Systematic identification and modeling of rare and common genetic risk factors for sarcoidosis

在过去的几年里，全基因组关联研究发现了相当数量的结节病常见遗传风险变异，其中大多数是由应用项目的主要调查者发现的。然而，人们对这些变异在疾病过程中的作用知之甚少，结节病的很大一部分遗传性仍不清楚。因此，该应用项目接近于迄今为止对结节病遗传基础的最全面的调查，包括系统地鉴定罕见的变异和对人类白细胞抗原区域进行详细的遗传分析。为了将遗传发现转化为致病机制和临床应用，将对相关变异的功能特性和建模进行详细的研究。申请人已经获得了前所未有的规模的跨国样本收集，这对识别罕见的风险变异至关重要。它包括用于发现变异的4,400名结节病患者和10,500名对照个体的全基因组基因数据库，以及用于确认发现的&gt；4,600名结节病患者和&gt；8,800名对照的DNA样本。该项目的优势在于：1)全球最大的结节病患者和对照的基因数据库集；2)独特的多国结节病患者和复制对照集合；以及3)现场所需的所有技术。这为实现以下项目目标提供了一个很好的基础：-检测人类白细胞抗原基因和单倍型与结节病的关联--识别结节病的其他常见风险变种--识别结节病的新的罕见风险变种--结节病eQTL数据库的汇编--识别可能受风险变种影响的蛋白质--为疾病发病机制的改进模型构建蛋白质网络--评估风险变种的预测价值为实现这些目标，将重新分析广泛的基因组范围的基因数据集，重点放在人类白细胞抗原相关性和罕见变种上。此外，还将使用美美病例对照数据集进行荟萃分析。来自这些分析的候选风险变异将在欧洲起源的六个独立的结节病人群中进行复制。为了弥合基因研究和细胞过程之间的差距，新的和已知的遗传风险因素将在电子计算机分析中进行详细的分析，使用公共可用的工具以及将由申请人汇编的结节病专用eQTV数据库。所获得的功能假说将被整合到基于遗传相互作用和蛋白质-蛋白质相互作用的结节病发病机制的精细化模型中。这些结果有望为疾病过程中遗传因素的相互作用提供重要的见解，并将进一步用于患者分类和风险评估。

In the past years, a reasonable number of common genetic risk variants for sarcoidosis have been discovered by genome-wide association studies, in its majority by the principle investigator of the applied project. However, few is known on the role of these variants in the disease process, and a large proportion of the heritability of sarcoidosis remains to be unexplained. Therefore, the applied project approaches the to-date most comprehensive investigation of the genetic basis of sarcoidosis, including the systemic identification of rare variants and a detailed genetic analysis of the HLA region. In order to translate genetic findings to pathogenic mechanism and to clinical application, a detailed investigation of the functional properties and modeling of associated variants will be applied.The applicant has acquired a multinational sample collection of unprecedented size, which is critical for the identification of rare risk variants. It comprises genome-wide genotype datasets of >4,400 sarcoidosis patients and >10,500 control individuals for variant discovery and DNA samples of >4,600 sarcoidosis patients and >8,800 controls for confirmation of the findings.A strength of this project is the availability of i) the largest genotype dataset of sarcoidosis patients and controls worldwide for screening ii) a unique multi-national collection of sarcoidosis patients and controls for replication and iii) all required technology on-site. This provides an excellent basis to reach the following project aims:-Detection of associations of HLA genotypes and -haplotypes with sarcoidosis -Identification of additional common risk variants for sarcoidosis-Identification of novel rare risk variants for sarcoidosis-Compilation of a sarcoidosis eQTL database -Identification of proteins potentially affected by risk variants-Protein network construction for a refined model of disease pathogenesis-Evaluation of the predictive value of the risk variantsTo achieve these objectives extensive genome-wide genotype datasets will be re-analyzed with a focus on HLA associations and rare variants. In addition, a meta-analysis with an US-American case-control dataset will be performed. Candidate risk variants from these analyses will be subjected to replication in six independent sarcoidosis populations of European origin. In order to bridge the gap between genetic studies and cellular processes, novel and known genetic risk factors will be subjected to detailed in silico analyses, using public available tools as well as a sarcoidosis specific eQTV database, which will be compiled by the applicant. The obtained functional hypotheses will be integrated in a refined model of sarcoidosis pathogenesis based on genetic interaction as well as protein-protein-interaction. These results are expected to provide important insights on the interaction of genetic factors in the disease processes and will further be used for patient classification and risk estimation.