Schizophrenia susceptibility by copy number variation in the Ashkenazim

描述(申请人提供)：精神分裂症(SZ)是一种严重的精神障碍，具有强烈的遗传易感性。SZ的遗传力估计为70%-90%。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。CNV可能是SZ遗传易感性的未知来源，并可能对先前的遗传学研究产生混杂的影响。在这里，我们建议使用平均间距为1.5kb的寡核苷酸标记阵列，在1000例无关的德系犹太人SZ病例和对照中以及300例SZ病例的父母中，调查整个非重复的人类基因组。使用这个种群分离株来限制遗传异质性，我们将识别大的(&gt；100kb)和小的(-15-100kb)CNV，包括频繁的(&gt；1%)和罕见的(&lt；1%)。我们将通过定量TaqMan聚合酶链式反应从这四类中的每一类中确定选定的CNV。我们将通过长程聚合酶链式反应、DNA测序或FISH来确定断裂点的特征。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。我们将比较300个三联体的CNV以确认基因传播，并与剩余的200例SZ病例和500名对照一起，我们将编码CNV基因座。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约1700个非冗余CNV，并将在数据生成后一个月内公开发布这些数据。这些数据将通过对三组、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相关的统计显著证据。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(SZ)是一种严重的精神疾病，至少部分由患者基因组的DNA变异引起。一类新的变异是DNA片段的缺失或复制。使用可以扫描人类基因组以寻找这种“拷贝数变异”的阵列，我们将检查1000个无关的德系犹太人病例和对照，以及600名SZ父母。虽然在AJ体面个体中没有发现SZ的高频率，但这一群体的相对隔离将降低基因组的复杂性，使分析变得容易。这项研究不仅将是对人类这种类型变异的第一次大规模检查，而且还可能识别可能影响个人是否会患上SZ的变异。

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.