Next Generation Sequencing for Disease Mapping in a Founder Population

描述(由申请人提供)： 项目摘要精神分裂症(SZ)具有较高的遗传率(~80%)和较高的兄弟姐妹复发率(S~10岁)，但易感基因的鉴定已被证明具有极大的挑战性。这个名为“在创始人人群中绘制疾病图谱的下一代测序”的应用程序旨在通过利用一组独特的德系犹太人(AJ)精神分裂症/分裂情感障碍患者(n~1000)和匹配良好的德系犹太人对照(n~2000)，识别与疾病相关的罕见变异。这些样本已经具有作为以前资助的项目(RC2 MH089964)的一部分生成的GWAS数据(Illumina Omni1-Quad Platform)。在这项提案中，我们打算利用下一代测序从300例病例和500例对照中获得高质量、高深度(50x)的全基因组数据，以获得最大的基因组信息量，这是基于一种应用于GWAS数据的新的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，我们将能够将所有基因组变异的80%归因于完整的样本集。相比之下，从欧洲或欧美异种繁殖的种群中提取的相同数量的样本只允许归因于总种群变异性的20%-25%。这种归因，再加上全队列中额外计划的基因分型，将极大地增强使用单标记和折叠统计方法检测显著相关的罕见变异的能力。然后，将在包含AJ和非AJ病例和对照的公开可获得的SZ队列(例如，GAIN)中进行复制和推广。所有的DNA都已经收集好了，马上就可以测序了。根据我们初步的Gwas数据，以及其他常见的复杂疾病，如乳腺癌和帕金森病的文献，AJ人群很可能在稀有易感等位基因子集上得到丰富。因此，这些等位基因可能具有比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，从而增强了检测疾病相关基因座的能力。值得注意的是，即使在AJ人群中这些疾病的发病率没有明显增加的情况下，这种丰富也可能发生。除了提供有关罕见变异在这种毁灭性和致残性疾病的遗传结构中所起作用的信息数据外，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，还将提供与确定和解释下一代测序数据相关的计算方法开发，以供更广泛的遗传学/基因组学社区共享。

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.