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

描述(申请人提供)：精神分裂症(SZ)是一种严重的精神疾病，具有强烈的遗传易感性影响。到目前为止，利用连锁和关联研究来确定易感基因座的密集努力只取得了有限的成功。最近人们认识到，以复制和缺失的形式出现的广泛拷贝数变异(CNV)经常发生在人类基因组中，并且是一个在很大程度上未被调查的个体遗传变异的来源。这项研究旨在调查CNV可能是SZ遗传易感性的未知原因的假设。为了实现这一点，我们将使用德系犹太人人口来限制基因异质性。我们将首先通过询问具有210万个特征寡核苷酸阵列(平均密度为1.5kb)的整个非重复人类基因组和竞争性基因组杂交方案，来表征CNV在500个德系犹太人对照中的分布。我们预计识别约2,000个非冗余CNV，大(&gt；100kb)和小(-15-100kb)，频繁(&gt；1%)和罕见(&lt；1%)。我们将通过另一种技术从这四个类别中的每一个中确定选定的CNV，例如定量TaqMan聚合酶链式反应(TaqMan PCR)或FISH到染色体中期。利用先前在这些样本的四个基因组区域进行的高密度SNP基因分型，我们将研究单个CNV和侧翼SNPs之间的连锁不平衡模式。接下来，我们将对500例AJ SZ病例以及600例这些病例的父母进行全基因组CNV的特征分析。对于常见的(&gt；1%频率的CNV)，这些数据将通过三者、病例和对照的联合分析来评估，以寻找一个或多个CNV基因座与SZ相关的统计上的显著证据。在SZ病例中罕见的(1%)CNV的存在将在先前确定的连接区域以及谷氨酸基因区域或附近进行评估。重要的CNV基因座将被仔细检查它们是否接近基因或进化上保守的序列。这项研究将导致详细检查阿什肯纳齐姆地区的CNV，提供第一批大规模的人类CNV评估之一，并识别可能影响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1%的总人口，但这种疾病的原因尚不清楚。我们建议调查人类基因组中的缺失或复制是否与精神分裂症易感性有关；这些变异可能包含有关精神分裂症发展过程中的基因以及最终生物学过程的重要线索。

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.