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障碍，给患者和家庭带来沉重负担，是密集遗传学研究的主题。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，在疾病的遗传易感性和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很好的证实，而与神经精神疾病的相关性现在正在显现。表观遗传学对精神分裂症(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性、DNA甲基化(DNaM)前体对SZ精神症状的影响以及SZ候选基因dNaM变异的证据的支持。这一协调应用建立在六个调查组之间现有合作的坚实基础上，这些小组拥有已经建立和资助的基础设施，如果没有这些基础设施，这项研究就不可能进行。我们之前已经与三个专注于SZ遗传学的大型财团(MGI、COGS、PAARTNERS)合作，使用病例对照的方法研究SZ的表观遗传学，这些财团已经对特征良好的患者进行了广泛的遗传和表型研究，包括定量神经认知表型。在这里，我们探讨了目前正在研究的先证者家庭成员中SZ的表观遗传学，以及表观遗传学变异与执行功能、记忆、语言和情绪处理等定量神经认知表型的关系。我们的具体目标是：(2)定量评估跨越1000个SZ家庭的全基因组400万个CpG位点的甲基化，检查每个先证者的平均3个家庭成员，总共3000个家庭成员；(2)使用这些数据来估计SZ家庭全基因组甲基化的遗传力，进行基于家庭的表观遗传关联，并执行基于家庭的Gwas数据与dNaM的整合；以及(3)检查跨家庭可用的神经认知表型，以估计甲基化与家庭内和家庭之间的认知效率之间的关系。这项拟议的研究为确定家族表观遗传学对SZ的贡献提供了一种新颖、及时、强大和全面的策略，将人类疾病表观遗传技术的专业知识与合作联盟网络结合起来，产生大量具有良好特征的SZ患者及其家庭成员样本。 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负担，是密集遗传学研究的主题，但对表观遗传变异的研究，如DNA甲基化，是对传统遗传病研究的必要补充，因为表观遗传标记受年龄和环境的影响。该项目将提供一种全面的全基因组方法来研究精神分裂症的家族基础，利用我们正在进行的对现有精神分裂症患者队列的研究，通过检查家庭成员与精神分裂症相关的甲基化变化的遗传性，并通过将这些变化与患者及其家庭成员的认知数量缺陷联系起来。这项研究为确定家族表观遗传对精神分裂症的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.