Epigenetic age acceleration (EAA), defined as the difference between chronological age and epigenetically predicted age, was calculated from multiple gestational epigenetic clocks (Bohlin, EPIC overlap, and Knight) using DNA methylation levels from cord blood in three large population-based birth cohorts: the Generation R Study (The Netherlands), the Avon Longitudinal Study of Parents and Children (United Kingdom), and the Norwegian Mother, Father and Child Cohort Study (Norway). We hypothesized that a lower EAA associates prospectively with increased ADHD symptoms. We tested our hypotheses in these three cohorts and meta-analyzed the results (n = 3383). We replicated previous research on the association between gestational age (GA) and ADHD. Both clinically measured gestational age as well as epigenetic age measures at birth were negatively associated with ADHD symptoms at ages 5–7 years (clinical GA: β = −0.04, p < 0.001, Bohlin: β = −0.05, p = 0.01; EPIC overlap: β = −0.05, p = 0.01; Knight: β = −0.01, p = 0.26). Raw EAA (difference between clinical and epigenetically estimated gestational age) was positively associated with ADHD in our main model, whereas residual EAA (raw EAA corrected for clinical gestational age) was not associated with ADHD symptoms across cohorts. Overall, findings support a link between lower gestational age (either measured clinically or using epigenetic-derived estimates) and ADHD symptoms. Epigenetic age acceleration does not, however, add unique information about ADHD risk independent of clinically estimated gestational age at birth.

表观遗传年龄加速 (EAA) 定义为实足年龄与表观遗传预测年龄之间的差异，是使用三个基于人口的大型出生队列中脐带血的 DNA 甲基化水平，根据多个妊娠表观遗传时钟（Bohlin、EPIC 重叠和 Knight）计算得出的：R 一代研究（荷兰）、雅芳父母和儿童纵向研究（英国）以及挪威母亲、父亲和儿童队列研究（挪威）。我们假设 EAA 较低与 ADHD 症状增加存在前瞻性相关。我们在这三个队列中测试了我们的假设，并对结果进行了荟萃分析 ( n  = 3383)。我们重复了之前关于胎龄 (GA) 和 ADHD 之间关联的研究。临床测量的胎龄以及出生时的表观遗传年龄测量均与 5-7 岁时的 ADHD 症状呈负相关（临床 GA：β  = -0.04，p  < 0.001，Bohlin：β  = -0.05，p  = 0.01；EPIC重叠：β  = -0.05，p  = 0.01；奈特：β  = -0.01，p  = 0.26）。在我们的主要模型中，原始 EAA（临床胎龄与表观遗传学估计胎龄之间的差异）与 ADHD 呈正相关，而残余 EAA（根据临床胎龄校正的原始 EAA）与队列中的 ADHD 症状无关。总体而言，研究结果支持较低胎龄（通过临床测量或使用表观遗传推算）与 ADHD 症状之间的联系。然而，表观遗传年龄的加速并不会增加关于 ADHD 风险的独特信息，独立于临床估计的出生胎龄。