4/5:Family-Based Genome-Wide Methylation Scan in Neurocognition and Schizophrenia

描述（申请人提供）：精神分裂症是一种常见的严重致残性疾病，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。这一协调的应用程序建立在六个研究小组之间现有合作的坚实基础上，具有已经建立和资助的基础设施，没有这些基础设施，这项研究就不可能进行。我们之前已经建立了一个合作，调查表观遗传学的SZ使用病例对照的方法与现有的样本，通过合作与三个大财团专注于SZ的遗传学（MGI，COGS，PAARTNERS），已经进行了广泛的遗传学和表型研究的良好特征的患者，包括定量神经认知表型。在这里，我们的方法SZ的表观遗传学在家庭成员的先证者目前正在研究中，以及表观遗传变异的关系，定量神经认知表型，如执行功能，记忆，语言和情绪处理。我们的具体目标是：（2）在1000个SZ家族中定量评估> 400万个CpG位点的全基因组甲基化，每个先证者平均检查3个家族成员，总共3000个家族成员;（2）利用这些数据估计SZ家系全基因组甲基化的遗传度，与SZ进行基于家族的表观遗传关联，并将GWAS数据与DNAm进行基于家族的整合;和（3）检查跨家族可用的神经认知表型以估计家族内和跨家族的甲基化和认知效率之间的关系。拟议的研究提供了一种新的，及时的，强大的，全面的战略，以确定家族表观遗传的贡献SZ，结合人类疾病的表观遗传技术的专业知识与合作财团的网络产生大量的SZ患者及其家庭成员的良好表征的样本。 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，这是密集的遗传研究的主题，但表观遗传变异的研究，如DNA甲基化，是传统遗传疾病研究的重要补充，因为表观遗传标记受年龄和环境的影响。该项目将提供一个全面的全基因组方法的精神分裂症的家族基础，利用我们正在进行的研究现有的队列精神分裂症患者通过检查家庭成员的精神分裂症相关的甲基化变化的遗传性，并将这些变化与患者和家庭成员的认知定量缺陷。这项研究为确定精神分裂症的家族表观遗传贡献提供了一种新颖、及时和有力的策略。

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.