Identification of Causal Variants in Psoriasis

描述（由申请人提供）：全基因组关联研究（GWAS）已经成功地确定了大约36个牛皮癣易感位点。然而，这些基因座的因果变异在很大程度上仍然未知，很可能还有大量其他基因座有待确定。在本提案中，我们寻求一种综合策略来识别牛皮癣常见和罕见的因果变异，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的。我们通过对5例欧洲血统银屑病GWAS（共4832例和10103例对照）进行meta分析来提高统计能力，并通过与2例亚洲血统银屑病GWAS（共1588例和3566例对照）的比较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确定假定的因果变异，该方法利用了最近发布的人类调控元件全基因组图谱。通过对11,141例病例和11,020例对照的独立样本进行随访基因分型，进一步验证了因果变异。在第二个目标中，我们专注于识别罕见的编码变体。为了提高我们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了外显子组测序，然后将鉴定出的罕见变异推算到GWAS队列中4,832例病例和10,103例对照。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，我们创建了银屑病调节路线图，定义了非编码变体如何影响细胞谱系特异性基因表达，并进一步使用细胞分析测试编码变体对功能的影响。总的来说，拟议工作的预期结果将是：首先，在已确定的银屑病位点上建立高质量的推定因果snp清单；第二，在新基因座上发现常见和罕见的因果变异；第三，建立一个路线图，通过它我们可以了解这些变异对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和寻找新的生物制剂奠定重要和必要的基础

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.