A Whole Methylome CpG-SNP Association Study of Psychosis in Blood and Brain Tissue.
A Whole Methylome CpG-SNP Association Study of Psychosis in Blood and Brain Tissue.
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血液和脑组织中精神病的全甲基化 CpG-SNP 关联研究。
DOI：
10.1093/schbul/sbv182
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发表时间：
2016
影响因子：
6.6
通讯作者：
Aberg,KarolinaA
中科院分区：
文献类型：
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作者：
vandenOord,EdwinJCG;Clark,ShaunnaL;Xie,LinYing;Shabalin,AndreyA;Dozmorov,MikhailG;Kumar,Gaurav;SwedishSchizophreniaConsortium;Vladimirov,VladimirI;Magnusson,PatrikKE;Aberg,KarolinaA
突变的 CpG 位点 (CpG-SNP) 是人类疾病的潜在热点，因为除了序列变异之外，它们还可能表现出 DNA 甲基化的个体差异。我们进行了全甲基化关联研究（MWAS），以测试这些位点的甲基化差异是否与精神分裂症相关。我们使用从精神分裂症病例和对照的 1408 个血液样本和 66 个死后脑样本 (BA10) 中提取的 DNA，通过甲基 CpG 结合域蛋白富集基因组测序 (MBD-seq) 分析了所有常见的 CpG-SNP。血液 MWAS 中的 7 个 CpG-SNP 通过了我们的 FDR 阈值 0.1。在大脑中甲基化的 CpG-SNP 中，94% 在血液中也被甲基化。这显着超过了偶然预期的 46.2% 重叠（P 值 < 1.0×10−8），并且证明了脑组织中血液的复制结果是合理的。 CpG-SNP rs3796293 在IL1RA 中重复（P 值 = .003），具有相同方向的作用。该位点通过 736 个独立病例对照血液样本的靶向亚硫酸氢盐焦磷酸测序得到进一步验证（P 值 < 9.5×10−4）。我们在大脑 MWAS 中的最高结果（P 值 = 8.8×10−7）是位于 ENC1 潜在启动子中的 CpG-SNP rs16872141。总体而言，我们的结果表明 CpG-SNP 甲基化可能反映环境损害的影响，并可以提供血液中的生物标志物，从而有可能改善疾病管理。
Mutated CpG sites (CpG-SNPs) are potential hotspots for human diseases because in addition to the sequence variation they may show individual differences in DNA methylation. We performed methylome-wide association studies (MWAS) to test whether methylation differences at those sites were associated with schizophrenia. We assayed all common CpG-SNPs with methyl-CpG binding domain protein-enriched genome sequencing (MBD-seq) using DNA extracted from 1408 blood samples and 66 postmortem brain samples (BA10) of schizophrenia cases and controls. Seven CpG-SNPs passed our FDR threshold of 0.1 in the blood MWAS. Of the CpG-SNPs methylated in brain, 94% were also methylated in blood. This significantly exceeded the 46.2% overlap expected by chance (P-value < 1.0×10−8) and justified replicating findings from blood in brain tissue. CpG-SNP rs3796293 inIL1RAPreplicated (P-value = .003) with the same direction of effects. This site was further validated through targeted bisulfite pyrosequencing in 736 independent case-control blood samples (P-value < 9.5×10−4). Our top result in the brain MWAS (P-value = 8.8×10−7) was CpG-SNP rs16872141 located in the potential promoter ofENC1.Overall, our results suggested that CpG-SNP methylation may reflect effects of environmental insults and can provide biomarkers in blood that could potentially improve disease management.