Somatic Mosaicism in Schizophrenia and Control Brains

 描述（申请人提供）：精神分裂症（SCZ）是一种具有相当高的发病率、死亡率以及个人和社会成本的破坏性神经精神疾病。通过家族和双胞胎数据，以及最近通过全基因组关联研究（GWAS）和测序研究，遗传因素已被强烈地牵连。表观遗传修饰在各种医学和神经系统疾病中发挥着公认的作用，并且也与SCZ有关。体细胞镶嵌是一个探索不足，但潜在的SCZ非常重要的贡献者。已经有一些有趣的暗示，体细胞镶嵌可能在SCZ中发挥作用，但这种可能性的评估有待严格的实验，这是本提案的首要目标。我们的项目的主要目标是确定和表征的程度，体细胞的变化，在死后的人脑样本与SCZ和控制个人。在我们团队成员的工作之后，我们将严格评估来自Common Mind Consortium的一大批死后人脑中的体细胞镶嵌现象，我们团队的成员已经在分析基因型，mRNA-seq和表观基因组图谱。这些大脑来自SCZ患者（250）和对照组（50+）。我们将寻找反转录转座事件，拷贝数变异（CNV）和单核苷酸变异（SNV）。所有数据将通过Sage Bionetworks Synapse平台提供给研究界。我们已经集合了关键人员、样本资源、技术知识和分析策略，以便能够评估体细胞变异在大脑中的作用，并开始解开SCZ生物学。

 DESCRIPTION (provided by applicant): Schizophrenia (SCZ) is a generally devastating neuropsychiatric illness with considerable morbidity, mortality, and personal and societal cost. Genetic factors have been strongly implicated via family and twin data, and more recently directly through genome-wide association studies (GWAS) and sequencing studies. Epigenetic modifications play a well-accepted role in a variety of medical and neurological illnesses, and are also implicated in SCZ. Somatic mosaicism is an underexplored, but potentially very important contributor to SCZ. There have been some intriguing hints that somatic mosaicism may play a role in SCZ, but assessment of this possibility awaits rigorous experiments, and that is the overarching goal of this proposal. The primary objective of our project is to identify and characterize the extent of somatic variation in post-mortem human brain samples from individuals with SCZ and controls. Following on work of members of our team, we will rigorously assess the somatic mosaicism in a large cohort of post-mortem human brains from the Common Mind Consortium, which members of our group are already analyzing for genotype, mRNA-seq and epigenome mapping. These brains are from individuals with SCZ (250) and controls (50+). We will look for retrotransposition events, copy number variants (CNVs) and single nucleotide variants (SNVs). All data will be made available to the research community through the Sage Bionetworks Synapse Platform. We have assembled the critical personnel, sample resources, technological know-how, and analytic strategies to be able to assess the role of somatic variation in the brain as well as begin to unravel SCZ biology.