Bipolar I susceptibility by copy number variation in an isolated population

孤立群体中拷贝数变异的双相 I 易感性

• 批准号: 7866573
• 负责人: Stephen T. Warren
• 金额: $ 73.97万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-25 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7866573
• 关键词: Affect; Age; Alleles; Ashkenazim; Biological; Biological Process; Bipolar Disorder; Candidate Disease Gene; Categories; Clinical; Collection; Conserved Sequence; Copy Number Polymorphism; Data; Data Set; Detection; Development; Diagnostic; Disease; Elements; Family history of; Frequencies; Gender; General Population; Genes; Genetic; Genetic Predisposition to Disease; Genetic Variation; Genomic Hybridizations; Genomics; Genotype; Heritability; Human Genome; Individual; Investigation; Joints; Lesion; Mental disorders; Morbidity - disease rate; Oligonucleotide Microarrays; Onset of illness; Parents; Patients; Population; Predisposition; Protocols documentation; SNP genotyping; Sampling; Schizophrenia; Source; Subgroup; Surveys; Symptoms; Technology; Testing; Variant; base; case control; density; follower of religion Jewish; genome-wide; meetings; offspring; public health relevance; statistics; success; transmission process; Affect; Age; Alleles; Ashkenazim; Biological; Biological Process; Bipolar Disorder; Candidate Disease Gene; Categories; Clinical; Collection; Conserved Sequence; Copy Number Polymorphism; Data; Data Set; Detection; Development; Diagnostic; Disease; Elements; Family history of; Frequencies; Gender; General Population; Genes; Genetic; Genetic Predisposition to Disease; Genetic Variation; Genomic Hybridizations; Genomics; Genotype; Heritability; Human Genome; Individual; Investigation; Joints; Lesion; Mental disorders; Morbidity - disease rate; Oligonucleotide Microarrays; Onset of illness; Parents; Patients; Population; Predisposition; Protocols documentation; SNP genotyping; Sampling; Schizophrenia; Source; Subgroup; Surveys; Symptoms; Technology; Testing; Variant; base; case control; density; follower of religion Jewish; genome-wide; meetings; offspring; public health relevance; statistics; success; transmission process

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.

描述（由申请人提供）：双相情感障碍（BPI）是一种严重的精神疾病，对易感性具有强大的遗传影响。遗传力，是遗传变异的人群中表型变异的比例，估计为90％。但是，迄今为止使用链接和关联研究同时使用联系和关联研究来确定敏感性基因座的强烈努力仅取得了有限的成功。最近，人们对以重复和缺失的形式进行了广泛的拷贝数变化（CNV）经常发生在人类基因组中，并且可能是个人遗传变异的主要贡献。但是，CNV尚未在典型的遗传研究中进行采样，因此可能是BPI遗传易感性的未被认可的来源，并且可能对先前的疾病研究产生混乱的影响。我们在这里提议在366个案例的BPI三重奏以及另外162个BPI案例中描述CNV，这是Ashkenazi犹太血统的所有案例。我们将使用210万个特征寡核苷酸阵列和具有竞争性的基因组杂交方案，以1.1 kb的平均密度调查整个非重复的人基因组，可靠地检测到CNV 8KB及更大。对于常见（> 1％频率）CNV，将评估数据对CNV的变形传输到受影响的BPI后代。此外，将通过比较510个独立的BPI病例和500个先前评估了针对全基因组CNV的先前评估的ASHKENAZI对照组来评估BPI连锁区域以及在先前确定的候选基因区域中存在过多的（<1％）CNV。重要的CNV基因座将通过替代技术验证，断点将通过PCR和/或定量基因分型策略解决，并且将仔细仔细审查其与基因或进化保守的序列的近距离。我们进一步建议在此处讨论的366个BPI三重奏和162例BPI病例的联合数据集中探索关联，以及500名精神分裂症（SZ）患者（包括300 SZ三重奏）和500个对照组，所有Ashkenazi犹太血统的所有对照，在其中CNV检测中都已经在进行CNV检测。有人提出，BPI和精神分裂症可能不能代表不同的实体，而是类似生物病变的不同表现。这些疾病之间的实质重叠在临床表现和通过连锁和关联确定的基因组基因座中的实质重叠支持。我们的联合数据集是来自近交的同类数据集，它有可能检验BPI和SZ是精神病连续性的一部分的主张，并揭示了CNV易于精神病。 公共卫生相关性：双相情感障碍是一种严重的精神疾病，影响约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双极I易感性有关。这些变体可能具有有关这些基因的重要线索，最终涉及躁郁症发展的生物学过程。