Abstract
Background
Exposure to early-life adversity is known to predict DNA methylation (DNAm) patterns
that may be related to psychiatric risk. However, few studies have investigated whether
adversity has time-dependent effects based on the age at exposure.
Methods
Using a two-stage structured life course modeling approach, we tested the hypothesis
that there are sensitive periods when adversity induces greater DNAm changes. We tested
this hypothesis in relation to two alternatives: an accumulation hypothesis, in which
the effect of adversity increases with the number of occasions exposed, regardless
of timing; and a recency model, in which the effect of adversity is stronger for more
proximal events. Data came from the Accessible Resource for Integrated Epigenomic
Studies, a subsample of mother–child pairs from the Avon Longitudinal Study of Parents
and Children (n = 691–774).
Results
After covariate adjustment and multiple testing correction, we identified 38 CpG sites
that were differentially methylated at 7 years of age following exposure to adversity.
Most loci (n = 35) were predicted by the timing of adversity, namely exposures before 3 years
of age. Neither the accumulation nor recency of the adversity explained considerable
variability in DNAm. A standard epigenome-wide association study of lifetime exposure
(vs. no exposure) failed to detect these associations.
Conclusions
The developmental timing of adversity explains more variability in DNAm than the accumulation
or recency of exposure. Very early childhood appears to be a sensitive period when
exposure to adversity predicts differential DNAm patterns. Classification of individuals
as exposed versus unexposed to early-life adversity may dilute observed effects.
Keywords
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References
- Effects of poverty on children.Future Child. 1997; 7: 55-71
- Cumulative adversity in childhood and emergent risk factors for long-term health.J Pediatr. 2014; 164: 631-638
- Child abuse and neglect: Potential derailment from normal developmental pathways.NYS Psychologist. 2007; 19: 2-6
- Family disruption in childhood and risk of adult depression.Am J Psychiatry. 2003; 160: 939-946
- Risky families: Family social environments and the mental and physical health of offspring.Psychol Bull. 2002; 128: 330-366
- Stress and depression.Annu Rev Clin Psychol. 2005; 1: 293-319
- The effects of stressful life events on depression.Annu Rev Psychol. 1997; 48: 191-214
- Childhood social environment, emotional reactivity to stress, and mood and anxiety disorders across the life course.Depress Anxiety. 2010; 27: 1087-1094
- Childhood adversities and first onset of psychiatric disorders in a national sample of US adolescents.JAMA Psychiatry. 2012; 69: 1151-1160
- The long-term health consequences of child physical abuse, emotional abuse, and neglect: A systematic review and meta-analysis.PLoS Med. 2012; 9: e1001349
- Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions.Nat Neurosci. 2013; 16: 33-41
- Early-life stress interactions with the epigenome: Potential mechanisms driving vulnerability toward psychiatric illness.Behav Pharmacol. 2014; 25: 341-351
- Epigenetic signaling in psychiatric disorders: Stress and depression.Dialogues Clin Neurosci. 2014; 16: 281-295
- DNA methylation: A mechanism for embedding early life experiences in the genome.Child Dev. 2013; 84: 49-57
- The interaction between stressful life events and leukocyte telomere length is associated with PTSD.Mol Psychiatry. 2014; 19: 855-856
- Epigenetic vestiges of early developmental adversity: Childhood stress exposure and DNA methylation in adolescence.Child Dev. 2013; 84: 58-75
- Child abuse and epigenetic mechanisms of disease risk.Am J Prev Med. 2013; 44: 101-107
- Annual research review: DNA methylation as a mediator in the association between risk exposure and child and adolescent psychopathology.J Child Psychol Psychiatry. 2017; 59: 303-322
- Sensitive periods in development: Structural characteristics and causal interpretations.Psychol Bull. 1989; 105: 179-197
- Sensitive periods in the development of the brain and behavior.J Cogn Neurosci. 2004; 16: 1412-1425
- Influence of maternal care on the developing brain: Mechanisms, temporal dynamics and sensitive periods.Front Neuroendocrinol. 2016; 40: 52-66
- Timing is everything: The when and how of environmentally induced changes in the epigenome of animals.Epigenetics. 2011; 6: 791-797
- Epigenetic reprogramming in mammals.Hum Mol Genet. 2005; 14: R47-R58
- Developmental timing of the effects of maternal care on gene expression and epigenetic regulation of hormone receptor levels in female rats.Endocrinology. 2013; 154: 4340-4351
