Bipolar I susceptibility by copy number variation in an isolated population

描述（由申请人提供）：双相I型障碍（BPI）是一种严重的精神疾病，对易感性有很强的遗传影响。遗传力，即群体中可归因于遗传变异的表型变异的比例，估计> 90%。然而，迄今为止，使用连锁和关联研究来识别易感基因座的巨大努力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，并可能是一个主要的贡献者个体的遗传变异。然而，在典型的遗传学研究中，CNV尚未被采样，因此可能是BPI遗传易感性的一个未被认识的来源，并可能对先前的疾病调查产生混淆影响。我们建议在这里的特点CNV在366例父母BPI三人加上额外的162例BPI情况下，所有的德系犹太血统。我们将调查整个非重复的人类基因组，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协议，可靠地检测CNV 8 kb及更大。对于常见（>1%频率）CNV，将评估CNV向受影响BPI后代的扭曲传播的数据。此外，通过比较510例独立的BPI病例和500例德系犹太人对照的全基因组CNV，评估BPI连锁区以及先前鉴定的候选基因区或附近是否存在过量的罕见（< 1%）CNV。将使用替代技术验证重要的CNV基因座，将使用PCR和/或定量基因分型策略解析断点，并将仔细检查变体与基因或进化保守序列的接近程度。我们进一步建议在这里讨论的366个BPI三人组和162个BPI病例的联合数据集中探索相关性，加上500名精神分裂症（SZ）患者（包括300名SZ三人组）和500名对照组，所有这些患者都是德系犹太人后裔，CNV检测已经在进行中。有人认为，BPI和精神分裂症可能并不代表不同的实体，而是类似生物学病变的不同表现。这是由这些疾病之间的大量重叠支持的，在临床表现和通过连锁和关联鉴定的基因组位点两者中。我们的联合数据集是来自近亲繁殖人群的同类数据集中最大的，有可能测试BPI和SZ是精神疾病连续体的一部分的断言，并揭示易患精神疾病的CNV。 公共卫生相关性：双相I型障碍是一种严重的精神疾病，影响约1%的一般人群，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双相I型易感性有关;这些变异可能包含有关基因的重要线索，并最终涉及双相I型障碍的发展的生物学过程。

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.