Schizophrenia susceptibility by copy number variation in the Ashkenazim

德系犹太人拷贝数变异对精神分裂症的易感性

• 批准号: 7798637
• 负责人: Stephen T. Warren
• 金额: $ 79.43万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-15 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7798637
• 关键词: Alleles; Ashkenazim; Chromosomes; Code; Conserved Sequence; Copy Number Polymorphism; DNA; DNA Sequence; Data; Data Analyses; Data Quality; Elements; Equilibrium; Evaluation; Fluorescent in Situ Hybridization; Frequencies; Gene Frequency; Generations; Genes; Genetic; Genetic Heterogeneity; Genetic Predisposition to Disease; Genetic Variation; Genome; Genomics; Genotype; Glutamates; Heritability; Human; Human Genome; Individual; Joints; Linkage Disequilibrium; Mental disorders; Metaphase; Oligonucleotide Microarrays; Oligonucleotides; Parents; Patients; Pattern; Population; Predisposition; Relative (related person); SNP genotyping; Sampling; Scanning; Schizophrenia; Source; Stretching; Surveys; Variant; case control; density; follower of religion Jewish; genome-wide; meetings; statistics; success; transmission process

DESCRIPTION (provided by applicant): Schizophrenia (SZ) is a severe psychiatric disorder with a strong genetic susceptibility. Heritability is estimated to be 70-90% for SZ. Intense efforts using both linkage and association studies to identify susceptibility loci thus far have met only limited success. Recently it has been appreciated that widespread copy number variation (CNV), in the form of duplications and deletions, frequently occurs in the human genome and is a largely unsurveyed source of individual genetic variation. CNV may be an unrecognized source of SZ genetic susceptibility and potentially a confounding influence on prior genetic studies. We propose here to survey the entire nonrepetitive human genome, using arrays with oligonucleotide markers at an average spacing of 1.5 kb, in 1,000 unrelated Ashkenazi Jewish SZ cases and controls as well as in parents of 300 of the SZ cases. Using this population isolate to limit genetic heterogeneity, we will identify large (>100 kb) and small (-15 - 100 kb) CNV, both frequent (> 1%) and rare (< 1%). We will confirm selected CNV from each of these four classes by quantitative TaqMan PCR. We will characterize breakpoints by long-range PCR followed by DNA sequencing or by FISH to metaphase chromosomes. Using prior high-density SNP genotyping in four genomic regions in these samples, we will investigate linkage disequilibrium patterns between individual CNVs and flanking SNPs. We will compare the CNV of the 300 trios to confirm genetic transmission and, along with the remaining 200 SZ cases and 500 controls, we will code CNV loci. CNVs with overlapping breakpoints will be initially coded as alleles of one locus but will also be evaluated as distinct loci as well. We expect to identify ~1,700 nonredundant CNVs in this study and we will publicly release this data within one month of its generation. These data will be evaluated by joint analysis of trios, cases, and controls for statistically significant evidence of association of one or more CNV loci with SZ. This study will result in a detailed examination of CNV in the Ashkenazim, providing one of the first large-scale evaluations of CNV in humans, and identify CNV loci that may influence SZ susceptibility. Schizophrenia (SZ) is a severe psychiatric disorder that is caused, at least in part, by variation in the DNA of patients' genomes. A new class of variation is the deletion or duplications of stretches of DNA. Using arrays that can scan the human genome for this "copy number variation", we will examine 1,000 unrelated Ashkenazi Jewish cases and controls as well as in 600 SZ parents. Although SZ is not found at an elevated frequency in individuals of AJ decent, the relative isolation of this population will reduce genome complexity, easing analysis. This study will not only be one of the first large-scale examinations of this type of variation in humans but may also identify variants that may influence whether or not an individual will suffer from SZ.

描述（由申请人提供）：精神分裂症（SZ）是一种具有很强遗传易感性的严重精神疾病。 SZ 的遗传力估计为 70-90%。迄今为止，使用连锁和关联研究来确定易感位点的大量努力仅取得了有限的成功。最近人们认识到，以重复和缺失形式出现的广泛拷贝数变异（CNV）经常发生在人类基因组中，并且是个体遗传变异的一个很大程度上未经调查的来源。 CNV 可能是 SZ 遗传易感性的一个未被识别的来源，并且可能对先前的遗传研究产生混杂的影响。我们在此建议使用平均间距为 1.5 kb 的寡核苷酸标记阵列，在 1,000 个不相关的德系犹太人 SZ 病例和对照以及 300 个 SZ 病例的父母中调查整个非重复人类基因组。使用该群体分离物来限制遗传异质性，我们将识别大 (>100 kb) 和小 (-15 - 100 kb) CNV，包括常见 (> 1%) 和罕见 (< 1%)。我们将通过定量 TaqMan PCR 确认从这四类中每一类中选择的 CNV。我们将通过长程 PCR、随后进行 DNA 测序或通过 FISH 对中期染色体进行表征来表征断点。利用先前对这些样本的四个基因组区域进行的高密度 SNP 基因分型，我们将研究个体 CNV 和侧翼 SNP 之间的连锁不平衡模式。我们将比较 300 个三人组的 CNV 以确认遗传传播，并且与其余 200 个 SZ 病例和 500 个对照一起，我们将对 CNV 基因座进行编码。具有重叠断点的 CNV 最初将被编码为一个基因座的等位基因，但也将被评估为不同的基因座。我们预计在这项研究中识别出约 1,700 个非冗余 CNV，我们将在生成后一个月内公开发布该数据。这些数据将通过三重奏、病例和对照的联合分析来评估，以获得一个或多个 CNV 基因座与 SZ 关联的统计显着证据。这项研究将对阿什肯纳兹人的 CNV 进行详细检查，提供人类 CNV 的首次大规模评估之一，并确定可能影响 SZ 易感性的 CNV 位点。精神分裂症 (SZ) 是一种严重的精神疾病，至少部分是由患者基因组 DNA 变异引起的。一类新的变异是 DNA 片段的删除或重复。使用可以扫描人类基因组以查找这种“拷贝数变异”的阵列，我们将检查 1,000 名不相关的德系犹太人病例和对照以及 600 名深圳父母。尽管 SZ 在 AJ 血统的个体中发现的频率并不高，但该群体的相对隔离将降低基因组的复杂性，从而简化分析。这项研究不仅是对人类此类变异的首次大规模检查之一，而且还可能确定可能影响个体是否患有精神分裂症的变异。