Next Generation Sequencing for Disease Mapping in a Founder Population

用于创建人群疾病图谱的下一代测序

• 批准号: 9128294
• 负责人: Ariel Darvasi
• 金额: $ 21.15万
• 依托单位: FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9128294
• 关键词: Affect; Algorithms; Alleles; American; Architecture; Ashkenazim; Back; Biology; Collaborations; Collection; Communities; Complex; Computing Methodologies; Consensus; Cost Sharing; DNA; DNA Resequencing; Data; Diagnosis; Disease; European; Founder Generation; Frequencies; Funding; Future; Gene Frequency; Gene Targeting; Genetic; Genetic Heterogeneity; Genome; Genomic Segment; Genomics; Genotype; Haplotypes; Health; Heritability; Heterogeneity; Incidence; Individual; Institutes; Institution; International; Life; Literature; Maps; Medical Research; Methodology; National Institute of Mental Health; Odds Ratio; Parkinson Disease; Patients; Phenotype; Play; Population; Recurrence; Research Personnel; Resources; Role; Sampling; Schizoaffective Disorders; Schizophrenia; Siblings; Source; Susceptibility Gene; Technology; Variant; analytical method; base; case control; cohort; cost; disability; follow-up; follower of religion Jewish; genetic risk factor; genetic variant; genome sequencing; genome wide association study; genome-wide; genomic variation; identity by descent; malignant breast neoplasm; member; method development; next generation sequencing; novel; rare variant; repository; risk variant; severe mental illness; targeted sequencing

DESCRIPTION (provided by applicant): Project Summary Schizophrenia (SZ) is characterized by high heritability (~80%) and elevated sibling recurrence ( s ~ 10), yet the identification of susceptibility genes has proven extremely challenging. This application entitled "Next Generation Sequencing for Disease Mapping in a Founder Population" aims to identify rare variants associated with illness by utilizing a unique cohort of Ashkenazi Jewish (AJ) patients with schizophrenia/schizoaffective disorder (n~1000) and well-matched Ashkenazi controls (n~2000). These samples already have GWAS data (Illumina Omni1-Quad platform) generated as part of a previously-funded project (RC2 MH089964). In this proposal, we intend to utilize next-generation sequencing to obtain high-quality, high-depth (>50x) whole-genome data from 300 cases and 500 controls selected from this cohort for maximum genomic informativeness, based on a novel genomewide haplotype sharing approach applied to the GWAS data. Due to the limited number of founders in the Ashkenazi population, we will then be able to impute >80% of all genomic variation back into the full set of samples. By contrast, the same number of samples derived from outbred European or European-American populations would permit imputation of only 20-25% of the total population variability. This imputation, combined with additional planned genotyping in the full cohort, will greatly enhance power to detect significantly associated rare variants using both single-marker and collapsing statistical approaches. Replication and extension will then be performed in publicly available SZ cohorts (e.g., GAIN) containing both AJ and non-AJ cases and controls. All DNA has already been collected and is immediately ready for sequencing. Based on our preliminary GWAS data, as well as literature from other common, complex disorders such as breast cancer and Parkinson's disease, the AJ population is likely to be enriched for a subset rare susceptibility alleles. Such alleles may therefore have higher allele frequencies and odds ratios than those detectable in other populations, providing enhanced power to detect disease-relevant loci. Notably, this enrichment can occur even in the absence of detectably increased incidence of these disorders in the AJ population. In addition to providing informative data on the role of rare variants in the genetic architecture of this devastating and disabling disorder, sequencing of the control cohort will provide an invaluable resource for future studies of many complex disorders. Moreover, computational methods development relevant to the ascertainment and interpretation of next-generation sequencing data will also be made available for sharing with the broader genetics/genomics community.

描述（由申请人提供）： 精神分裂症（SZ）的特点是高遗传率（~80%）和同胞复发率升高（s ~ 10），但易感基因的鉴定已被证明极具挑战性。这项名为“创始人人群疾病图谱的下一代测序”的申请旨在通过利用患有精神分裂症/情感障碍的德系犹太人（AJ）患者（n~1000）和匹配良好的德系犹太人对照（n~2000）的独特队列来识别与疾病相关的罕见变异。这些样本已经具有作为先前资助的项目（RC 2 MH 089964）的一部分生成的GWAS数据（Illumina Omni 1-Quad平台）。在这项提案中，我们打算利用下一代测序技术，从该队列中选择的300例病例和500例对照中获得高质量、高深度（> 50倍）的全基因组数据，以获得最大的基因组信息，这是基于一种适用于GWAS数据的新型全基因组单倍型共享方法。由于德系犹太人群体中创始人的数量有限，我们将能够将>80%的所有基因组变异推回到完整的样本集中。相比之下，来自远交欧洲或欧美人群的相同数量的样本将允许插补总人群变异的20-25%。这种插补，结合全队列中额外计划的基因分型，将大大提高使用单标记和折叠统计方法检测显著相关罕见变异的能力。然后将在公开可用的SZ队列中进行复制和扩展（例如，GAIN），包含AJ和非AJ病例和对照。所有的DNA都已经收集完毕，并立即准备测序。根据我们的初步GWAS数据，以及其他常见的，复杂的疾病，如乳腺癌和帕金森氏病的文献，AJ人群很可能是一个子集罕见的易感等位基因富集。因此，这些等位基因可能具有比在其他人群中可检测到的等位基因频率和优势比更高的等位基因频率和优势比，从而提供了检测疾病相关基因座的增强的能力。值得注意的是，即使在AJ人群中这些疾病的发生率没有可检测到的增加的情况下，这种富集也可以发生。除了提供关于罕见变异在这种破坏性和致残性疾病的遗传结构中的作用的信息数据外，对照队列的测序将为许多复杂疾病的未来研究提供宝贵的资源。此外，与下一代测序数据的确定和解释相关的计算方法开发也将与更广泛的遗传学/基因组学社区共享。