Design Approaches for Sequencing Disease-Associated Regions in Psoriasis

描述(申请人提供)：目前，常见多因素疾病的完整遗传解剖面临的主要挑战是因果变异的鉴定。高通量DNA测序技术的出现为鉴定这些因果变异提供了一个极其强大的新工具。然而，为设计和分析大规模平行DNA测序实验以识别因果变异而开发同样稳健的策略还处于初级阶段。在这一应用中，我们建议结合我们研究团队经过验证的表型鉴定、临床数据管理和生物统计学专业知识来解决这一重要问题，方法是评估利用新兴测序技术来加深我们对牛皮癣(一种常见的自身免疫性疾病)病理中所涉及的基因的理解的策略。我们的策略将重点放在以前与疾病易感性有关的遗传位点上，包括MHC 区域。为此，我们提出了以下具体目标：1.从特征良好、得到适当同意的多民族样本中收集DNA样本和详细的表型进行重新测序。 2.与测序中心(S)就序列数据生成，特别是跟踪数据的分析进行交互，以产生高质量的基因型和单倍型数据。3.进行有针对性的重新测序和随访，以确定至少10个已知的非MHC银屑病基因座的致病变异。4.对已知携带至少3个牛皮癣和/或牛皮癣关节炎易感基因的650 kb区间(HCG22-BAT5)进行长阅读靶向重测序。虽然我们根据自己的样本和可能获得的其他样本，就每个目标提出具体建议，但我们明白，实际的研究计划将取决于选定的研究、U01指导委员会的意见和技术发展。我们期待着与其他研究的同事一起工作，并相信我们在基因研究的统计设计和分析方面的优势、我们良好的合作记录以及我们独特的样本集将使我们能够为这一努力做出重要贡献。 相关性：这项工作将建立在最近对牛皮癣和其他疾病的遗传学研究的基础上，通过使用大规模DNA测序来识别牛皮癣患者与正常对照组之间的微小遗传差异。然后，这些信息将被用来确定这些差异中的哪些实际上导致了牛皮癣。一旦我们知道哪些差异驱动了疾病的进程，它们将成为开发更好的牛皮癣治疗方法的目标。

DESCRIPTION (provided by applicant): Currently, the major challenge facing the complete genetic dissection of common multifactorial diseases is the identification of causal variants. The advent of robust technologies for high-throughput DNA sequencing provides an extremely powerful new tool for the identification of such causal variants. However, the development of equally robust strategies for the design and analysis of massively parallel DNA sequencing experiments for identification of causal variants is in its infancy. In this application, we propose to combine the proven phenotyping, clinical data management, and biostatistical expertise of our research team to address this important problem, by evaluating strategies that utilize emerging sequencing technologies to further our understanding of loci implicated in the pathology of psoriasis, a common autoimmune disorder. Our strategies will focus on the genetic loci previously implicated in disease susceptibility, including the MHC region. To this end, we propose the following specific aims: 1. Assemble DNA samples and detailed phenotypes from well-characterized, appropriately consented multiethnic samples for resequencing. 2. Interact with the sequencing center(s) regarding sequence data generation and particularly on analysis of the trace data to produce high quality genotype and haplotype data. 3. Carry out targeted resequencing and follow-up to identify the causative variants at least ten known non-MHC psoriasis loci. 4. Carry out long-read targeted resequencing of a 650 kb interval (HCG22-BAT5) known to carry at least 3 susceptibility loci for psoriasis and/or psoriatic arthritis. While we make specific proposals in each of these aims based on our own samples and other samples likely to be available, we understand that actual study plans will depend on the studies selected, the views of the U01 Steering Committee, and on technology development. We look forward to working together with colleagues from the other studies and believe our strengths in statistical design and analysis of genetic studies, our strong record of collaboration, and our unique sample sets, will allow us to be important contributors to such an effort. RELEVANCE: This work will build on recent genetic studies of psoriasis and other diseases by using large-scale DNA sequencing to identify small genetic differences between people with psoriasis compared to normal controls. This information will then be used to identify which of these differences actually contribute to causing psoriasis. Once we know which of the differences drive the disease process, they will become targets for the development of better treatments for psoriasis.