Association of DNA Methylation Differences With Schizophrenia in an Epigenome-Wide Association Study.
Association of DNA Methylation Differences With Schizophrenia in an Epigenome-Wide Association Study.
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DOI：
10.1001/jamapsychiatry.2016.0144
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发表时间：
2016-05-01
期刊：
影响因子：
25.8
通讯作者：
Feinberg AP
中科院分区：
文献类型：
--
作者：
Montano C;Taub MA;Jaffe A;Briem E;Feinberg JI;Trygvadottir R;Idrizi A;Runarsson A;Berndsen B;Gur RC;Moore TM;Perry RT;Fugman D;Sabunciyan S;Yolken RH;Hyde TM;Kleinman JE;Sobell JL;Pato CN;Pato MT;Go RC;Nimgaonkar V;Weinberger DR;Braff D;Gur RE;Fallin MD;Feinberg AP
DNA甲基化可能在精神分裂症（SZ）中发挥重要作用，直接作为发病机制或作为风险的生物标志物。扫描全基因组DNA甲基化数据，以确定SZ病例和对照之间的差异甲基化CpG。表观全基因组关联研究始于2008年，使用Infinium HumanMethylation 450阵列（Illumina）上测量的456 513个CpG位点的DNA甲基化水平，在一个病例对照研究联盟中进行初步发现和独立复制集。主要分析使用一般线性回归，调整年龄、性别、人种/种族、吸烟、批次和细胞类型异质性。发现集包含689个SZ病例和645个对照（n = 1334），来自3个多地点财团：精神分裂症内表型遗传学财团，非裔美国人探索精神分裂症风险项目和精神分裂症多代家庭研究。复制集包含来自基因组精神病学队列的247例SZ病例和250例对照（n = 497）。与对照组相比，SZ病例基因组中差异甲基化位置的鉴定。在发现集中的689例病例参与者中，477例（69%）为男性，258例（37%）为非非洲裔美国人;在645例对照中，273例（42%）为男性，419例（65%）为非非洲裔美国人。在我们的复制组中，病例/对照组为76%男性和100%非非洲裔美国人。我们在发现集中的923个CpG上鉴定了SZ相关的甲基化差异（错误发现率，<0.2）。其中，625例显示相同方向的变化，包括172例重复组中P <0.05。从全基因组关联研究分析中，一些重复的差异甲基化位置位于排名靠前的SZ区域。在仔细校正细胞类型异质性和其他潜在混杂因素后，该分析确定了172个重复的与SZ的新关联。与以前的全基因组关联研究数据的重叠可以为SZ的遗传信号的功能相关性提供潜在的见解。
DNA methylation may play an important role in schizophrenia (SZ), either directly as a mechanism of pathogenesis or as a biomarker of risk. To scan genome-wide DNA methylation data to identify differentially methylated CpGs between SZ cases and controls. Epigenome-wide association study begun in 2008 using DNA methylation levels of 456 513 CpG loci measured on the Infinium HumanMethylation450 array (Illumina) in a consortium of case-control studies for initial discovery and in an independent replication set. Primary analyses used general linear regression, adjusting for age, sex, race/ethnicity, smoking, batch, and cell type heterogeneity. The discovery set contained 689 SZ cases and 645 controls (n = 1334), from 3 multisite consortia: the Consortium on the Genetics of Endophenotypes in Schizophrenia, the Project among African-Americans To Explore Risks for Schizophrenia, and the Multiplex Multigenerational Family Study of Schizophrenia. The replication set contained 247 SZ cases and 250 controls (n = 497) from the Genomic Psychiatry Cohort. Identification of differentially methylated positions across the genome in SZ cases compared with controls. Of the 689 case participants in the discovery set, 477 (69%) were men and 258 (37%) were non–African American; of the 645 controls, 273 (42%) were men and 419 (65%) were non–African American. In our replication set, cases/controls were 76% male and 100% non–African American. We identified SZ-associated methylation differences at 923 CpGs in the discovery set (false discovery rate, <0.2). Of these, 625 showed changes in the same direction including 172 with P < .05 in the replication set. Some replicated differentially methylated positions are located in a top-ranked SZ region from genome-wide association study analyses. This analysis identified 172 replicated new associations with SZ after careful correction for cell type heterogeneity and other potential confounders. The overlap with previous genome-wide association study data can provide potential insights into the functional relevance of genetic signals for SZ.
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影响因子：
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