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

5/5：全基因组甲基化扫描对精神分裂症的表观遗传贡献

基本信息

批准号：
7573888
负责人：
DAVID L. BRAFF
金额：
$ 3.86万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-30 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7573888
关键词：
Acquired Immunodeficiency Syndrome Affect African American Age Alabama Applications Grants Arts Biological Biological Assay Blood specimen Brain Brain region Budgets California Candidate Disease Gene Chemicals Clinical Services Collaborations Collection Communities Complement CpG dinucleotide Custom DNA DNA Methylation DNA Modification Process DNA Restriction Enzymes DNA Sequence Data Databases Diagnostic Disease Doctor of Medicine Doctor of Philosophy Environment Epigenetic Process Evaluation Event Experimental Designs Family Fostering Frequencies Funding Gene Expression Genes Genetic Genetic Models Genetic Polymorphism Genetic Predisposition to Disease Genetic Variation Genome Genomics Genotype Grant Gur Hereditary Disease Hippocampus (Brain)Human Individual Investigation Lead Leadership Link Lymphocyte Malignant Neoplasms Manuscripts Maps Masks Master of Public Health Measures Mental disorders Methods Methylation Modeling Molecular Molecular Genetics Mutation NIH Program Announcements National Institute of Mental Health Nature Neurocognitive Parents Participant Pathogenesis Patients Pattern Pennsylvania Personal Satisfaction Phenotype Population Heterogeneity Potassium Hydroxide Prefrontal Cortex Proteins Public Health Publications Publishing Research Research Design Research Personnel Research Project Grants Resources Risk Role Sampling Sampling Studies Scanning Schizophrenia Score Screening procedure Site Superior temporal gyrus Symptoms Technology Testing Tissues Twin Multiple Birth United States National Institutes of Health Universities Ursidae Family Validation Variant Washington Work Writing alcohol use disorder base bisulfite brain tissue case control data integration design epigenetic variation follow-up genome wide association study imprint interdisciplinary approach member mind control neuropsychiatry proband repository sample collection sex tool

项目摘要

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.

描述（由申请人提供）：精神分裂症是一种常见的，严重的致残性疾病，对患者和家庭负担很大，并且是强化遗传研究的主题。表观遗传变异的研究是对常规遗传疾病研究的重要补充，因为DNA序列的表型后果取决于其表观遗传环境。与序列变化不同，表观遗传标记，即DNA和相关蛋白的化学修饰，受年龄和环境的影响，在疾病的遗传易感性与与终身表观遗传暴露有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建立得很好，并且与神经精神疾病的相关性现在已经出现。对精神分裂症（SZ）的表观遗传学贡献得到了重要的，但通常忽略了MZ双胞胎之间的不一致，DNA甲基化（DNAM）前体对SZ精神病症状的影响以及SZ候选基因DNAM变化的证据。尽管全基因组关联研究正在进行SZ，但尚未采取类似的努力来识别表观遗传变化，这主要是由于技术局限性。在这里，我们建议通过结合申请人最近开发的DNAM分析的强大实验和统计全基因组分析来确定对SZ的潜在表观遗传学贡献，其中三个大型且特征良好的财团重点是SZ（MGI，COGS，PAARTNER）的遗传学，这些财团已经进行了广泛的遗传和遗传研究。我们的具体目的是：（1）使用1000 SZ病例 / 1000年龄 /性别频率匹配的对照淋巴细胞DNA以及140 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）测量；（2）在从NIMH遗传学存储库中的2000病例 / 2000对照的独立样本中复制9,880个CpG位点的GWM发现，并对DNAM进行细微地图，并检查前50个基因候选者的表达模式；（3）将这些表观遗传发现与已经在这些样品上收集的遗传数据相结合。这些研究将对SZ的表观遗传学进行首次全面评估，并为SZ遗传学数据提供前所未有的补充，从而允许整合遗传，环境和表观遗传学对SZ的影响。从重要的治疗角度来看，由于表观遗传变化可能可逆，因此这些研究也可能导致令人兴奋的SZ治疗途径。公共卫生相关性：精神分裂症是一种常见的，严重的残疾疾病，为患者和家庭带来沉重的负担，这是强化遗传研究的主题。表观遗传变异（例如DNA甲基化）的研究是对常规遗传疾病研究的重要补充。与序列变化不同，表观遗传标记受年龄和环境的影响。该项目将为SZ的表观遗传学提供一种全面的基因组方法，从而使最先进的实验性和统计方法对DNA甲基化的分析进行了对SZ表型专家的出色网络进行确定和评估的样本集，以高度协作的方式进行了工作。