Bipolar I susceptibility by copy number variation in an isolated population

描述（由申请人提供）：双相情感障碍（BPI）是一种严重的精神障碍，遗传对易感性有很强的影响。遗传率，即种群中可归因于遗传变异的表型变异的比例，估计为90%。然而，到目前为止，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。近年来，人们认识到拷贝数变异（CNV）以重复和缺失的形式广泛存在于人类基因组中，可能是个体遗传变异的主要因素。然而，在典型的遗传研究中没有对CNV进行采样，因此可能是BPI遗传易感性的一个未被识别的来源，并可能对先前的疾病调查产生混淆影响。我们建议在366例父母BPI三人组和另外162例BPI病例中表征CNV，所有这些病例都是德系犹太人后裔。我们将调查整个非重复性人类基因组，平均密度为1.1 kb，使用210万个特征寡核苷酸阵列和竞争性基因组杂交方案，可靠地检测8kb及以上的CNV。对于常见（>.1 %频率）的CNV，将对CNV向受影响的BPI后代的扭曲传播进行数据评估。此外，通过比较510例独立的BPI病例和500例德系犹太人对照，将评估BPI连锁区域以及先前确定的候选基因区域或附近是否存在过量的罕见（< 1%）CNV。重要的CNV位点将通过替代技术进行验证，断点将通过PCR和/或定量基因分型策略解决，变体将仔细检查其与基因或进化保守序列的接近程度。我们进一步建议在本文讨论的366例BPI三人组和162例BPI病例的联合数据集中探索相关性，加上500例精神分裂症（SZ）患者（包括300例SZ三人组）和500例对照，所有德系犹太人后裔，CNV检测已经在进行中。有研究表明，BPI和精神分裂症可能并不代表不同的实体，而是类似生物病变的不同表现。这些疾病在临床表现和通过联系和关联确定的基因组位点上的大量重叠支持了这一点。我们的联合数据集是来自近亲繁殖人群的同类数据中最大的，有可能测试BPI和SZ是精神疾病连续体的一部分的断言，并揭示CNV易患精神疾病。公共卫生相关性：I型双相情感障碍是一种严重的精神疾病，约占总人口的1%，但导致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重复是否与双相I易感性有关；这些变异可能包含有关基因的重要线索，以及最终涉及双相I型障碍发展的生物学过程。

DESCRIPTION (provided by applicant): Bipolar I disorder (BPI) is a severe psychiatric disorder with a strong genetic influence on susceptibility. Heritability, the proportion of phenotypic variation in a population that is attributable to genetic variation, is estimated to be >90%. However, 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 may be a major contributor to individual genetic variation. However, CNV has not been sampled in typical genetic studies, and may therefore be an unrecognized source of BPI genetic susceptibility and potentially a confounding influence on prior investigations of disease. We propose here to characterize CNV in 366 case-parent BPI trios plus an additional 162 BPI cases, all of Ashkenazi Jewish descent. We will survey the entire nonrepetitive human genome, at an average density of 1.1 kb, using 2.1 million feature oligonucleotide arrays and a competitive genomic hybridization protocol, reliably detecting CNV 8kb and larger. For common (>1% frequency) CNV, the data will be evaluated for distorted transmission of CNV to affected BPI offspring. Additionally, presence of excess rare (< 1%) CNV in BPI linkage regions as well as in or near previously identified candidate gene regions will be evaluated by comparison of 510 independent BPI cases and 500 Ashkenazi controls previously assessed for genome-wide CNV. Significant CNV loci will be validated with an alternate technology, breakpoints will be resolved with PCR and/or quantitative genotyping strategies, and variants will be carefully scrutinized for their proximity to genes or evolutionarily conserved sequences. We further propose to explore association in a joint dataset of the 366 BPI trios and 162 BPI cases discussed here, plus 500 schizophrenia (SZ) patients (including 300 SZ trios) and 500 controls, all of Ashkenazi Jewish descent, in whom CNV detection is already proceeding. It has been suggested that BPI and schizophrenia may not represent distinct entities, but instead are varying manifestations of a similar biological lesion. This is supported by the substantial overlap between these disorders, in both clinical presentation and genomic loci identified by linkage and association. Our joint dataset, the largest of its kind from an inbred population, has the potential to test the assertion that BPI and SZ are part of a continuum of psychiatric illness, and reveal CNV that predispose to psychiatric illness. PUBLIC HEALTH RELEVANCE: Bipolar I disorder is a severe psychiatric illness 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 bipolar I susceptibility; these variants may harbor important clues about the genes, and ultimately the biological process, involved in the development of Bipolar I disorder.