innovation programme (Grant no. 848158 ).

Funding Information:
Research reported in this publication was supported by the National Institute of Mental Health of the National Institutes of Health [Award Number R01MH113930; PI: ECD]. The NIMH had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.The UK Medical Research Council and Wellcome (Grant ref: 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. A comprehensive list of grants funding is available on the ALSPAC website (http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf). This research was specifically funded by grants from the BBSRC (BBI025751/1; BB/I025263/1), IEU (MC_UU_12013/1; MC_UU_12013/2; MC_UU_12013/8, MRC_UU_00011/5), National Institute of Child and Human Development (R01HD068437), NIH (5RO1AI121226-02), and CONTAMED EU (212502). This publication is the work of the authors, and all authors will serve as guarantors for the contents of this paper.Dr. Walton is funded by CLOSER, whose mission is to maximize the use, value and impact of longitudinal studies (www.closer.ac.uk). CLOSER was funded by the Economic and Social Research Council (ESRC) and the Medical Research Council (MRC) between 2012 and 2021 (grant reference: ES/K000357/1). The funders took no role in the design, execution, analysis or interpretation of the data or in the writing up of the findings. Dr. Walton is also supported by the European Union's Horizon 2020 research and innovation programme (Grant no. 848158).

Publisher Copyright:
© 2022 Elsevier Ltd

Keywords

ALSPAC
Childhood adversity
Epigenetics
Plasticity
Sensitive periods

ASJC Scopus subject areas

Endocrinology, Diabetes and Metabolism
Endocrinology
Endocrine and Autonomic Systems
Psychiatry and Mental health
Biological Psychiatry

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.psyneuen.2022.105854

PNEC_pre-proof_Zhu_2022.PDFAccepted author manuscript, 942 KBLicence: CC BY

https://www.sciencedirect.com/science/article/pii/S0306453022001950

Cite this

@article{278b2446bc044fd481fc533608622861,

title = "Examining the epigenetic mechanisms of childhood adversity and sensitive periods: a gene set-based approach",

abstract = "Background: Sensitive periods are developmental stages of heightened plasticity when life experiences, including exposure to childhood adversity, have the potential to exert more lasting impacts. Epigenetic mechanisms, including DNA methylation (DNAm), may provide a pathway through which adversity induces long-term biological changes. DNAm shifts may be more likely to occur during sensitive periods, especially within genes that regulate the timing of sensitive periods. Here, we investigated the possibility that childhood adversity during specific life stages is associated with DNAm changes in genes known to regulate the timing and duration of sensitive periods. Methods: Genome-wide DNAm profiles came from the Avon Longitudinal Study of Parents and Children (n = 785). We first used principal component analysis (PCA) to summarize DNAm variation across 530 CpG sites mapped to the promoters of 58 genes previously-identified as regulating sensitive periods. Gene-level DNAm summaries were calculated for genes regulating sensitive period opening (n genes = 15), closing (n genes = 36), and expression (n genes = 8). We then performed linear discriminant analysis (LDA) to test associations between seven types of parent-reported, time-varying measures of exposure to childhood adversity and DNAm principal components. To our knowledge, this is the first time LDA has been applied to analyze functionally grouped DNAm data to characterize associations between an environmental exposure and epigenetic differences. Results: Suggestive evidence emerged for associations between sexual or physical abuse as well as financial hardship during middle childhood, and DNAm of genetic pathways regulating sensitive period opening and expression. However, no statistically significant associations were identified after multiple testing correction. Conclusions: Our gene set-based method combining PCA and LDA complements epigenome-wide approaches. Although our results were largely null, these findings provide a proof-of-concept for studying time-varying exposures and gene- or pathway-level epigenetic modifications. ",

keywords = "ALSPAC, Childhood adversity, Epigenetics, Plasticity, Sensitive periods",

author = "Yiwen Zhu and Lussier, {Alexandre A.} and Smith, {Andrew D.A.C.} and Simpkin, {Andrew J.} and Suderman, {Matthew J.} and Esther Walton and Relton, {Caroline L.} and Dunn, {Erin C.}",

