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，对易感性具有强烈的遗传影响。迄今为止，使用联系和关联研究同时识别易感基因座的强烈努力仅取得了有限的成功。最近，人们对以重复和缺失的形式进行了广泛的拷贝数变化（CNV），经常发生在人类基因组中，并且是个体遗传变异的很大程度上未受监测的来源。这项研究旨在调查CNV可能是SZ遗传易感性的原因。为此，我们将使用Ashkenazi犹太人人口来限制遗传异质性。我们将首先以210万个特征寡核苷酸阵列（平均密度1.5 kb）和竞争性的基因组杂交方案来审问整个非反复性人类基因组中CNV在500个Ashkenazi犹太控件中的分布。我们预计将确定约2,000个非冗余CNV，大（> 100 kb）和小（-15-100 kb），频繁（> 1％）和稀有（<1％）。我们将通过替代技术（例如定量的Taqman PCR或FISH与中期染色体）确认从这四个类别中的每一个中选择的CNV。在这些样品中的四个基因组区域中使用先前的高密度SNP基因分型，我们将研究单个CNV和侧翼SNP之间的连锁不平衡模式。接下来，我们将在500个AJ SZ案件中以及这些案件的600个父母中描述全基因组CNV。对于常见（> 1％的频率CNV），将通过对三重奏，病例和对照组的联合分析来评估这些数据，以证明一个或多个CNV基因座与SZ的统计学上有重要的证据。在先前鉴定的连锁区域以及谷氨酸基因区域或附近，将评估SZ病例中罕见（<1％）CNV的存在。明显的CNV基因座将仔细检查其与基因或进化保守的序列的接近。这项研究将导致对Ashkenazim中CNV的详细检查，从而为人类中CNV提供了最早的大规模评估之一，并确定可能影响SZ易感性的CNV基因座。精神分裂症是一种严重的精神疾病，影响了普通人群的1％，但这种疾病的原因仍然未知。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的易感性有关；这些变体可能具有有关这些基因的重要线索，最终涉及精神分裂症发展的生物学过程。