Case-control meta-analysis of blood DNA methylation and autism spectrum disorder.
Case-control meta-analysis of blood DNA methylation and autism spectrum disorder.
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血液DNA甲基化和自闭症谱系障碍的病例对照荟萃分析。
DOI：
10.1186/s13229-018-0224-6
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发表时间：
2018
期刊：
影响因子：
6.2
通讯作者：
Ladd-Acosta C
中科院分区：
文献类型：
--
作者：
Andrews SV;Sheppard B;Windham GC;Schieve LA;Schendel DE;Croen LA;Chopra P;Alisch RS;Newschaffer CJ;Warren ST;Feinberg AP;Fallin MD;Ladd-Acosta C
一些报告已经表明表观遗传机制在ASD病因学中的作用。自闭症谱系障碍（ASD）的表观基因组关联研究（EWAS）可能揭示特定的生物学机制。然而，ASD病例与对照组的研究受到死后时间和样本量非常小的限制。来自活体血液或唾液采样的报告在样本量和/或基因组覆盖率方面也非常有限。我们提出了迄今为止最大的ASD病例对照EWAS，结合了基于人群的病例对照和病例-同胞配对研究的数据。来自探索早期发育研究（SEED 1）中儿童的968份血液样本的DNA用于使用Illumina 450 K Beadchip在453例病例和515例对照的485，512个CpG位点处生成表观基因组全阵列DNA甲基化（DNAm）数据。Simons Simplex Collection（SSC）提供了另外343例病例及其未受影响兄弟姐妹的450 K阵列DNAm数据。我们对两个数据集的结果进行了EWAS荟萃分析，并对反映生物学变异和技术混淆（如细胞类型、批次和血统）的主要来源的性别和替代变量进行了调整。我们将EWAS的结果与之前基于大脑的分析结果进行了比较。我们还使用SEED样品中可用的SNP基因型数据测试了ASD EWAS CpG作为meQTL关联的靶标的富集。在这项对796例病例和858例对照的血液DNA进行的荟萃分析中，没有一个CpG达到p < 1.12 × 10− 7的Bonferroni发现阈值。7个CpG在p < 1 × 10− 5时显示差异，48个在p <1 × 10− 4时显示差异。在前7名中，5名也显示出基于大脑的ASD关联，通常具有较大的效应量，并且前48名总体上在小脑样本的效应方向上显示出适度的一致性（r = 0.31）。最后，我们观察到EWAS CpG命中中由SNP（meQTL靶标）控制的CpG位点富集的暗示性证据，这在EWAS和meQTL发现p值阈值之间是一致的。在该样本量中，没有单个CpG位点显示病例和对照之间足够大的DNAm差异以实现表观基因组范围的显著性。然而，我们的研究结果表明，从血液样本中观察疾病相关性的潜力。在达到提示性统计学显著性的七个位点中，我们在大脑样本中的相同位点观察到一致且更强的效应。使用血液样本的ASD发现导向EWAS可能需要更大的样本和统一的遗传数据，以进一步了解ASD中的DNA差异。本文的在线版本（10.1186/s13229-018-0224-6）包含补充材料，可供授权用户使用。
Several reports have suggested a role for epigenetic mechanisms in ASD etiology. Epigenome-wide association studies (EWAS) in autism spectrum disorder (ASD) may shed light on particular biological mechanisms. However, studies of ASD cases versus controls have been limited by post-mortem timing and severely small sample sizes. Reports from in-life sampling of blood or saliva have also been very limited in sample size and/or genomic coverage. We present the largest case-control EWAS for ASD to date, combining data from population-based case-control and case-sibling pair studies. DNA from 968 blood samples from children in the Study to Explore Early Development (SEED 1) was used to generate epigenome-wide array DNA methylation (DNAm) data at 485,512 CpG sites for 453 cases and 515 controls, using the Illumina 450K Beadchip. The Simons Simplex Collection (SSC) provided 450K array DNAm data on an additional 343 cases and their unaffected siblings. We performed EWAS meta-analysis across results from the two data sets, with adjustment for sex and surrogate variables that reflect major sources of biological variation and technical confounding such as cell type, batch, and ancestry. We compared top EWAS results to those from a previous brain-based analysis. We also tested for enrichment of ASD EWAS CpGs for being targets of meQTL associations using available SNP genotype data in the SEED sample. In this meta-analysis of blood-based DNA from 796 cases and 858 controls, no single CpG met a Bonferroni discovery threshold of p < 1.12 × 10− 7. Seven CpGs showed differences at p < 1 × 10− 5 and 48 at 1 × 10− 4. Of the top 7, 5 showed brain-based ASD associations as well, often with larger effect sizes, and the top 48 overall showed modest concordance (r = 0.31) in direction of effect with cerebellum samples. Finally, we observed suggestive evidence for enrichment of CpG sites controlled by SNPs (meQTL targets) among the EWAS CpG hits, which was consistent across EWAS and meQTL discovery p value thresholds. No single CpG site showed a large enough DNAm difference between cases and controls to achieve epigenome-wide significance in this sample size. However, our results suggest the potential to observe disease associations from blood-based samples. Among the seven sites achieving suggestive statistical significance, we observed consistent, and stronger, effects at the same sites among brain samples. Discovery-oriented EWAS for ASD using blood samples will likely need even larger samples and unified genetic data to further understand DNAm differences in ASD. The online version of this article (10.1186/s13229-018-0224-6) contains supplementary material, which is available to authorized users.
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