4/5-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，给患者和家人带来沉重的负担，是密集的遗传学研究的主题。表观遗传变异的研究是对传统遗传病研究的重要补充，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和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很好的证实，而与神经精神疾病的相关性现在正在显现。表观遗传学对精神分裂症(SZ)的贡献得到了MZ双胞胎之间重要但经常被忽视的不一致性、DNA甲基化(DNaM)前体对SZ精神症状的影响以及SZ候选基因dNaM变异的证据的支持。虽然SZ的全基因组关联研究正在进行中，但还没有进行类似的努力来识别表观遗传学变化，这主要是由于技术限制。在这里，我们建议通过结合申请人最近开发的强大的实验和统计全基因组dNaM分析方法来确定SZ的潜在表观遗传学贡献，三个大型和特征良好的联合体专注于SZ的遗传学(MGI，COGS，PAARTNERS)，它们已经进行了广泛的遗传和表型研究。我们的具体目标是：(1)使用1000个SZ病例/1000个年龄/性别频率匹配的对照淋巴细胞DNA以及140个SZ/140对照大脑，比较SZ病例和对照之间的全基因组甲基化扫描(GWMS)方法；(2)复制来自NIMH基因库的2000个病例/2000对照的独立样本中9,880个CpG位点的GWM结果，并精细绘制dNaM并检查前50个候选基因的表达模式；以及(3)将这些表观遗传学发现与这些样本上已经收集的遗传数据相结合。这些研究将首次全面评估SZ的表观遗传学，并对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，由于表观遗传学改变可能是可逆的，这些研究也可能为SZ治疗带来令人兴奋的新途径。与公共卫生相关：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负担，是密集基因研究的主题。表观遗传变异的研究，如DNA甲基化，是传统遗传病研究的重要补充；与序列变异不同，表观遗传标记受年龄和环境的影响。该项目将为深圳表观遗传学提供一种全面的全基因组方法，利用最先进的实验和统计方法对样本集进行DNA甲基化分析，该样本集由深圳杰出的表型专家网络以高度协作的方式识别和评估。

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.