5/5:Family-Based Genome-Wide Methylation Scan in Neurocognition and Schizophrenia

5/5：神经认知和精神分裂症中基于家族的全基因组甲基化扫描

基本信息

批准号：
7853230
负责人：
DAVID L. BRAFF
金额：
$ 3.29万
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：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7853230
关键词：
Affect Age Candidate Disease Gene Case-Control Studies Chemicals Cognition Cognitive Collaborations Complement DNA DNA Methylation DNA Modification Process DNA Sequence Data Defect Diagnosis Disease Emotions Environment Epigenetic Process Family Family member Foundations Frequencies Funding Genetic Genetic Predisposition to Disease Hand Hereditary Disease Heritability Language Link Lymphocyte Malignant Neoplasms Memory Methods Methylation National Institute of Mental Health Neurocognition Neurocognitive Patients Phenotype Process Proteins Relative (related person)Research Research Infrastructure Research Personnel Risk Sampling Scanning Schizophrenia Series Signal Transduction Site Symptoms Technology Twin Multiple Birth Variant Work base case control cohort epigenetic variation executive function genome wide association study genome-wide human disease mind control neuropsychiatry novel proband public health relevance repository sex trait

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. This coordinated application builds on a strong foundation of an existing collaboration between six groups of investigators, with an already established and funded infrastructure, without which this research would not be possible. We have previously established a collaboration to investigate the epigenetics of SZ using a case-control approach with existing samples by collaborating with three large Consortia focusing on the genetics of SZ (MGI, COGS, PAARTNERS) that have already carried out extensive genetic and phenotypic studies on well-characterized patients, including quantitative neurocognitive phenotypes. Here we approach the epigenetics of SZ in the family members of the probands currently under study, as well as the relationship of epigenetic variation to quantitative neurocognitive phenotypes such as executive function, memory, language and emotion processing. Our Specific Aims are: (2) To quantitatively assess methylation of >4 million CpG sites genome-wide, across 1000 SZ families, examining an average of 3 family members per proband with a total of 3000 family members; (2) To use these data to estimate the heritability of genome-wide methylation in SZ families, to perform family-based epigenetic association with SZ and to perform family-based integration of GWAS data with DNAm; and (3) to examine neurocognitive phenotypes available across families to estimate the relationship between methylation and cognitive efficiency within and across families. The proposed research offers a novel, timely, powerful, and comprehensive strategy for determining the familial epigenetic contribution to SZ, combining expertise in epigenetic technology of human disease with a network of collaborating consortia yielding large well-characterized samples of patients with SZ and their family members. 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, but the study of epigenetic variation, such as DNA methylation, is an essential complement to conventional genetic disease studies, as epigenetic marks are affected by age and the environment. This project will provide a comprehensive genome-wide approach to the familial basis of schizophrenia, leveraging our ongoing study of an existing cohort of schizophrenic patients by examining family members for heritability of schizophrenia-related methylation changes, and by relating these changes to quantitative defects in cognition in patients and family members. The research offers a novel, timely, and powerful strategy for determining the familial epigenetic contribution to schizophrenia.

描述（由申请人提供）：精神分裂症是一种常见的严重致残性疾病，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。这项协调的应用程序建立在六组调查人员之间现有合作的基础上，并具有已经建立和资助的基础设施，没有这项研究将是不可能的。我们以前已经建立了一项合作，通过与三个大型财团合作，使用病例对照方法与现有样本进行了调查的表观遗传学，重点介绍了SZ（MGI，COGS，PAARTNERS）的遗传学，这些遗传学已经对含量良好的患者进行了广泛的遗传和表型研究，包括量化的遗传和表型研究。在这里，我们接近目前正在研究的证据的家庭成员中SZ的表观遗传学，以及表观遗传变异与定量神经认知表型（例如执行功能，记忆，语言和情感处理）的关系。我们的具体目的是：（2）在1000 sz家族中定量评估> 400万个CpG地点的甲基化，每位证据平均有3个家庭成员，共有3000个家庭成员；（2）使用这些数据来估计SZ家族中全基因组甲基化的遗传力，以与SZ进行基于家庭的表观遗传学关联，并与DNAM进行基于家庭的GWAS数据集成；（3）检查跨家族可用的神经认知表型，以估计家庭内部和跨家族内部和认知效率之间的关系。拟议的研究提供了一种新颖，及时，有力和全面的策略，用于确定家族性表观遗传学对SZ的贡献，将人类疾病表观遗传技术的专业知识与合作财团的网络相结合，提供了大量SZ患者及其家人及其家人的良好特征样本。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，对患者和家庭带来沉重的负担，这是强化遗传研究的主题，但是对表观遗传学变异（例如DNA甲基化）的研究是对常规遗传疾病研究的重要补充，因为年龄和环境都影响了表观遗传学标记。该项目将为精神分裂症的家族基础提供全面的全基因组方法，通过研究与精神分裂症相关的甲基化变化的家庭成员的持续研究，并通过研究与患者和家庭成员认知的定量缺陷有关的遗传性的持续研究。该研究提供了一种新颖，及时且有力的策略，用于确定家族性表观遗传学对精神分裂症的贡献。