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Combined effects of genotype and childhood adversity shape variability of DNA methylation across age.

ABSTRACT: Lasting effects of adversity, such as exposure to childhood adversity (CA) on disease risk, may be embedded via epigenetic mechanisms but findings from human studies investigating the main effects of such exposure on epigenetic measures, including DNA methylation (DNAm), are inconsistent. Studies in perinatal tissues indicate that variability of DNAm at birth is best explained by the joint effects of genotype and prenatal environment. Here, we extend these analyses to postnatal stressors. We investigated the contribution of CA, cis genotype (G), and their additive (G?+?CA) and interactive (G?×?CA) effects to DNAm variability in blood or saliva from five independent cohorts with a total sample size of 1074 ranging in age from childhood to late adulthood. Of these, 541 were exposed to CA, which was assessed retrospectively using self-reports or verified through social services and registries. For the majority of sites (over 50%) in the adult cohorts, variability in DNAm was best explained by G?+?CA or G?×?CA but almost never by CA alone. Across ages and tissues, 1672 DNAm sites showed consistency of the best model in all five cohorts, with G?×?CA interactions explaining most variance. The consistent G?×?CA sites mapped to genes enriched in brain-specific transcripts and Gene Ontology terms related to development and synaptic function. Interaction of CA with genotypes showed the strongest contribution to DNAm variability, with stable effects across cohorts in functionally relevant genes. This underscores the importance of including genotype in studies investigating the impact of environmental factors on epigenetic marks.

SUBMITTER: Czamara D

PROVIDER: S-EPMC7851167 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Combined effects of genotype and childhood adversity shape variability of DNA methylation across age.

Czamara Darina D Tissink Elleke E Tuhkanen Johanna J Martins Jade J Awaloff Yvonne Y Drake Amanda J AJ Khulan Batbayar B Palotie Aarno A Winter Sibylle M SM Nemeroff Charles B CB Craighead W Edward WE Dunlop Boadie W BW Mayberg Helen S HS Kinkead Becky B Mathew Sanjay J SJ Iosifescu Dan V DV Neylan Thomas C TC Heim Christine M CM Lahti Jari J Eriksson Johan G JG Räikkönen Katri K Ressler Kerry J KJ Provençal Nadine N Binder Elisabeth B EB

Translational psychiatry 20210201 1

Lasting effects of adversity, such as exposure to childhood adversity (CA) on disease risk, may be embedded via epigenetic mechanisms but findings from human studies investigating the main effects of such exposure on epigenetic measures, including DNA methylation (DNAm), are inconsistent. Studies in perinatal tissues indicate that variability of DNAm at birth is best explained by the joint effects of genotype and prenatal environment. Here, we extend these analyses to postnatal stressors. We inv ...[more]

PMID: 33526782

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Project description:BackgroundIn the first study of its kind, we examine the association between growth and development in early life and DNAm age biomarkers in mid-life.MethodsParticipants were from the Medical Research Council National Survey of Health and Development (n = 1376). Four DNAm age acceleration (AgeAccel) biomarkers were measured when participants were aged 53 years: AgeAccelHannum; AgeAccelHorvath; AgeAccelLevine; and AgeAccelGrim. Exposure variables included: relative weight gain (standardised residuals from models of current weight z-score on current height, and previous weight and height z-scores); and linear growth (standardised residuals from models of current height z-score on previous height and weight z-scores) during infancy (0-2 years, weight gain only), early childhood (2-4 years), middle childhood (4-7 years) and late childhood to adolescence (7-15 years); age at menarche; and pubertal stage for men at 14-15 years. The relationship between relative weight gain and linear growth and AgeAccel was investigated using conditional growth models. We replicated analyses from the late childhood to adolescence period and pubertal timing among 240 participants from The National Child and Development Study (NCDS).ResultsA 1SD increase in relative weight gain in late childhood to adolescence was associated with 0.50 years (95% CI 0.20, 0.79) higher AgeAccelGrim. Although the CI includes the null, the estimate was similar in NCDS [0.57 years (95% CI - 0.01, 1.16)] There was no strong evidence that relative weight gain and linear growth in childhood was associated with any other AgeAccel biomarker. There was no relationship between pubertal timing in men and AgeAccel biomarkers. Women who reached menarche ≥ 12 years had 1.20 years (95% CI 0.15, 2.24) higher AgeAccelGrim on average than women who reached menarche < 12 years; however, this was not replicated in NCDS and was not statistically significant after Bonferroni correction.ConclusionsOur findings generally do not support an association between growth and AgeAccel biomarkers in mid-life. However, we found rapid weight gain during pubertal development, previously related to higher cardiovascular disease risk, to be associated with older AgeAccelGrim. Given this is an exploratory study, this finding requires replication.

Dataset Information

Combined effects of genotype and childhood adversity shape variability of DNA methylation across age.

Publications

Combined effects of genotype and childhood adversity shape variability of DNA methylation across age.

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