Design Approaches for Sequencing Disease-Associated Regions in Psoriasis

描述（由申请人提供）：目前，常见多因素疾病的完整遗传解剖所面临的主要挑战是鉴定致病变异。强大的高通量DNA测序技术的出现为鉴定这种致病变异提供了非常强大的新工具。然而，同样强大的策略，用于设计和分析大规模并行DNA测序实验，以确定因果变异的发展还处于起步阶段。在本申请中，我们建议结合联合收割机的证明表型，临床数据管理，和生物统计学专业知识，我们的研究团队，以解决这个重要的问题，通过评估战略，利用新兴的测序技术，以进一步了解基因座牵连的银屑病，一种常见的自身免疫性疾病的病理。我们的策略将集中在以前与疾病易感性有关的遗传位点，包括MHC 地区为此，我们提出以下具体目标：1.从充分表征的、适当同意的多种族样本中收集DNA样本和详细的表型进行重新测序。 2.与测序中心就序列数据生成进行互动，特别是分析痕量数据，以生成高质量的基因型和单倍型数据。3.进行靶向重测序和随访，以确定至少10个已知的非MHC银屑病位点的致病变体。4.对已知携带至少3个银屑病和/或银屑病关节炎易感基因座的650 kb间隔（HCG 22-BAT 5）进行长读段靶向重测序。虽然我们根据我们自己的样本和其他可能获得的样本对这些目标提出了具体建议，但我们理解实际的研究计划将取决于所选择的研究、U 01指导委员会的意见以及技术发展。我们期待着与其他研究的同事合作，并相信我们在遗传研究的统计设计和分析方面的优势，我们强大的合作记录以及我们独特的样本集将使我们成为这一努力的重要贡献者。 相关性：这项工作将建立在最近对银屑病和其他疾病的遗传研究的基础上，通过使用大规模DNA测序来确定银屑病患者与正常对照组之间的微小遗传差异。 这些信息将被用来确定哪些差异实际上有助于引起牛皮癣。一旦我们知道哪些差异驱动疾病过程，它们将成为开发更好的银屑病治疗方法的目标。

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.