Psychiatric and Neurodevelopmental Genetics Unit, Centre for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Department of Psychiatry, Harvard Medical School, Harvard University, Boston, MA, USA; Stanley Center for Psychiatric Research, The Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA.
Psychiatric and Neurodevelopmental Genetics Unit, Centre for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Department of Epidemiology, Harvard T H Chan School of Public Health, Harvard University, Boston, MA, USA.
Lancet Child Adolesc Health. 2023 Aug;7(8):532-543. doi: 10.1016/S2352-4642(23)00127-X. Epub 2023 Jun 14.
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.
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 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.
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 ≥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.
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.
Canadian Institutes of Health Research, Cohort and Longitudinal Studies Enhancement Resources, EU's Horizon 2020, US National Institute of Mental Health.
童年逆境是决定整个发育过程中健康的一个重要因素，与改变的 DNA 甲基化特征有关，而这些特征在发育敏感时期暴露于逆境的儿童中可能更为常见。然而，目前尚不清楚逆境是否在儿童期和青春期具有持续的表观遗传关联。我们旨在通过前瞻性纵向队列研究中的数据，使用敏感时期、风险积累和近期生活历程假说，来研究时间变化的逆境（通过出生到 11 岁之间的暴露来定义）与全基因组 DNA 甲基化之间的关系，这些数据来自于前瞻性纵向队列研究。
我们首先在阿冯纵向研究父母与子女（ALSPAC）前瞻性队列研究中，研究了出生到 11 岁之间的童年逆境暴露时间与 15 岁时血液 DNA 甲基化之间的关系。我们的分析样本包括具有 DNA 甲基化数据和出生到 11 岁之间完整的童年逆境数据的 ALSPAC 参与者。我们分析了七种逆境（照顾者的身体或情感虐待、性或身体虐待[由任何人]、母亲的精神病理学、单亲家庭、家庭不稳定、经济困难和邻里劣势），这些逆境在出生到 11 岁之间由母亲报告了五次到八次。我们使用结构生命历程建模方法（SLCMA）来识别儿童逆境和青少年 DNA 甲基化之间的时间变化关联。使用 R 阈值为 0.035（即逆境解释的 DNA 甲基化变异的≥3.5%）来确定顶端基因座。我们使用 Raine 研究和未来家庭和儿童福利研究（FFCWS）的数据来尝试复制这些关联。我们还评估了我们之前从 7 岁时血液 DNA 甲基化中识别出的逆境-DNA 甲基化关联在青春期的持久性，以及逆境对 0-15 岁年龄的 DNA 甲基化轨迹的影响。
在 ALSPAC 队列的 13988 名儿童中，有 609-665 名儿童（311-337[50-51%]名男孩和 298-332[49-50%]名女孩）至少有一项 7 种童年逆境之一和 15 岁时的 DNA 甲基化数据完整。逆境暴露与 15 岁时的 DNA 甲基化差异有关，有 41 个基因座（R≥0.035）。SLCMA 最常选择敏感时期作为生活历程假说。20（49%）个基因座与 3 至 5 岁之间发生的逆境有关。单亲家庭的暴露与 41 个基因座中的 20 个（49%）的 DNA 甲基化差异有关，经济困难的暴露与 9 个（22%）基因座的变化有关，身体或性虐待与 4 个（10%）基因座的变化有关。我们使用 Raine 研究中的青少年血液 DNA 甲基化和 FFCWS 中的唾液 DNA 甲基化，复制了 18（90%）个与单亲家庭暴露有关的基因座的关联方向，以及 28 个基因座中的 18（64%）个基因座的关联方向。在两个队列中，11 个单亲家庭基因座的效应方向都得到了复制。15 岁时的 DNA 甲基化差异不存在于 7 岁时，而在 7 岁时发现的差异在 15 岁时不再明显。我们还从这些稳定和持续的模式中确定了六个不同的 DNA 甲基化轨迹。
这些发现强调了童年逆境对整个发育过程中 DNA 甲基化谱的时间变化影响，这可能将暴露于逆境与儿童和青少年潜在的不良健康结果联系起来。如果得到证实，这些表观遗传特征最终可以作为疾病发生过程的生物指标或早期预警信号，帮助识别处于童年逆境不良健康后果风险更高的人群。
加拿大卫生研究院、队列和纵向研究增强资源、欧盟地平线 2020、美国国家心理健康研究所。
