Investigating the Role of Genomic Copy Number Variation in Risk for 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，对易感性有很强的遗传影响。利用连锁和关联研究来鉴定易感基因座的努力到目前为止只取得了有限的成功。最近，人们已经认识到，广泛的拷贝数变异（CNV），在复制和缺失的形式，经常发生在人类基因组中，是一个很大程度上未调查的个体遗传变异的来源。本研究旨在探讨CNV可能是SZ遗传易感性未被认识的原因的假设。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。我们将首先在500德系犹太人控制的CNV的分布特征，通过询问整个非重复的人类基因组与210万功能寡核苷酸阵列（平均密度1.5 kb）和竞争性基因组杂交协议。我们预计将鉴定约2，000个非冗余的CNV，大的（>100 kb）和小的（约15 - 100 kb），常见的（> 1%）和罕见的（< 1%）。我们将通过一种替代技术，如定量TaqMan PCR或通过FISH对中期染色体，从这四个类别中的每一个中确认所选择的CNV。利用这些样本中四个基因组区域的高密度SNP基因分型，我们将研究个体CNVs和侧翼SNP之间的连锁不平衡模式。接下来，我们将描述500例AJ SZ病例以及这些病例的600例父母的全基因组CNV。对于常见（>1%频率的CNV），将通过联合分析三人组、病例组和对照组来评估这些数据，以获得一个或多个CNV基因座与SZ相关的统计学显著性证据。SZ病例中罕见（< 1%）CNV的存在将在先前鉴定的连锁区以及谷氨酸基因区或其附近进行评价。将仔细检查重要的CNV基因座与基因或进化保守序列的接近程度。这项研究将导致对德系犹太人CNV的详细检查，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基因座。 精神分裂症是一种严重的精神疾病，影响1%的普通人群，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易感性有关;这些变异可能包含有关基因的重要线索，并最终涉及精神分裂症发展的生物学过程。

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.