Identification of Causal Variants in Psoriasis

银屑病致病变异的鉴定

基本信息

批准号：
8584976
负责人：
Wilson Liao
金额：
$ 46.58万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-19 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8584976
关键词：
Address Affect American Architecture Asians Autoimmune Diseases Bioinformatics Biological Cell Lineage Cellular Assay Code Complex DNA Sequence Data Set Disease European Foundations Frequencies Functional RNA Future Gene Expression Gene Frequency Genes Genetic Genetic Polymorphism Genetic Variation Genome Genotype Histocompatibility Testing Human Immune Immunologist Inflammatory International Knowledge Lead Link Linkage Disequilibrium Maps Mediating Meta-Analysis Methods Minor Morbidity - disease rate Outcome Pathogenesis Phenotype Predisposition Psoriasis Regulatory Element Relative (related person)Research Design Sampling Statistical Models Technology Testing Translating Variant Work cell type cohort exome sequencing follow-up genome wide association study genome-wide improved insight multidisciplinary novel novel strategies public health relevance skin disorder

项目摘要

DESCRIPTION (provided by applicant): Genome-wide association studies (GWAS) have successfully identified approximately 36 psoriasis susceptibility loci. However, the causal variants at these loci remain largely unknown, and it is very likely that a large number of additional loci remain to be identified. In this proposal, we pursue a comprehensive strategy to identify both common and rare causal variants in psoriasis, and then perform targeted functional studies of these variants. In the first aim, we focus on the identification of common causal variants, the majority of which are expected to be regulatory. We improve statistical power by performing a meta-analysis of 5 European ancestry psoriasis GWAS totaling 4,832 cases and 10,103 controls, and further refine causal regions by comparison with 2 Asian ancestry psoriasis GWAS totaling 1,588 cases and 3,566 controls. From within causal regions, putative causal variants are identified using a novel bioinformatics approach that takes advantage of the recent release of a genome-wide map of human regulatory elements. Causal variants are further validated by follow-up genotyping in an independent sample of 11,141 cases and 11,020 controls. In the second aim, we focus on the identification of rare, coding variants. To increase our statistical power to detect rare variant associations, we perform exome sequencing of 500 severe-phenotype psoriasis cases and then impute the identified rare variants onto a GWAS cohort of 4,832 cases and 10,103 controls. Putative causal variants are again validated in independent cohorts. In the third aim, we create a psoriasis regulatory roadmap that defines how non-coding variants impact cell lineage specific gene expression, and further test coding variants for functional impact using cellular assays. Overall, the expected outcome of the proposed work will be first, a high quality list of putative causal SNPs at established psoriasis loci; second, the discovery of common and rare causal variants at novel loci; and third, the establishment of a roadmap by which we can understand the impact of these variants in specific cell types relevant to psoriasis. These advances will establish an important and necessary foundation that will guide future mechanistic studies of psoriasis and will identify new biological targets for therapy.

描述（由申请人提供）：全基因组关联研究 (GWAS) 已成功鉴定出大约 36 个银屑病易感位点。然而，这些基因座的因果变异在很大程度上仍然未知，并且很可能还有大量其他基因座有待鉴定。在本提案中，我们采取综合策略来识别银屑病常见和罕见的致病变异，然后对这些变异进行有针对性的功能研究。在第一个目标中，我们专注于识别常见的因果变异，其中大多数预计是监管性的。我们通过对 5 个欧洲血统银屑病 GWAS 总计 4,832 例和 10,103 个对照进行荟萃分析，提高了统计功效，并通过与 2 个亚洲血统银屑病 GWAS 总计 1,588 例和 3,566 个对照进行比较，进一步细化因果区域。从因果区域内，使用一种新颖的生物信息学方法来识别假定的因果变异，该方法利用了最近发布的人类调控元件的全基因组图谱。通过对 11,141 例病例和 11,020 例对照的独立样本进行后续基因分型，进一步验证因果变异。在第二个目标中，我们专注于识别罕见的编码变异。为了提高检测罕见变异关联的统计能力，我们对 500 例严重表型银屑病病例进行外显子组测序，然后将识别出的罕见变异归入 4,832 例病例和 10,103 名对照的 GWAS 队列中。假定的因果变异再次在独立队列中得到验证。在第三个目标中，我们创建了一个银屑病监管路线图，定义非编码变异如何影响细胞谱系特异性基因表达，并使用细胞测定进一步测试编码变异的功能影响。总体而言，拟议工作的预期成果将是：首先，在已确定的银屑病位点上提供一份高质量的假定因果 SNP 列表；其次，在新位点发现常见和罕见的因果变异；第三，建立一个路线图，通过该路线图我们可以了解这些变异对与牛皮癣相关的特定细胞类型的影响。这些进展将为指导未来银屑病的机制研究奠定重要且必要的基础，并确定新的生物治疗方法。治疗的目标。