一项全基因组关联研究中DNA甲基化差异与精神分裂症的关联
Association of DNA Methylation Differences With Schizophrenia in an Epigenome-Wide Association Study.
作者信息
Montano Carolina, Taub Margaret A, Jaffe Andrew, Briem Eirikur, Feinberg Jason I, Trygvadottir Rakel, Idrizi Adrian, Runarsson Arni, Berndsen Birna, Gur Ruben C, Moore Tyler M, Perry Rodney T, Fugman Doug, Sabunciyan Sarven, Yolken Robert H, Hyde Thomas M, Kleinman Joel E, Sobell Janet L, Pato Carlos N, Pato Michele T, Go Rodney C, Nimgaonkar Vishwajit, Weinberger Daniel R, Braff David, Gur Raquel E, Fallin Margaret Daniele, Feinberg Andrew P
机构信息
Medical Scientist Training Program and Predoctoral Training Program in Human Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland2Center for Epigenetics, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
出版信息
JAMA Psychiatry. 2016 May 1;73(5):506-14. doi: 10.1001/jamapsychiatry.2016.0144.
IMPORTANCE
DNA methylation may play an important role in schizophrenia (SZ), either directly as a mechanism of pathogenesis or as a biomarker of risk.
OBJECTIVE
To scan genome-wide DNA methylation data to identify differentially methylated CpGs between SZ cases and controls.
DESIGN, SETTING, AND PARTICIPANTS: 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.
MAIN OUTCOMES AND MEASURES
Identification of differentially methylated positions across the genome in SZ cases compared with controls.
RESULTS
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.
CONCLUSIONS AND RELEVANCE
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.
重要性
DNA甲基化可能在精神分裂症（SZ）中发挥重要作用，既可以直接作为发病机制，也可以作为风险生物标志物。
目的
扫描全基因组DNA甲基化数据，以识别SZ病例与对照之间差异甲基化的CpG位点。
设计、设置和参与者：2008年开始的全基因组关联研究，使用Illumina公司的Infinium HumanMethylation450芯片测量了456513个CpG位点的DNA甲基化水平，该研究在一个病例对照研究联盟中进行初步发现，并在一个独立的复制集中进行。主要分析使用一般线性回归，并对年龄、性别、种族/民族、吸烟、批次和细胞类型异质性进行了调整。发现集包含来自3个多中心联盟的689例SZ病例和645例对照（n = 1334）：精神分裂症内表型遗传学联盟、非裔美国人探索精神分裂症风险项目以及精神分裂症多重多代家系研究。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）。
主要结果和测量指标
识别SZ病例与对照相比全基因组中差异甲基化的位置。
结果
在发现集中的689例病例参与者中，477例（69%）为男性，258例（37%）为非非裔美国人；在645例对照中，273例（42%）为男性，419例（65%）为非非裔美国人。在我们的复制集中，病例/对照中男性占76%，非非裔美国人占100%。我们在发现集中识别出923个与SZ相关的甲基化差异CpG位点（错误发现率<0.2）。其中，625个显示出相同方向的变化，包括在复制集中172个P < 0.05的位点。一些重复的差异甲基化位置位于全基因组关联研究分析中排名靠前的SZ区域。
结论和相关性
经过对细胞类型异质性和其他潜在混杂因素的仔细校正后，该分析确定了172个与SZ重复的新关联。与先前全基因组关联研究数据的重叠可以为SZ遗传信号的功能相关性提供潜在见解。
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