Meijer Mandy, Klein Marieke, Caramaschi Doretta, Clark Shaunna L, Cosin-Tomas Marta, Koen Nastassja, Lu Xueling, Mulder Rosa H, Röder Stefan W, Zhang Yining, Zilich Lea, Bustamente Mariona, Deuschle Michael, Felix Janine F, González Juan Ramos, Gražulevičiene Regina, Streit Fabian, Wright John, Carracedo Angel, Cecil Charlotte A M, Corpeleijn Eva, Hartman Catharina A, Herberth Gunda, Huels Anke, Relton Caroline, Snieder Harold, Stein Dan J, Sunyer Jordi, Witt Stephanie H, Zar Heather J, Zenclussen Ana C, Franke Barbara, Copeland William, Aberg Karolina A, van den Oord Edwin J C G
Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, The Netherlands.
Faculty of Health and Life Science, Psychology, Unviersity of Exeter, Exeter, UK.
medRxiv. 2025 Apr 17:2025.04.16.25325956. doi: 10.1101/2025.04.16.25325956.
Studying DNA methylation (DNAm) can provide insights into gene-regulatory mechanisms underlying attention-deficit/hyperactivity disorder (ADHD). While most DNAm studies were performed in bulk tissue, this study used statistical deconvolution to identify cell type-specific DNAm profiles, from five major blood cell types, associated with childhood ADHD symptoms.
We performed meta-analyses of methylome-wide association studies (MWAS) for ADHD symptoms (age=4-16 years) in peripheral blood collected during childhood and in cord blood. The investigated cohorts included seven array-based methylation datasets assaying up to 450K CpGs from the Pregnancy And Childhood Epigenetics Consortium (N=2 934 peripheral blood; N=2 546 cord blood) and a sequencing-based methylation dataset assaying nearly all 28 million CpGs in blood from the Great Smoky Mountain Study (GSMS; N=583).
The meta-analyses resulted in methylome-wide significant (FDR<0.05) ADHD associations in CD8T cells ( and for peripheral blood, and, in cord blood, in monocytes (), CD8T cells ( and ), and NK cells (). Notably, several significant sites detected in peripheral blood ( and ) were also detected in cord blood. Furthermore, extended MWAS of all sites available for GSMS detected 69 and 17 additional CpGs in monocytes and granulocytes, respectively. In this first cell type-specific MWAS for ADHD, we identified DNAm associations for ADHD symptoms; some associations were seen in both peripheral blood and cord blood, suggesting potential susceptibility markers for increased ADHD risk.
These findings show that cell type-specific analyses and sequencing-based approaches can increase insights into the epigenetic patterns associated with ADHD symptoms in childhood.
研究DNA甲基化（DNAm）有助于深入了解注意力缺陷多动障碍（ADHD）潜在的基因调控机制。虽然大多数DNAm研究是在大块组织中进行的，但本研究使用统计反卷积方法从五种主要血细胞类型中识别与儿童ADHD症状相关的细胞类型特异性DNAm谱。
我们对儿童期采集的外周血和脐带血中ADHD症状（年龄4至16岁）的全基因组甲基化关联研究（MWAS）进行了荟萃分析。所研究的队列包括七个基于阵列的甲基化数据集，这些数据集检测了来自妊娠与儿童表观遗传学联盟的多达45万个CpG位点（外周血N = 2934；脐带血N = 2546），以及一个基于测序的甲基化数据集，该数据集检测了大烟山研究（GSMS；N = 583）血液中几乎所有的2800万个CpG位点。
荟萃分析在CD8T细胞中发现了全基因组显著（FDR<0.05）的ADHD关联（外周血中为 和 ，脐带血中，在单核细胞（）、CD8T细胞（ 和 ）和自然杀伤细胞（）中也有发现。值得注意的是，在外周血中检测到的几个显著位点（ 和 ）在脐带血中也被检测到。此外，对GSMS所有可用位点进行的扩展MWAS分别在单核细胞和粒细胞中检测到另外69个和17个CpG位点。在这项首个针对ADHD的细胞类型特异性MWAS中，我们确定了与ADHD症状相关的DNAm关联；外周血和脐带血中均发现了一些关联，提示可能存在ADHD风险增加的潜在易感性标志物。
这些发现表明，细胞类型特异性分析和基于测序的方法可以增进对儿童期与ADHD症状相关的表观遗传模式的理解。
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