Investigating the Role of Genomic Copy Number Variation in Risk for Schizophrenia

研究基因组拷贝数变异在精神分裂症风险中的作用

基本信息

批准号：
7582379
负责人：
Jennifer Gladys Mulle
金额：
$ 5.17万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-04-16 至 2010-04-15
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Schizophrenia (SZ) is a severe psychiatric disorder with a strong genetic influence on susceptibility. 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. This study is designed to investigate the hypothesis that CNV may be an unrecognized cause of SZ genetic susceptibility. To accomplish this, we will use an Ashkenazi Jewish population to limit genetic heterogeneity. We will first characterize the distribution of CNV in 500 Ashkenazi Jewish controls, by interrogating the entire nonrepetitive human genome with 2.1 million feature oligonucleotide arrays (average density 1.5 kb) and a competitive genomic hybridization protocol. We expect to identify ~2,000 nonredundant CNVs, large (>100 kb) and small (-15 - 100 kb), frequent (> 1%) and rare (< 1%). We will confirm selected CNV from each of these four classes by an alternate technology, such as quantitative TaqMan PCR 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. Next, we will characterize whole-genome CNV in 500 AJ SZ cases as well as 600 parents of these cases. For common (>1% frequency CNV), 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. The presence of rare (< 1%) CNV in SZ cases will be evaluated in previously identified linkage regions as well as in or near glutamate gene regions. Significant CNV loci will be carefully scrutinized for their proximity to genes or evolutionarily conserved sequences. 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 is a severe psychiatric disorder that affects 1% of the general population, but causes of this disorder remain unknown. We propose to investigate whether deletions or duplications in the human genome are related to schizophrenia susceptibility; these variants may harbor important clues about the genes, and ultimately the biological process, involved in development of schizophrenia.

描述（由申请人提供）：精神分裂症（SZ）是一种严重的精神疾病，遗传对易感性有很强的影响。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。本研究旨在调查 CNV 可能是 SZ 遗传易感性的一个未被识别的原因这一假设。为了实现这一目标，我们将使用德系犹太人群体来限制遗传异质性。我们将首先通过使用 210 万个特征寡核苷酸阵列（平均密度 1.5 kb）和竞争性基因组杂交方案询问整个非重复人类基因组，来表征 500 个德系犹太人对照中的 CNV 分布。我们期望识别约 2,000 个非冗余 CNV，大的 (>100 kb) 和小的 (-15 - 100 kb)、频繁的 (> 1%) 和罕见的 (< 1%)。我们将通过替代技术（例如定量 TaqMan PCR 或通过 FISH 检测中期染色体）从这四个类别中确认选定的 CNV。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。接下来，我们将描述 500 个 AJ SZ 病例以及这些病例的 600 个父母的全基因组 CNV。对于常见的（>1% 频率的 CNV），这些数据将通过三重奏、病例和对照的联合分析来评估，以获取一个或多个 CNV 基因座与 SZ 关联的统计显着证据。 SZ 病例中罕见 (< 1%) CNV 的存在将在先前确定的连锁区域以及谷氨酸基因区域内或附近进行评估。将仔细检查重要的 CNV 基因座是否与基因或进化上保守的序列接近。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。精神分裂症是一种严重的精神疾病，影响总人口的 1%，但这种疾病的病因仍不清楚。我们建议研究人类基因组中的缺失或重复是否与精神分裂症易感性有关；这些变异可能蕴藏着有关基因以及最终涉及精神分裂症发展的生物过程的重要线索。