note = "Funding Information: The UK Medical Research Council and Wellcome (Grant ref: 217065/Z/19/Z ) and the University of Bristol provide core support for ALSPAC. A comprehensive list of grants funding is available on the ALSPAC website ( http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf ). This research was specifically funded by grants from the BBSRC ( BBI025751/1 ; BB/I025263/1 ), IEU ( MC_UU_12013/1 ; MC_UU_12013/2 ; MC_UU_12013/8 , MRC_UU_00011/5 ), National Institute of Child and Human Development ( R01HD068437 ), NIH ( 5RO1AI121226-02 ), and CONTAMED EU ( 212502 ). This publication is the work of the authors, and all authors will serve as guarantors for the contents of this paper. Funding Information: Research reported in this publication was supported by the National Institute of Mental Health of the National Institutes of Health [Award Number R01MH113930 ; PI: ECD]. The NIMH had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Funding Information: Dr. Walton is funded by CLOSER, whose mission is to maximize the use, value and impact of longitudinal studies ( www.closer.ac.uk ). CLOSER was funded by the Economic and Social Research Council (ESRC) and the Medical Research Council (MRC) between 2012 and 2021 (grant reference: ES/K000357/1 ). The funders took no role in the design, execution, analysis or interpretation of the data or in the writing up of the findings. Dr. Walton is also supported by the European Union{\textquoteright}s Horizon 2020 research and innovation programme (Grant no. 848158 ). Funding Information: Research reported in this publication was supported by the National Institute of Mental Health of the National Institutes of Health [Award Number R01MH113930; PI: ECD]. The NIMH had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.The UK Medical Research Council and Wellcome (Grant ref: 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. A comprehensive list of grants funding is available on the ALSPAC website (http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf). This research was specifically funded by grants from the BBSRC (BBI025751/1; BB/I025263/1), IEU (MC_UU_12013/1; MC_UU_12013/2; MC_UU_12013/8, MRC_UU_00011/5), National Institute of Child and Human Development (R01HD068437), NIH (5RO1AI121226-02), and CONTAMED EU (212502). This publication is the work of the authors, and all authors will serve as guarantors for the contents of this paper.Dr. Walton is funded by CLOSER, whose mission is to maximize the use, value and impact of longitudinal studies (www.closer.ac.uk). CLOSER was funded by the Economic and Social Research Council (ESRC) and the Medical Research Council (MRC) between 2012 and 2021 (grant reference: ES/K000357/1). The funders took no role in the design, execution, analysis or interpretation of the data or in the writing up of the findings. Dr. Walton is also supported by the European Union's Horizon 2020 research and innovation programme (Grant no. 848158). Publisher Copyright: {\textcopyright} 2022 Elsevier Ltd",

year = "2022",

month = oct,

day = "31",

doi = "10.1016/j.psyneuen.2022.105854",

language = "English",

volume = "144",

journal = "Psychoneuroendocrinology",

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TY - JOUR

T1 - Examining the epigenetic mechanisms of childhood adversity and sensitive periods: a gene set-based approach

AU - Zhu, Yiwen

AU - Lussier, Alexandre A.

AU - Smith, Andrew D.A.C.

AU - Simpkin, Andrew J.

AU - Suderman, Matthew J.

AU - Walton, Esther

AU - Relton, Caroline L.

AU - Dunn, Erin C.

N1 - Funding Information: The UK Medical Research Council and Wellcome (Grant ref: 217065/Z/19/Z ) and the University of Bristol provide core support for ALSPAC. A comprehensive list of grants funding is available on the ALSPAC website ( http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf ). This research was specifically funded by grants from the BBSRC ( BBI025751/1 ; BB/I025263/1 ), IEU ( MC_UU_12013/1 ; MC_UU_12013/2 ; MC_UU_12013/8 , MRC_UU_00011/5 ), National Institute of Child and Human Development ( R01HD068437 ), NIH ( 5RO1AI121226-02 ), and CONTAMED EU ( 212502 ). This publication is the work of the authors, and all authors will serve as guarantors for the contents of this paper. Funding Information: Research reported in this publication was supported by the National Institute of Mental Health of the National Institutes of Health [Award Number R01MH113930 ; PI: ECD]. The NIMH had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Funding Information: Dr. Walton is funded by CLOSER, whose mission is to maximize the use, value and impact of longitudinal studies ( www.closer.ac.uk ). CLOSER was funded by the Economic and Social Research Council (ESRC) and the Medical Research Council (MRC) between 2012 and 2021 (grant reference: ES/K000357/1 ). The funders took no role in the design, execution, analysis or interpretation of the data or in the writing up of the findings. Dr. Walton is also supported by the European Union’s Horizon 2020 research and innovation programme (Grant no. 848158 ). Funding Information: Research reported in this publication was supported by the National Institute of Mental Health of the National Institutes of Health [Award Number R01MH113930; PI: ECD]. The NIMH had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.The UK Medical Research Council and Wellcome (Grant ref: 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. A comprehensive list of grants funding is available on the ALSPAC website (http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf). This research was specifically funded by grants from the BBSRC (BBI025751/1; BB/I025263/1), IEU (MC_UU_12013/1; MC_UU_12013/2; MC_UU_12013/8, MRC_UU_00011/5), National Institute of Child and Human Development (R01HD068437), NIH (5RO1AI121226-02), and CONTAMED EU (212502). This publication is the work of the authors, and all authors will serve as guarantors for the contents of this paper.Dr. Walton is funded by CLOSER, whose mission is to maximize the use, value and impact of longitudinal studies (www.closer.ac.uk). CLOSER was funded by the Economic and Social Research Council (ESRC) and the Medical Research Council (MRC) between 2012 and 2021 (grant reference: ES/K000357/1). The funders took no role in the design, execution, analysis or interpretation of the data or in the writing up of the findings. Dr. Walton is also supported by the European Union's Horizon 2020 research and innovation programme (Grant no. 848158). Publisher Copyright: © 2022 Elsevier Ltd

