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

描述（由申请人提供）：精神分裂症是一种常见的严重致残疾病，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。这个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，已经建立和资助了基础设施，没有这些基础设施，这项研究将不可能进行。我们之前已经建立了一项合作，通过与三个专注于SZ遗传学的大型联盟（MGI， COGS, partners）合作，利用现有样本使用病例对照方法研究SZ的表观遗传学，这些联盟已经对特征明确的患者进行了广泛的遗传和表型研究，包括定量的神经认知表型。在此，我们探讨了SZ在先证者家族成员中的表观遗传学，以及表观遗传变异与执行功能、记忆、语言和情绪加工等定量神经认知表型的关系。我们的具体目标是：(2)在1000个SZ家族中，每个先证平均检查3个家族成员，共3000个家族成员，定量评估全基因组中4,400万个CpG位点的甲基化；(2)利用这些数据估计SZ家族全基因组甲基化的遗传力，对SZ进行基于家族的表观遗传关联，并对GWAS数据与DNAm进行基于家族的整合；(3)研究家族间可用的神经认知表型，以估计甲基化与家族内和家族间认知效率之间的关系。拟议的研究提供了一种新颖、及时、强大和全面的策略来确定家族表观遗传对SZ的影响，将人类疾病表观遗传技术的专业知识与合作联盟网络相结合，产生大量SZ患者及其家庭成员的特征样本。

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.