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个牛皮癣易感性位点。但是，这些基因座的因果变体在很大程度上仍然未知，而且很可能仍然有许多其他基因座有待鉴定。在此提案中，我们采取了一项综合策略，以确定牛皮癣中常见和罕见的因果变异，然后对这些变体进行有针对性的功能研究。在第一个目的中，我们专注于识别常见因果变体，其中大多数是监管的。我们通过对5个欧洲血统的牛皮癣进行荟萃分析，共计4,832例和10,103例对照，并通过与2个亚洲血统牛皮癣GWAS进行比较，从而提高统计能力，总共有4,832例，并进一步完善了因果区域。从因果区域内，使用一种新型的生物信息学方法来鉴定推定的因果变异，该方法利用了最近发布的人类调节元素的全基因组图。通过在11,141例病例和11,020个对照组的独立样本中，通过随访基因分型进一步验证因果变异。在第二个目标中，我们专注于识别稀有编码变体的识别。为了提高我们检测罕见变体关联的统计能力，我们进行了500个严重表型牛皮癣病例的外显子组测序，然后将所鉴定的稀有变体算作4,832病例和10,103个对照组的GWAS队列。推定的因果变体再次在独立人群中验证。在第三个目标中，我们创建了牛皮癣调节路线图，该路线图定义了非编码变体如何影响细胞谱系特定的基因表达，并进一步测试编码变体，以使用细胞测定进行功能影响。总体而言，拟议工作的预期结果将是首先，这是既定的牛皮癣基因群的高质量因果SNP的高质量名单；其次，在新基因座发现常见和罕见的因果变体；第三，建立了路线图，我们可以通过该图来理解这些变体对与牛皮癣相关的特定细胞类型的影响。这些进步将建立一个重要和必要的基础，该基础将指导牛皮癣的未来机械研究，并将确定新的生物学治疗的靶标。