Schizophrenia susceptibility by copy number variation in the Ashkenazim

描述（申请人提供）：精神分裂症（SZ）是一种严重的精神疾病，具有很强的遗传易感性。据估计，SZ的遗传率为70-90%。迄今为止，利用连锁和关联研究来确定易感位点的大量努力只取得了有限的成功。最近，人们认识到广泛的拷贝数变异（CNV），以重复和缺失的形式，经常发生在人类基因组中，是一个很大程度上未被调查的个体遗传变异的来源。CNV可能是SZ遗传易感性的一个未被认识的来源，并且可能对先前的遗传研究产生混淆影响。在此，我们建议在1000例无亲缘关系的德系犹太人SZ病例和对照以及300例SZ病例的父母中，使用平均间隔为1.5 kb的寡核苷酸标记阵列来调查整个非重复性人类基因组。利用这一群体分离物来限制遗传异质性，我们将鉴定出大（> - 100 kb）和小（-15 - 100 kb）的CNV，它们既常见（> - 1%），也罕见（< 1%）。我们将通过定量TaqMan PCR从这四个类别中选择CNV进行确认。我们将通过远程PCR，随后进行DNA测序或FISH到中期染色体来表征断点。利用这些样本中四个基因组区域的高密度SNP基因分型，我们将研究单个CNVs与侧链SNP之间的连锁不平衡模式。我们将比较300例三胞胎的CNV以确认遗传传播，并与其余200例SZ病例和500例对照一起，对CNV位点进行编码。具有重叠断点的CNVs最初将被编码为一个位点的等位基因，但也将被评估为不同的位点。我们预计在这项研究中发现约1,700个非冗余CNVs，我们将在数据生成后一个月内公开发布这些数据。这些数据将通过三人组、病例组和对照组的联合分析进行评估，以寻找一个或多个CNV位点与SZ相关的统计学显著证据。这项研究将对阿什肯纳兹犹太人的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的变异引起的。一类新的变异是DNA片段的删除或复制。我们将使用能够扫描人类基因组的这种“拷贝数变异”的阵列，检查1000个不相关的德系犹太人病例和对照，以及600名SZ父母。虽然SZ在AJ体面个体中没有发现频率升高，但该群体的相对分离将降低基因组复杂性，简化分析。这项研究不仅将是对人类这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.