Abstract
BACKGROUND: Childhood adversity is a potent determinant of health across development and is associated with altered DNA methylation signatures, which might be more common in children exposed during sensitive periods in development. However, it remains unclear whether adversity has persistent epigenetic associations across childhood and adolescence. We aimed to examine the relationship between time-varying adversity (defined through sensitive period, accumulation of risk, and recency life course hypotheses) and genome-wide DNA methylation, measured three times from birth to adolescence, using data from a prospective, longitudinal cohort study.
METHODS: We first investigated the relationship between the timing of exposure to childhood adversity between birth and 11 years and blood DNA methylation at age 15 years in the Avon Longitudinal Study of Parents and Children (ALSPAC) prospective cohort study. Our analytic sample included ALSPAC participants with DNA methylation data and complete childhood adversity data between birth and 11 years. We analysed seven types of adversity (caregiver physical or emotional abuse, sexual or physical abuse [by anyone], maternal psychopathology, one-adult households, family instability, financial hardship, and neighbourhood disadvantage) reported by mothers five to eight times between birth and 11 years. We used the structured life course modelling approach (SLCMA) to identify time-varying associations between childhood adversity and adolescent DNA methylation. Top loci were identified using an R 2 threshold of 0·035 (ie, ≥3·5% of DNA methylation variance explained by adversity). We attempted to replicate these associations using data from the Raine Study and Future of Families and Child Wellbeing Study (FFCWS). We also assessed the persistence of adversity-DNA methylation associations we previously identified from age 7 blood DNA methylation into adolescence and the influence of adversity on DNA methylation trajectories from ages 0-15 years.
FINDINGS: Of 13 988 children in the ALSPAC cohort, 609-665 children (311-337 [50-51%] boys and 298-332 [49-50%] girls) had complete data available for at least one of the seven childhood adversities and DNA methylation at 15 years. Exposure to adversity was associated with differences in DNA methylation at 15 years for 41 loci (R 2 ≥0·035). Sensitive periods were the most often selected life course hypothesis by the SLCMA. 20 (49%) of 41 loci were associated with adversities occurring between age 3 and 5 years. Exposure to one-adult households was associated with differences in DNA methylation at 20 [49%] of 41 loci, exposure to financial hardship was associated with changes at nine (22%) loci, and physical or sexual abuse was associated with changes at four (10%) loci. We replicated the direction of associations for 18 (90%) of 20 loci associated with exposure to one-adult household using adolescent blood DNA methylation from the Raine Study and 18 (64%) of 28 loci using saliva DNA methylation from the FFCWS. The directions of effects for 11 one-adult household loci were replicated in both cohorts. Differences in DNA methylation at 15 years were not present at 7 years and differences identified at 7 years were no longer apparent by 15 years. We also identified six distinct DNA methylation trajectories from these patterns of stability and persistence.
INTERPRETATION: These findings highlight the time-varying effect of childhood adversity on DNA methylation profiles across development, which might link exposure to adversity to potential adverse health outcomes in children and adolescents. If replicated, these epigenetic signatures could ultimately serve as biological indicators or early warning signs of initiated disease processes, helping identify people at greater risk for the adverse health consequences of childhood adversity.
FUNDING: Canadian Institutes of Health Research, Cohort and Longitudinal Studies Enhancement Resources, EU's Horizon 2020, US National Institute of Mental Health.
| Original language | English |
|---|---|
| Pages (from-to) | 532-543 |
| Number of pages | 12 |
| Journal | The Lancet Child & Adolescent Health |
| Volume | 7 |
| Issue number | 8 |
| Early online date | 13 Jun 2023 |
| DOIs | |
| Publication status | Published - 31 Aug 2023 |
Bibliographical note
FundingCanadian Institutes of Health Research, Cohort and Longitudinal Studies Enhancement Resources, EU's Horizon 2020, US National Institute of Mental Health.