- Early life stress confers lifelong stress susceptibility in mice via ventral tegmental area OTX2.Science. 2017; 356: 1185-1188
- Early life adversity alters normal sex-dependent developmental dynamics of DNA methylation.Dev Psychopathol. 2016; 28: 1259-1272
- Adverse life events and allele-specific methylation of the serotonin transporter gene (SLC6A4) in adolescents: The TRAILS study.Psychosom Med. 2015; 77: 246-255
- Methylation of NR3C1 and SLC6A4 and internalizing problems. The TRAILS study.J Affect Disord. 2015; 180: 97-103
- DNA methylation at stress-related genes is associated with exposure to early life institutionalization.Am J Phys Anthropol. 2016; 161: 84-93
- Associations with early-life socio-economic position in adult DNA methylation.Int J Epidemiol. 2012; 41: 62-74
- Differential DNA methylation in peripheral blood mononuclear cells in adolescents exposed to significant early but not later childhood adversity.Dev Psychopathol. 2016; 28: 1385-1399
- Analysis of DNA methylation in young people: Limited evidence for an association between victimization stress and epigenetic variation in blood.Am J Psychiatry. 2018; 175: 517-529
- Model selection of the effect of binary exposures over the life course.Epidemiology. 2015; 26: 719-726
- A structured approach to modelling the effects of binary exposure variables over the life course.Int J Epidemiol. 2009; 38: 528-537
- The last two decades of life course epidemiology and its relevance for research on ageing.Int J Epidemiol. 2016; 45: 973-988
- A Life Course Approach to Chronic Disease Epidemiology.Oxford University Press, Oxford, UK2004
- A life course approach to chronic disease epidemiology: Conceptual models, empirical challenges, and interdisciplinary perspectives.Int J Epidemiol. 2002; 31: 285-293
- Dialectical Processes in Developmental Psychopathology.in: Sameroff A.J. Lewis M. Miller S.M. Handbook of Developmental Psychopathology. Springer US, Boston, MA2000: 23-40
- Cumulative risk and child development.Psychol Bull. 2013; 139: 342-396
- Protective factors in children's responses to stress and disadvantage.Ann Acad Med Singapore. 1979; 8: 324-338
- Child-, adolescent- and young adult-onset depressions: Differential risk factors in development?.Psychol Med. 2011; 41: 2265-2274
- Cohort profile: The ‘children of the 90s’—the index offspring of the Avon Longitudinal Study of Parents and Children.Int J Epidemiol. 2012; 42: 111-127
- ALSPAC: The Avon Longitudinal Study of Parents and Children I. Study methodology.Paediatr Perinat Epidemiol. 2001; 15: 74-87
- Cohort profile: The Avon Longitudinal Study of Parents and Children: ALSPAC mothers cohort.Int J Epidemiol. 2013; 42: 97-110
- Data resource profile: Accessible Resource for Integrated Epigenomic Studies (ARIES).Int J Epidemiol. 2015; 44: 1181-1190
- The epigenetic impacts of social stress: How does social adversity become biologically embedded?.Epigenomics. 2016; 8: 1653-1669
- Early-life adversity and long-term neurobehavioral outcomes: Epigenome as a bridge?.Hum Genomics. 2017; 11: 34
- Biological embedding of psychosocial stress over the life course.in: Moskalev A. Vaiserman A.M. Epigenetics of Aging and Longevity. Academic Press, Cambridge, MA2018: 251-270
- Epigenetic alterations associated with war trauma and childhood maltreatment.Behav Sci Law. 2015; 33: 701-721
- SLC6A4 methylation as an epigenetic marker of life adversity exposures in humans: A systematic review of literature.Neurosci Biobehav Rev. 2016; 71: 7-20
- Childhood adversity and epigenetic regulation of glucocorticoid signaling genes: Associations in children and adults.Dev Psychopathol. 2016; 28: 1319-1331
- Epigenetics and gene expression profile in first-episode psychosis: The role of childhood trauma.Neurosci Biobehav Rev. 2017; 83: 226-237
- Perinatal maternal mental health, fetal programming and child development.Healthcare (Basel). 2015; 3: 1212-1227
- Early origins of mental disorder-risk factors in the perinatal and infant period.BMC Psychiatry. 2016; 16: 270
- Parenting, SES-risk, and later young adult health: Exploration of opposing indirect effects via DNA methylation.Child Dev. 2016; 87: 111-121
- Differential patterns of whole-genome DNA methylation in institutionalized children and children raised by their biological parents.Dev Psychopathol. 2012; 24: 143-155
- Adolescent depression linked to socioeconomic status? Molecular approaches for revealing premorbid risk factors.Bioessays. 2017; 39
- Social factors and leukocyte DNA methylation of repetitive sequences: The multi-ethnic study of atherosclerosis.PLoS One. 2013; 8: e54018
- Exposure to violence accelerates epigenetic aging in children.Sci Rep. 2017; 7: 8962
- Future directions in childhood adversity and youth psychopathology.J Clin Child Adolesc Psychol. 2016; 45: 361-382
