Fine-mapping the MHC associations in rheumatoid arthritis from GWAS data

描述(由申请人提供)： 类风湿性关节炎是一种致残性疾病，影响多达1%的成年人。与 RA的遗传度估计约为60%，主要的遗传关联与6号染色体上主要组织相容性复合体(MHC)区域的人类白细胞抗原-DRB1基因有关。20多年前，共同表位假说涉及到人类白细胞抗原-DRB1蛋白亚基中的一小段氨基酸(残基70-74)，为后续的类风湿关节炎研究奠定了坚实的基础。然而，DRB1内的因果变异和DRB1外的关联的存在仍然不确定。在这个项目中，我们开发了一个补偿程序来重新分析RA的现有Gwas数据集，以便精细地映射MHC中的关联信号。除了输入经典的人类白细胞抗原等位基因外，我们还关注了特定的氨基酸多态在经典的人类白细胞抗原蛋白中的作用。我们将分析来自多个种族(欧洲人、非裔美国人、汉族和韩国人)的数据集，以增加识别因果变量的能力。最终，我们项目的见解可以帮助识别RA发病机制中的(自身)抗原。我们的分析策略广泛适用于RA以外的领域，并可能有助于基于现有的GWAS数据解释MHC与许多其他免疫相关疾病的关联。我们将与人类遗传学社区共享我们的软件工具。

DESCRIPTION (provided by applicant): Rheumatoid arthritis is a disabling disease that affects up to 1% of the adult population. With the heritability of RA estimated at about 60%, the major genetic association has been linked to the HLA-DRB1 gene within the major histocompatibility complex (MHC) region on chromosome 6. More than 20 years ago, the "shared epitope" hypothesis implicated a short stretch of amino acids (residues 70-74) in the HLA-DRB1 protein subunit, providing a solid foundation for subsequent RA studies. Yet uncertainty remains as to the causal variants within DRB1 and the existence of associations outside DRB1. In this project, we develop an imputation procedure to re-analyze existing GWAS data sets of RA in order to fine-map association signals in the MHC. Besides imputing classical HLA alleles, we also focus on the role of specific amino acid polymorphisms within the classical HLA proteins. We will analyze data sets from multiple ethnicities (European, African American, Han Chinese and Korean) in order to increase power to identify causal variants. Ultimately, insights from our project can help identify the (self-)antigens targeted in RA pathogenesis. Our analytic strategy is broadly applicable beyond RA, and could help interpret MHC associations for many other immune-related diseases based on existing GWAS data. We will share our software tools with the human genetics community.