Funding Information:
This work was supported by the National Institute of Mental Health of the National Institutes of Health (grant number R01MH113930 awarded to ECD). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. ECD and AAL were also supported by a grant from One Mind. AAL is supported by a postdoctoral fellowship from the Canadian Institutes of Health Research (CIHR). EW is funded by CLOSER, which is funded by the Economic and Social Research Council (ESRC) and the Medical Research Council (MRC) between 2012 and 2017. Its initial 5-year grant has since been extended to March 2021 by the ESRC (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. EW is also supported by the EU's Horizon 2020 research and innovation programme (grant number 848158). We are extremely grateful to all the families who took part in the ALSPAC study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, and nurses. The UK MRC and the Wellcome Trust (grant reference 217065/Z/19/Z) and the University of Bristol, Bristol, UK, provide core support for ALSPAC. A comprehensive list of grants funding ALSPAC. is available online. ALSPAC was specifically funded by grants from the Biotechnology and Biological Sciences Research Council (BBI025751/1; BB/I025263/1), Medical Research Council Integrative Epidemiology Unit (MC_UU_00011/5), National Institute of Child and Human Development (R01HD068437), National Institutes of Health (5RO1AI121226-02), and CONTAMED EU (212502). This publication is the work of the authors, who will serve as guarantors for the contents of this paper. We would like to acknowledge the Raine Study participants and their families for their ongoing participation in the study and the Raine Study team for study coordination and data collection. We also thank the National Health and Medical Research Council (NHMRC) for their long-term contribution to funding the study over the past 30 years. The core management of the Raine Study is funded by The University of Western Australia, Curtin University, and Murdoch University, Perth, WA, Australia; Telethon Kids Institute and the Raine Medical Research Foundation, Nedlands, WA, Australia; Women and Infants Research Foundation, Subiaco, WA, Australia; Edith Cowan University, Joondalup, WA, Australia; and The University of Notre Dame Australia, Fremantle, WA and Broome, WA, Australia. The Pawsey Supercomputing Centre, Perth, WA, Australia, provided computation resources to carry out analyses required with funding from the Australian Government and the Government of Western Australia. The Gen2-1, 2, 3, 5, 8, 10-year follow-ups were supported by grants from the NHMRC and The Raine Medical Research Foundation. DNA or GWAS data from the Gen2-17 year follow-up were support by grants from the NHMRC (ID 572613, ID 403981, ID 1059711) and CIHR (MOP-82893). FFCWS was provided by the National Institute of Child Health and Human Development (grants R01HD036916, R01HD039135, and R01HD040421) and by a consortium of private foundations. Epigenetic data generation and processing were funded through grants by the National Institute on Minority Health and Health Disparities (R01MD011716 to CM), the National Institute of Child Health and Human Development (R01HD076592 to DAN), the National Institute of Mental Health (R01MH103761), and the National Heart, Lung, and Blood Institute (R01HL149869 to DAN). Finally, we would also like to thank Garrett Fitzmaurice for his guidance on the characterisation of DNA methylation trajectories across development. We also thank Elizabeth Leblanc for her assistance with the prediction of age at pubertal onset using superimposition by translation and rotation.
Funding Information:
This work was supported by the National Institute of Mental Health of the National Institutes of Health (grant number R01MH113930 awarded to ECD). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. ECD and AAL were also supported by a grant from One Mind. AAL is supported by a postdoctoral fellowship from the Canadian Institutes of Health Research (CIHR). EW is funded by CLOSER, which is funded by the Economic and Social Research Council (ESRC) and the Medical Research Council (MRC) between 2012 and 2017. Its initial 5-year grant has since been extended to March 2021 by the ESRC (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. EW is also supported by the EU's Horizon 2020 research and innovation programme (grant number 848158). We are extremely grateful to all the families who took part in the ALSPAC study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, and nurses. The UK MRC and the Wellcome Trust (grant reference 217065/Z/19/Z) and the University of Bristol, Bristol, UK, provide core support for ALSPAC. A comprehensive list of grants funding ALSPAC . is available online. ALSPAC was specifically funded by grants from the Biotechnology and Biological Sciences Research Council (BBI025751/1; BB/I025263/1), Medical Research Council Integrative Epidemiology Unit (MC_UU_00011/5), National Institute of Child and Human Development (R01HD068437), National Institutes of Health (5RO1AI121226-02), and CONTAMED EU (212502). This publication is the work of the authors, who will serve as guarantors for the contents of this paper. We would like to acknowledge the Raine Study participants and their families for their ongoing participation in the study and the Raine Study team for study coordination and data collection. We also thank the National Health and Medical Research Council (NHMRC) for their long-term contribution to funding the study over the past 30 years. The core management of the Raine Study is funded by The University of Western Australia, Curtin University, and Murdoch University, Perth, WA, Australia; Telethon Kids Institute and the Raine Medical Research Foundation, Nedlands, WA, Australia; Women and Infants Research Foundation, Subiaco, WA, Australia; Edith Cowan University, Joondalup, WA, Australia; and The University of Notre Dame Australia, Fremantle, WA and Broome, WA, Australia. The Pawsey Supercomputing Centre, Perth, WA, Australia, provided computation resources to carry out analyses required with funding from the Australian Government and the Government of Western Australia. The Gen2-1, 2, 3, 5, 8, 10-year follow-ups were supported by grants from the NHMRC and The Raine Medical Research Foundation. DNA or GWAS data from the Gen2-17 year follow-up were support by grants from the NHMRC (ID 572613, ID 403981, ID 1059711) and CIHR (MOP-82893). FFCWS was provided by the National Institute of Child Health and Human Development (grants R01HD036916, R01HD039135, and R01HD040421) and by a consortium of private foundations. Epigenetic data generation and processing were funded through grants by the National Institute on Minority Health and Health Disparities (R01MD011716 to CM), the National Institute of Child Health and Human Development (R01HD076592 to DAN), the National Institute of Mental Health (R01MH103761), and the National Heart, Lung, and Blood Institute (R01HL149869 to DAN). Finally, we would also like to thank Garrett Fitzmaurice for his guidance on the characterisation of DNA methylation trajectories across development. We also thank Elizabeth Leblanc for her assistance with the prediction of age at pubertal onset using superimposition by translation and rotation.
