Identification of Causal Variants in Psoriasis

描述（由申请人提供）：全基因组关联研究（GWAS）已成功确定了约36个银屑病易感基因座。然而，这些基因座的致病变异在很大程度上仍是未知的，很可能还有大量的其他基因座有待鉴定。在这项提案中，我们追求一种全面的策略来识别银屑病中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。我们通过对5例欧洲血统银屑病GWAS（共4，832例病例和10，103例对照）进行荟萃分析来提高统计功效，并通过与2例亚洲血统银屑病GWAS（共1，588例病例和3，566例对照）进行比较来进一步细化因果区域。从因果区域内，使用一种新的生物信息学方法，利用最近发布的人类调控元件的全基因组图谱的优势，确定了推定的因果变异。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，进一步验证了因果变异。在第二个目标中，我们专注于鉴定罕见的编码变体。为了提高我们检测罕见变异相关性的统计能力，我们对500例严重表型银屑病病例进行了外显子组测序，然后将鉴定出的罕见变异体归算到4，832例病例和10，103例对照的GWAS队列中。在独立的队列中再次验证假定的因果变异。在第三个目标中，我们创建了银屑病监管路线图，定义了非编码变体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体的功能影响。总体而言，拟议工作的预期成果将是第一，在已建立的银屑病基因座上推定的因果SNP的高质量列表;第二，在新基因座上发现常见和罕见的因果变体;第三，建立路线图，通过该路线图，我们可以了解这些变体在与银屑病相关的特定细胞类型中的影响。这些进展将建立一个重要和必要的基础，将指导未来的机制研究银屑病，并将确定新的生物学 治疗的目标

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.