PY - 2022/10/31

Y1 - 2022/10/31

N2 - Background: Sensitive periods are developmental stages of heightened plasticity when life experiences, including exposure to childhood adversity, have the potential to exert more lasting impacts. Epigenetic mechanisms, including DNA methylation (DNAm), may provide a pathway through which adversity induces long-term biological changes. DNAm shifts may be more likely to occur during sensitive periods, especially within genes that regulate the timing of sensitive periods. Here, we investigated the possibility that childhood adversity during specific life stages is associated with DNAm changes in genes known to regulate the timing and duration of sensitive periods. Methods: Genome-wide DNAm profiles came from the Avon Longitudinal Study of Parents and Children (n = 785). We first used principal component analysis (PCA) to summarize DNAm variation across 530 CpG sites mapped to the promoters of 58 genes previously-identified as regulating sensitive periods. Gene-level DNAm summaries were calculated for genes regulating sensitive period opening (n genes = 15), closing (n genes = 36), and expression (n genes = 8). We then performed linear discriminant analysis (LDA) to test associations between seven types of parent-reported, time-varying measures of exposure to childhood adversity and DNAm principal components. To our knowledge, this is the first time LDA has been applied to analyze functionally grouped DNAm data to characterize associations between an environmental exposure and epigenetic differences. Results: Suggestive evidence emerged for associations between sexual or physical abuse as well as financial hardship during middle childhood, and DNAm of genetic pathways regulating sensitive period opening and expression. However, no statistically significant associations were identified after multiple testing correction. Conclusions: Our gene set-based method combining PCA and LDA complements epigenome-wide approaches. Although our results were largely null, these findings provide a proof-of-concept for studying time-varying exposures and gene- or pathway-level epigenetic modifications.

AB - Background: Sensitive periods are developmental stages of heightened plasticity when life experiences, including exposure to childhood adversity, have the potential to exert more lasting impacts. Epigenetic mechanisms, including DNA methylation (DNAm), may provide a pathway through which adversity induces long-term biological changes. DNAm shifts may be more likely to occur during sensitive periods, especially within genes that regulate the timing of sensitive periods. Here, we investigated the possibility that childhood adversity during specific life stages is associated with DNAm changes in genes known to regulate the timing and duration of sensitive periods. Methods: Genome-wide DNAm profiles came from the Avon Longitudinal Study of Parents and Children (n = 785). We first used principal component analysis (PCA) to summarize DNAm variation across 530 CpG sites mapped to the promoters of 58 genes previously-identified as regulating sensitive periods. Gene-level DNAm summaries were calculated for genes regulating sensitive period opening (n genes = 15), closing (n genes = 36), and expression (n genes = 8). We then performed linear discriminant analysis (LDA) to test associations between seven types of parent-reported, time-varying measures of exposure to childhood adversity and DNAm principal components. To our knowledge, this is the first time LDA has been applied to analyze functionally grouped DNAm data to characterize associations between an environmental exposure and epigenetic differences. Results: Suggestive evidence emerged for associations between sexual or physical abuse as well as financial hardship during middle childhood, and DNAm of genetic pathways regulating sensitive period opening and expression. However, no statistically significant associations were identified after multiple testing correction. Conclusions: Our gene set-based method combining PCA and LDA complements epigenome-wide approaches. Although our results were largely null, these findings provide a proof-of-concept for studying time-varying exposures and gene- or pathway-level epigenetic modifications.

KW - ALSPAC

KW - Childhood adversity

KW - Epigenetics

KW - Plasticity

KW - Sensitive periods

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U2 - 10.1016/j.psyneuen.2022.105854

DO - 10.1016/j.psyneuen.2022.105854

M3 - Article

SN - 0306-4530

VL - 144

JO - Psychoneuroendocrinology

JF - Psychoneuroendocrinology

M1 - 105854

ER -

Examining the epigenetic mechanisms of childhood adversity and sensitive periods: a gene set-based approach

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

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