DNA甲基化与青少年期行为问题、灰质体积及负面生活事件的关联：来自纵向IMAGEN研究的证据
Associations of DNA Methylation With Behavioral Problems, Gray Matter Volumes, and Negative Life Events Across Adolescence: Evidence From the Longitudinal IMAGEN Study.
作者信息
Sun Yan, Jia Tianye, Barker Edward D, Chen Di, Zhang Zuo, Xu Jiayuan, Chang Suhua, Zhou Guangdong, Liu Yun, Tay Nicole, Luo Qiang, Chang Xiao, Banaschewski Tobias, Bokde Arun L W, Flor Herta, Grigis Antoine, Garavan Hugh, Heinz Andreas, Martinot Jean-Luc, Paillère Martinot Marie-Laure, Artiges Eric, Nees Frauke, Orfanos Dimitri Papadopoulos, Paus Tomáš, Poustka Luise, Hohmann Sarah, Millenet Sabina, Fröhner Juliane H, Smolka Michael N, Walter Henrik, Whelan Robert, Lu Lin, Shi Jie, Schumann Gunter, Desrivières Sylvane
机构信息
National Institute on Drug Dependence, Peking University Hospital, Beijing, China; Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom.
Institute of Science and Technology for Brain-Inspired Intelligence, Ministry of Education-Key Laboratory of Computational Neuroscience and Brain-Inspired Intelligence and Research and Research Institute of Intelligent Complex Systems, Fudan University, Shanghai, China; Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom.
出版信息
Biol Psychiatry. 2023 Feb 15;93(4):342-351. doi: 10.1016/j.biopsych.2022.06.012. Epub 2022 Jun 22.
BACKGROUND
Negative life events (NLEs) increase the risk for externalizing behaviors (EBs) and internalizing behaviors (IBs) in adolescence and adult psychopathology. DNA methylation associated with behavioral problems may reflect this risk and long-lasting effects of NLEs.
METHODS
To identify consistent associations between blood DNA methylation and EBs or IBs across adolescence, we conducted longitudinal epigenome-wide association studies (EWASs) using data from the IMAGEN cohort, collected at ages 14 and 19 years (n = 506). Significant findings were validated in a separate subsample (n = 823). Methylation risk scores were generated by 10-fold cross-validation and further tested for their associations with gray matter volumes and NLEs.
RESULTS
No significant findings were obtained for the IB-EWAS. The EB-EWAS identified a genome-wide significant locus in a gene linked to attention-deficit/hyperactivity disorder (ADHD) (IQSEC1, cg01460382; p = 1.26 × 10). Other most significant CpG sites were near ADHD-related genes and enriched for genes regulating tumor necrosis factor and interferon-γ signaling, highlighting the relevance of EB-EWAS findings for ADHD. Analyses with the EB methylation risk scores suggested that it partly reflected comorbidity with IBs in late adolescence. Specific to EBs, EB methylation risk scores correlated with smaller gray matter volumes in medial orbitofrontal and anterior/middle cingulate cortices, brain regions known to associate with ADHD and conduct problems. Longitudinal mediation analyses indicated that EB-related DNA methylation were more likely the outcomes of problematic behaviors accentuated by NLEs, and less likely the epigenetic bases of such behaviors.
CONCLUSIONS
Our findings suggest that novel epigenetic mechanisms through which NLEs exert short and longer-term effects on behavior may contribute to ADHD.
背景
负面生活事件（NLEs）会增加青少年和成人精神病理学中出现外化行为（EBs）和内化行为（IBs）的风险。与行为问题相关的DNA甲基化可能反映了这种风险以及NLEs的长期影响。
方法
为了确定青少年时期血液DNA甲基化与EBs或IBs之间的一致性关联，我们使用来自IMAGEN队列的数据进行了纵向全基因组关联研究（EWASs），这些数据是在14岁和19岁时收集的（n = 506）。在一个单独的子样本（n = 823）中对显著发现进行了验证。通过10倍交叉验证生成甲基化风险评分，并进一步测试其与灰质体积和NLEs的关联。
结果
IB-EWAS未获得显著发现。EB-EWAS在一个与注意力缺陷多动障碍（ADHD）相关的基因中确定了一个全基因组显著位点（IQSEC1，cg01460382；p = 1.26 × 10）。其他最显著的CpG位点靠近与ADHD相关的基因，并富含调节肿瘤坏死因子和干扰素-γ信号传导的基因，突出了EB-EWAS发现与ADHD的相关性。对EB甲基化风险评分的分析表明，它部分反映了青春期后期与IBs的共病情况。特定于EBs，EB甲基化风险评分与内侧眶额皮质和前/中扣带回皮质中较小的灰质体积相关，这些脑区已知与ADHD和行为问题有关。纵向中介分析表明，与EB相关的DNA甲基化更可能是由NLEs加剧的问题行为的结果，而不太可能是此类行为的表观遗传基础。
结论
我们的研究结果表明，NLEs对行为产生短期和长期影响的新表观遗传机制可能导致ADHD。
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