- A new human genetic resource: A human DNA bank established as part of the Avon Longitudinal Study of Pregnancy and Childhood (ALSPAC).Eur J Hum Genet. 2000; 8: 653-660
- A comparison of feature selection and classification methods in DNA methylation studies using the Illumina Infinium platform.BMC Bioinformatics. 2012; 13: 59
- Complete pipeline for Infinium® Human Methylation 450K BeadChip data processing using subset quantile normalization for accurate DNA methylation estimation.Epigenomics. 2012; 4: 325-341
- Reference-free cell mixture adjustments in analysis of DNA methylation data.Bioinformatics. 2014; 30: 1431-1439
- The future of data analysis.Ann Math Statist. 1962; 33: 1-67
- Prenatal exposure to maternal smoking and offspring DNA methylation across the lifecourse: Findings from the Avon Longitudinal Study of Parents and Children (ALSPAC).Hum Mol Genet. 2015; 24: 2201-2217
- A structured approach to hypotheses involving continuous exposures over the life course.Int J Epidemiol. 2016; 45: 1271-1279
- Least angle regression.Ann Stat. 2004; 32: 407-499
- A significance test for the LASSO.Ann Stat. 2014; 42: 413-468
- Socio-economic disadvantage from childhood to adulthood and locomotor function in old age: A lifecourse analysis of the Boyd Orr and Caerphilly prospective studies.J Epidemiol Community Health. 2011; 65: 1014-1023
- Life course models of socioeconomic position and cardiovascular risk factors: 1946 birth cohort.Ann Epidemiol. 2011; 21: 589-597
- Maternal and childhood psychological factors predict chronic disabling fatigue at age 13 years.J Adolesc Health. 2015; 56: 181-187
- The timing of maternal depressive symptoms and child cognitive development: A longitudinal study.J Child Psychol Psychiatry. 2012; 53: 632-640
- Interindividual methylomic variation across blood, cortex, and cerebellum: Implications for epigenetic studies of neurological and neuropsychiatric phenotypes.Epigenetics. 2015; 10: 1024-1032
- Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources.Nat Protoc. 2008; 4: 44-57
- Analysis of protein-coding genetic variation in 60,706 humans.Nature. 2016; 536: 285-291
- Systematic identification of genetic influences on methylation across the human life course.Genome Biol. 2016; 17: 61
- EFORGE: A tool for identifying cell type-specific signal in epigenomic data.Cell Rep. 2016; 17: 2137-2150
- Longitudinal analysis of DNA methylation associated with birth weight and gestational age.Hum Mol Genet. 2015; 24: 3752-3763
- The impact of exposure to domestic violence on children and young people: A review of the literature.Child Abuse Negl. 2008; 32: 797-810
- Children exposed to domestic violence and child abuse: Terminology and taxonomy.Clin Child Fam Psychol Rev. 2003; 6: 151-160
- Violence exposure and traumatic stress symptoms as additional predictors of health problems in high-risk children.J Pediatr. 2005; 146: 349-354
- Burden and consequences of child maltreatment in high-income countries.Lancet. 2009; 373: 68-81
- DNA extracted from saliva for methylation studies of psychiatric traits: Evidence tissue specificity and relatedness to brain.Am J Med Genet B Neuropsychiatr Genet. 2015; 168B: 36-44
- Exact post-selection inference for sequential regression procedures.J Am Stat Assoc. 2016; 111: 600-620
- Reducing the risk of false discovery enabling identification of biologically significant genome-wide methylation status using the HumanMethylation450 array.BMC Genomics. 2014; 15: 51
- Discovery of cross-reactive probes and polymorphic CpGs in the Illumina Infinium HumanMethylation450 microarray.Epigenetics. 2013; 8: 203-209
Article Info
Publication History
Published online: January 21, 2019
Accepted:
December 16,
2018
Received in revised form:
December 4,
2018
Received:
February 28,
2018
Identification
Copyright
© 2019 Published by Elsevier Inc on behalf of Society of Biological Psychiatry.
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- Do Sensitive Periods Exist for Exposure to Adversity?Biological PsychiatryVol. 85Issue 10
- PreviewEarly environmental experiences exert a profound influence on brain development, with lasting effects on emotion, cognition, and behavior throughout the lifespan. However, knowledge of how environmental experiences become embedded biologically to shape neurocognitive development in humans remains remarkably limited. In this issue of Biological Psychiatry, Dunn et al. (1) test several accounts of how adversity influences peripheral DNA methylation patterns from birth through middle childhood. This work is innovative in empirically evaluating different conceptual models of adversity effects with longitudinal data on multiple forms of adversity.
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- ErratumBiological PsychiatryVol. 86Issue 1
