3/5: A Genome-Wide Methylation Scan for Epigenetic Contributions to Schizophrenia

描述（申请人提供）：精神分裂症是一种常见的，严重致残的疾病，给患者和家庭带来沉重的负担，是深入遗传研究的主题。表观遗传变异的研究是对传统遗传疾病研究的重要补充，因为DNA序列的表型结果取决于其表观遗传背景。与序列变异不同，表观遗传标记，即DNA和相关蛋白质的化学修饰，受到年龄和环境的影响，在疾病的遗传易感性与终身表观遗传暴露相关的至关重要的风险之间提供了重要的联系。表观遗传标记在癌症中的重要性已经得到了很好的证实，与神经精神疾病的相关性正在显现。精神分裂症（SZ）的表观遗传学贡献支持的重要，但往往被忽视的不一致性MZ双胞胎，DNA甲基化（DNAm）的前体对精神病症状的影响在SZ，和SZ候选基因的DNAm变异的证据。虽然SZ的全基因组关联研究正在进行中，但由于技术限制，尚未进行类似的努力来确定表观遗传变化。在这里，我们提出通过将申请人最近开发的用于DNA m分析的稳健的实验和统计全基因组方法与已经进行了广泛的遗传和表型研究的专注于SZ的遗传学的三个大型且充分表征的财团（MGI、COGS、PAARTNERS）相结合来确定对SZ的潜在表观遗传贡献。我们的具体目标是：（1）使用1000例SZ病例/ 1000例年龄/性别频率匹配的对照淋巴细胞DNA以及140例SZ / 140例对照脑比较SZ病例和对照之间的全基因组甲基化扫描（GWM）测量;（2）在9时重复GWM发现，来自NIMH Genetics Repository的2000例病例/ 2000例对照的独立样本中的880个CpG位点，并对DNAm进行精细作图，并检查前50个候选基因的表达模式;以及（3）将这些表观遗传学的发现与已经收集到的这些样本的遗传数据相结合。这些研究将首次全面评估SZ的表观遗传学，并为SZ遗传学数据提供前所未有的补充，从而整合遗传、环境和表观遗传对SZ的影响。从一个重要的治疗角度来看，由于表观遗传变化是潜在可逆的，这些研究也可能导致令人兴奋的SZ治疗的新途径。公共卫生相关性：精神分裂症是一种常见的，严重致残的疾病，给患者和家庭带来沉重的负担，这是深入遗传研究的主题。对表观遗传变异（如DNA甲基化）的研究是对传统遗传疾病研究的重要补充;与序列变异不同，表观遗传标记受年龄和环境的影响。该项目将为SZ的表观遗传学提供全面的全基因组方法，采用最先进的实验和统计方法分析由SZ表型专家以高度协作方式共同工作的杰出网络鉴定和评估的样本集的DNA甲基化。

DESCRIPTION (provided by applicant): Schizophrenia is a common, profoundly disabling disorder that carries a heavy burden for patients and families and is the subject of intensive genetic studies. The study of epigenetic variation is an essential complement to conventional genetic disease studies, since the phenotypic consequence of DNA sequence depends on its epigenetic context. Unlike sequence variation, epigenetic marks, i.e. chemical modifications of DNA and associated proteins, are affected by age and the environment, providing an important link between the genetic predisposition to disease and crucially important risks related to lifetime epigenetic exposures. The importance of epigenetic marks in cancer is well established, and the relevance to neuropsychiatric disease is now emerging. An epigenetic contribution to schizophrenia (SZ) is supported by important, but often ignored discordance among MZ twins, the effects of DNA methylation (DNAm) precursors on psychotic symptoms in SZ, and evidence for DNAm variation in SZ candidate genes. While genome-wide association studies are ongoing for SZ, no similar effort has yet been pursued to identify epigenetic changes, largely due to technology limitations. Here we propose to determine the potential epigenetic contribution to SZ by combining robust experimental and statistical genome-wide methods for DNAm analysis recently developed by the applicants, with three large and well-characterized Consortia focusing on the genetics of SZ (MGI, COGS, PAARTNERS) that have already carried out extensive genetic and phenotypic studies. Our specific aims are: (1) Compare genome-wide methylation scan (GWMs) measures between SZ cases and controls using 1000 SZ cases / 1000 age/sex frequency matched control lymphocyte DNA as well as 140 SZ / 140 control brains; (2) Replicate GWM findings at 9,880 CpG sites in an independent sample of 2000 cases / 2000 controls from the NIMH Genetics Repository and fine-map the DNAm and examine expression patterns for the top 50 gene candidates; and (3) Integrate these epigenetic discoveries with the genetic data already being collected on these samples. These studies will provide the first comprehensive evaluation of the epigenetics of SZ and provide an unprecedented complement to SZ genetics data, allowing integration of genetic, environmental, and epigenetic effects on SZ. From an important treatment perspective, since epigenetic changes are potentially reversible, these studies may also lead to exciting new avenues for SZ therapy. PUBLIC HEALTH RELEVANCE: Schizophrenia is a common, profoundly disabling disorder that carries a heavy burden for patients and families that is the subject of intensive genetic studies. The study of epigenetic variation, such as DNA methylation, is an essential complement to conventional genetic disease studies; unlike sequence variation, epigenetic marks are affected by age and the environment. This project will provide a comprehensive genome- wide approach to the epigenetics of SZ, bringing to bear state of the art experimental and statistical approaches to the analysis of DNA methylation on a sample set identified and assessed by an outstanding network of SZ phenotypic experts working together in a highly collaborative manner.