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

描述（由申请人提供）： 风湿性关节炎是一种致残性疾病，影响多达1%的成年人口。与 RA的遗传率估计约为60%，主要的遗传关联已与6号染色体上主要组织相容性复合体（MHC）区域内的HLA-DRB 1基因相关联。20多年前，“共享表位”假说暗示HLA-DRB 1蛋白亚基中的一小段氨基酸（残基70-74），为随后的RA研究提供了坚实的基础。然而，DRB 1内的因果变异和DRB 1外的关联的存在仍然存在不确定性。在这个项目中，我们开发了一个插补程序来重新分析现有的RA GWAS数据集，以精细映射MHC中的关联信号。除了输入经典的HLA等位基因，我们还专注于经典的HLA蛋白质内的特定氨基酸多态性的作用。我们将分析来自多个种族（欧洲人、非裔美国人、汉族人和韩国人）的数据集，以提高识别因果变异的能力。最终，我们项目的见解可以帮助确定RA发病机制中的（自身）抗原。我们的分析策略广泛适用于RA以外的疾病，并且可以根据现有的GWAS数据帮助解释许多其他免疫相关疾病的MHC相关性。我们将与人类遗传学社区分享我们的软件工具。

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.