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.

中文翻译：

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从青春期前到青春期后 DNA 甲基化的变化与青春期暴露有关。

背景青春期是一个以主要生物发育为特征的时期，这可能与DNA甲基化（DNA-M）的变化有关。然而，DNA-M 从青春期前到青春期后变化的程度如何，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如何与 DNA-M 的变化相关，尚不清楚。方法 使用 Illumina Infinium 阵列（450K 和 EPIC）分析怀特岛 (IOW) 出生队列中 325 名受试者（n = 140 名女性）的全血中 10 岁和 18 岁的基因组规模 DNA-M。线性混合模型用于检查青春期前后的 DNA-M 变化以及这些变化是否具有性别特异性。评估青春期相关因素和环境暴露因素与 DNA-M 变化的关联。在可比较的雅芳父母和儿童纵向研究 (ALSPAC) 队列中尝试复制结果。结果 在 IOW 队列中，在控制青春期前和青春期后的技术变异和细胞组成后，15,532 个胞嘧啶-磷酸-鸟嘌呤 (CpG) 位点（400,825 个 CpG，3.88%）显示出与青春期前相比具有统计学意义的 DNA-M 变化。 - 青春期到青春期后，性别不变（错误发现率 (FDR) = 0.05）。在这 15,532 个 CpG 中，10,212 个 CpG (66%) 在 ALSPAC 队列中复制。使用 Ingenuity Pathway Analysis (IPA) 进行的通路分析确定了与生殖系统生长和发育相关的重要生物学通路，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，我们鉴定了 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、非甾体类药物的使用和当前的吸烟状况显示，与 AHRR 基因等 15 个 CpG 的 DNA-M 变化具有统计学显着相关性。对于 10 岁时的 BMI，这种关联具有性别特异性。在 ALSPAC 队列中重复了有关当前吸烟状况的结果。结论 青春期转变与超过 15K CpG 时 DNA-M 的变化有关。已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的表观遗传状态的重要性。目前的吸烟状况与 AHRR 基因等 14 个基因的 15 个 CpG 处的 DNA-M 变化显示出统计学上的显着关联。对于 10 岁时的 BMI，这种关联具有性别特异性。在 ALSPAC 队列中重复了有关当前吸烟状况的结果。结论 青春期转变与超过 15K CpG 时 DNA-M 的变化有关。已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的表观遗传状态的重要性。目前的吸烟状况与 AHRR 基因等 14 个基因的 15 个 CpG 处的 DNA-M 变化显示出统计学上的显着关联。对于 10 岁时的 BMI，这种关联具有性别特异性。在 ALSPAC 队列中重复了有关当前吸烟状况的结果。结论 青春期转变与超过 15K CpG 时 DNA-M 的变化有关。已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的表观遗传状态的重要性。