Common DNA methylation alterations in multiple brain regions in autism.
Common DNA methylation alterations in multiple brain regions in autism.
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DOI：
10.1038/mp.2013.114
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发表时间：
2014-08
影响因子：
11
通讯作者：
Feinberg, A. P.
中科院分区：
文献类型：
--
作者：
Ladd-Acosta, C.;Hansen, K. D.;Briem, E.;Fallin, M. D.;Kaufmann, W. E.;Feinberg, A. P.
自闭症谱系障碍（ASD）是临床上越来越常见的神经发育障碍，其特征包括社交互动障碍、社交情境中的沟通障碍以及行为和兴趣的受限和重复模式，个体之间具有相当大的表型异质性。虽然ASD的遗传率估计值很高，但传统的基于遗传学的努力来识别ASD中涉及的基因，只产生了很少的可重复的候选基因，这些基因只占ASD的一小部分。越来越多的证据表明，环境和表观遗传因素在ASD的病因学中起着比以前认为的更重要的作用。为了开始了解表观遗传学对ASD的贡献，我们在一项对19例自闭症患者和21例无关对照的死后脑组织进行的初步研究中检测了DNA甲基化（DNAm），其中包括背外侧前额叶皮层、颞叶皮层和小脑。我们使用Infinium HumanMethylation 450 BeadChip测量了不同功能相关基因组区域的485，000多个CpG位点，并使用新的bumphunting方法和基于置换的多重检验校正方法鉴定了4个全基因组显著差异甲基化区域（DMR）。我们在一组不同的样本和不同的大脑区域中复制了在我们的全基因组筛选中确定的3/4 DMR。本研究中鉴定的DMR代表了ASD中常见甲基化位点改变的暗示性证据，并提供了几个有希望的新候选基因。
Autism spectrum disorders (ASD) are increasingly common neurodevelopmental disorders defined clinically by a triad of features including impairment in social interaction, impairment in communication in social situations, and restricted and repetitive patterns of behavior and interests, with considerable phenotypic heterogeneity among individuals. Although heritability estimates for ASD are high, conventional genetic-based efforts to identify genes involved in ASD have yielded only few reproducible candidate genes that account for only a small proportion of ASDs. There is mounting evidence to suggest environmental and epigenetic factors play a stronger role in the etiology of ASD than previously thought. To begin to understand the contribution of epigenetics to ASD, we have examined DNA methylation (DNAm) in a pilot study of post-mortem brain tissue from 19 autism cases and 21 unrelated controls, among three brain regions including dorsolateral prefrontal cortex, temporal cortex, and cerebellum. We measured over 485,000 CpG loci across a diverse set of functionally relevant genomic regions using the Infinium HumanMethylation450 BeadChip and identified 4 genome-wide significant differentially methylated regions (DMRs) using a novel bumphunting approach and a permutation-based multiple testing correction method. We replicated 3/4 DMRs identified in our genome-wide screen in a different set of samples and across different brain regions. The DMRs identified in this study represent suggestive evidence for commonly altered methylation sites in ASD and provide several promising new candidate genes.
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