4/5-A Genome-Wide Methylation Scan for Epigenetic Contributions to Schizophrenia

4/5-A 全基因组甲基化扫描，了解精神分裂症的表观遗传贡献

• 批准号: 7867958
• 负责人: RODNEY T PERRY
• 金额: $ 3.63万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 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/7867958
• 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; 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; Phenotype; Population Heterogeneity; Potassium Hydroxide; Prefrontal Cortex; Proteins; Publications; Publishing; Research; Research Design; Research Personnel; Research Project Grants; Resources; Risk; Role; Sampling; Sampling Studies; Scanning; Schizophrenia; 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; data sharing; design; epigenetic variation; follow-up; genome wide association study; genome-wide; imprint; interdisciplinary approach; member; mind control; neuropsychiatry; proband; public health relevance; repository; sample collection; sex; tool

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、严重致残的疾病，给患者和家庭带来了沉重的负担，是密集基因研究的主题。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，这在疾病的遗传易感性与与终生表观遗传暴露有关的至关重要的风险之间提供了重要联系。表观遗传标记在癌症中的重要性已经确立，并且与神经精神疾病的相关性正在出现。表观遗传对精神分裂症（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，DNA甲基化（DNAm）前体对SZ精神病症状的影响，以及SZ候选基因中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，但由于技术限制，尚未开展类似的工作来确定表观遗传变化。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的潜在表观遗传贡献，并与三个已经进行了广泛遗传和表型研究的大型和特征明确的联盟（MGI， COGS, partners）一起研究SZ的遗传学。我们的具体目标是：(1)使用1000例SZ病例/ 1000个年龄/性别频率匹配的对照淋巴细胞DNA和140例SZ / 140例对照大脑，比较SZ病例和对照组之间的全基因组甲基化扫描（GWMs）测量结果；(2)从NIMH基因库中提取2000个病例/ 2000个对照，在9880个CpG位点上重复GWM的发现，精细绘制DNAm图谱，并检查前50个候选基因的表达模式；(3)将这些表观遗传学发现与这些样本上已经收集到的遗传数据结合起来。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，这些研究也可能为SZ治疗带来令人兴奋的新途径。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，给患者和家庭带来了沉重的负担，是密集遗传研究的主题。表观遗传变异的研究，如DNA甲基化，是对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SZ的表观遗传学提供一个全面的全基因组方法，将最先进的实验和统计方法用于分析样本集的DNA甲基化，这些样本集由SZ表型专家组成的杰出网络以高度协作的方式共同确定和评估。