Individual longitudinal changes in DNA-methylome identify signatures of early-life adversity and correlate with later outcome

IF 4.3 2区 医学 Q1 NEUROSCIENCES
Annabel K. Short , Ryan Weber , Noriko Kamei , Christina Wilcox Thai , Hina Arora , Ali Mortazavi , Hal S. Stern , Laura Glynn , Tallie Z. Baram
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引用次数: 0

Abstract

Adverse early-life experiences (ELA) affect a majority of the world's children. Whereas the enduring impact of ELA on cognitive and emotional health is established, there are no tools to predict vulnerability to ELA consequences in an individual child. Epigenetic markers including peripheral-cell DNA-methylation profiles may encode ELA and provide predictive outcome markers, yet the interindividual variance of the human genome and rapid changes in DNA methylation in childhood pose significant challenges. Hoping to mitigate these challenges we examined the relation of several ELA dimensions to DNA methylation changes and outcome using a within-subject longitudinal design and a high methylation-change threshold.

DNA methylation was analyzed in buccal swab/saliva samples collected twice (neonatally and at 12 months) in 110 infants. We identified CpGs differentially methylated across time for each child and determined whether they associated with ELA indicators and executive function at age 5. We assessed sex differences and derived a sex-dependent ‘impact score’ based on sites that most contributed to methylation changes.

Changes in methylation between two samples of an individual child reflected age-related trends and correlated with executive function years later. Among tested ELA dimensions and life factors including income to needs ratios, maternal sensitivity, body mass index and infant sex, unpredictability of parental and household signals was the strongest predictor of executive function. In girls, high early-life unpredictability interacted with methylation changes to presage executive function. Thus, longitudinal, within-subject changes in methylation profiles may provide a signature of ELA and a potential predictive marker of individual outcome.

DNA-甲基组的个体纵向变化可识别早期生活逆境的特征,并与日后的结果相关联
早期不良生活经历(ELA)影响着世界上大多数儿童。虽然ELA对认知和情绪健康的持久影响已经得到证实,但目前还没有工具可以预测儿童个体易受ELA影响的程度。表观遗传标记(包括外周细胞 DNA 甲基化图谱)可能编码 ELA 并提供预测结果的标记,然而人类基因组的个体间差异和儿童期 DNA 甲基化的快速变化带来了巨大的挑战。为了减轻这些挑战,我们采用受试者内纵向设计和高甲基化变化阈值,研究了ELA的几个维度与DNA甲基化变化和结果的关系。我们确定了每个儿童在不同时期甲基化程度不同的 CpGs,并确定它们是否与 5 岁时的英语语言学习(ELA)指标和执行功能有关。我们评估了性别差异,并根据对甲基化变化贡献最大的位点得出了与性别相关的 "影响得分"。在经过测试的英语语言能力水平维度和生活因素(包括收入与需求比、母亲敏感性、体重指数和婴儿性别)中,父母和家庭信号的不可预测性是预测执行功能的最强因素。在女孩中,早期生活的高度不可预测性与甲基化变化相互作用,预示着执行功能。因此,甲基化特征的纵向、受试者内变化可能是ELA的特征,也是个体结果的潜在预测标志。
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来源期刊
Neurobiology of Stress
Neurobiology of Stress Biochemistry, Genetics and Molecular Biology-Biochemistry
CiteScore
9.40
自引率
4.00%
发文量
74
审稿时长
48 days
期刊介绍: Neurobiology of Stress is a multidisciplinary journal for the publication of original research and review articles on basic, translational and clinical research into stress and related disorders. It will focus on the impact of stress on the brain from cellular to behavioral functions and stress-related neuropsychiatric disorders (such as depression, trauma and anxiety). The translation of basic research findings into real-world applications will be a key aim of the journal. Basic, translational and clinical research on the following topics as they relate to stress will be covered: Molecular substrates and cell signaling, Genetics and epigenetics, Stress circuitry, Structural and physiological plasticity, Developmental Aspects, Laboratory models of stress, Neuroinflammation and pathology, Memory and Cognition, Motivational Processes, Fear and Anxiety, Stress-related neuropsychiatric disorders (including depression, PTSD, substance abuse), Neuropsychopharmacology.
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