青春期前到青春期后的 DNA 甲基化变化与青春期暴露有关。
Changes in DNA methylation from pre- to post-adolescence are associated with pubertal exposures.
机构信息
Department of Mathematical Sciences, University of Memphis, Memphis, TN, 38152, USA.
Division of Epidemiology, Biostatistics, and Environmental Health, University of Memphis, Memphis, TN, 38152, USA.
出版信息
Clin Epigenetics. 2019 Dec 2;11(1):176. doi: 10.1186/s13148-019-0780-4.
BACKGROUND
Adolescence is a period characterized by major biological development, which may be associated with changes in DNA methylation (DNA-M). However, it is unknown to what extent DNA-M varies from pre- to post-adolescence, whether the pattern of changes is different between females and males, and how adolescence-related factors are associated with changes in DNA-M.
METHODS
Genome-scale DNA-M at ages 10 and 18 years in whole blood of 325 subjects (n = 140 females) in the Isle of Wight (IOW) birth cohort was analyzed using Illumina Infinium arrays (450K and EPIC). Linear mixed models were used to examine DNA-M changes between pre- and post-adolescence and whether the changes were gender-specific. Adolescence-related factors and environmental exposure factors were assessed on their association with DNA-M changes. Replication of findings was attempted in the comparable Avon Longitudinal Study of Parents and Children (ALSPAC) cohort.
RESULTS
In the IOW cohort, after controlling for technical variation and cell compositions at both pre- and post-adolescence, 15,532 cytosine-phosphate-guanine (CpG) sites (of 400,825 CpGs, 3.88%) showed statistically significant DNA-M changes from pre-adolescence to post-adolescence invariant to gender (false discovery rate (FDR) = 0.05). Of these 15,532 CpGs, 10,212 CpGs (66%) were replicated in the ALSPAC cohort. Pathway analysis using Ingenuity Pathway Analysis (IPA) identified significant biological pathways related to growth and development of the reproductive system, emphasizing the importance of this period of transition on epigenetic state of genes. In addition, in IOW, we identified 1179 CpGs with gender-specific DNA-M changes. In the IOW cohort, body mass index (BMI) at age 10 years, age of growth spurt, nonsteroidal drugs use, and current smoking status showed statistically significant associations with DNA-M changes at 15 CpGs on 14 genes such as the AHRR gene. For BMI at age 10 years, the association was gender-specific. Findings on current smoking status were replicated in the ALSPAC cohort.
CONCLUSION
Adolescent transition is associated with changes in DNA-M at more than 15K CpGs. Identified pathways emphasize the importance of this period of transition on epigenetic state of genes relevant to cell growth and immune system development.
背景
青春期是一个以主要生物学发育为特征的时期，这可能与 DNA 甲基化（DNA-M）的变化有关。然而，目前尚不清楚 DNA-M 从青春期前到青春期后的变化程度，女性和男性之间的变化模式是否不同，以及青春期相关因素与 DNA-M 的变化有何关联。
方法
在伊斯特本（IOW）出生队列中，325 名受试者（女性 140 名）在 10 岁和 18 岁时使用 Illumina Infinium 阵列（450K 和 EPIC）对全血中的基因组规模 DNA-M 进行了分析。线性混合模型用于研究青春期前和青春期后 DNA-M 的变化，以及这些变化是否具有性别特异性。还评估了青春期相关因素和环境暴露因素与 DNA-M 变化的相关性。在可比的阿冯纵向研究父母和孩子（ALSPAC）队列中尝试了发现的复制。
结果
在 IOW 队列中，在控制了青春期前和青春期后的技术变化和细胞组成后，有 15532 个胞嘧啶-磷酸-鸟嘌呤（CpG）位点（在 400825 个 CpG 中，占 3.88%）显示出从青春期前到青春期后一致的性别特异性 DNA-M 变化（假发现率（FDR）= 0.05）。在这 15532 个 CpG 中，有 10212 个 CpG（66%）在 ALSPAC 队列中得到了复制。使用Ingenuity Pathway Analysis（IPA）进行的途径分析确定了与生殖系统生长和发育相关的重要生物学途径，强调了这一过渡时期对基因表观遗传状态的重要性。此外，在 IOW 中，我们确定了 1179 个具有性别特异性 DNA-M 变化的 CpG。在 IOW 队列中，10 岁时的体重指数（BMI）、生长突增年龄、非甾体类药物使用和当前吸烟状况与 14 个基因（如 AHRR 基因）的 15 个 CpG 上的 DNA-M 变化有统计学显著关联。对于 10 岁时的 BMI，这种关联具有性别特异性。关于当前吸烟状况的发现在 ALSPAC 队列中得到了复制。
结论
青春期过渡与超过 15K CpG 的 DNA-M 变化有关。确定的途径强调了这一过渡时期对与细胞生长和免疫系统发育相关的基因表观遗传状态的重要性。
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