A GWAS for IgA Nephropathy, the Most Common form of Glomerulonephritis

描述（由申请人提供）：在本研究中，我们计划对免疫球蛋白A肾病（IgAN，OMIM % 161950）进行首次全基因组关联研究（GWAS），这是一种未充分研究的疾病，是美国和全球肾衰竭的主要原因。它是亚洲人群中肾衰竭的最常见原因，也是年轻白人中最常见的原发性肾小球肾炎。与许多免疫介导的疾病相似，IgAN是一种遗传复杂的性状，疾病的遗传基础尚不清楚。为了进行GWAS，我们收集了最大的IgAN国际病例/对照队列。该研究人群包括从北京和上海招募的中国队列（> 2，000例活检记录的IgAN病例和> 2，000例健康对照）和从北美和欧洲招募的高加索/欧洲队列（>2000例活检记录的病例和2000例对照），招募工作在四个研究中心进行。关键是，这些研究的所有样本都在手中。来自中国北京的551例病例和441例对照的初始基因分型（Illumina 610四芯片）。对数据的分析表明，没有显著的分层（？= 1.005），并揭示了IgAN与HLA-DQA 2基因座的全基因组显著关联（p= 9 x10 -8）。此外，这个中等规模的队列揭示了染色体7 q31（p= 7 x10 -6），15 q13（p= 8x 10 -6），4 q21（p= 2x 10 -5）和3q26.2（p= 3x 10 -5）上的几个暗示性关联，突出了疾病的新候选基因。在本项目中，我们建议完成北京队列（共1200例IgAN病例/1200例对照）的基因分型，以确定对疾病有中度至较大影响的常见变异。接下来，我们将在来自上海的独立队列（750例病例/750例对照）和来自北美/欧洲的高加索人（2000例病例/2000例对照）中重复这些发现。这些研究将为IgAN的发病机制提供深入了解，为开发肾衰竭这一主要原因的诊断和治疗工具提供新的机会。 公共卫生相关性：免疫球蛋白A肾病（IgAN，OMIM % 161950），一种研究不足的疾病，是美国和全球肾衰竭的主要原因。这些遗传学研究将为IgAN的发病机制提供深入了解，为开发肾衰竭这一主要原因的诊断和治疗工具提供新的机会。

DESCRIPTION (provided by applicant): In this study, we propose to perform the first genome-wide association study (GWAS) for Immunoglobulin A Nephropathy (IgAN, OMIM %161950), an understudied disease that is a major cause of kidney failure in the U.S. and worldwide. It is the most common cause of kidney failure among Asian populations, and the most common form of primary glomerulonephritis among young Caucasians. Similar to many immune mediated disorders, IgAN is a genetically complex trait and genetic basis for disease is not known. To perform a GWAS, we have assembled the largest international case/control cohort of IgAN. This study population consists of a Chinese cohort recruited from Beijing and Shanghai ( >2,000 biopsy-documented cases of IgAN and >2,000 healthy controls) and a Caucasian/European cohort recruited the North America and Europe (>2000 biopsydocumented cases and 2000 controls), with the recruitment ongoing at four study sites. Critically, all the samples for these studies are in hand. Initial genotyping of 551 cases and 441 controls from Beijing, China (Illumina 610quad chip). Analyses of the data demonstrated absence of significant stratification (?=1.005) and revealed genome-wide significant association of IgAN with the HLA-DQA2 locus (p=9x10-8). In addition, In addition, this modest-sized cohort revealed several suggestive associations on chromosomes 7q31 (p=7x10-6), 15q13 (p=8x10-6), 4q21 (p=2x10-5), and 3q26.2 (p=3x10-5), highlighting novel candidate genes for disease. In this project, we propose to complete the genotyping of the Beijing cohort (total of 1200 IgAN cases/1200 controls) to identify common variants with modest to large effects on disease. We will next replicate these findings in independent cohorts from Shanghai (750 cases/750 controls) and Caucasians from North America/Europe (2000 cases/2000 controls). These studies will provide insight into the pathogenesis of IgAN, providing novel opportunities for development of diagnostic and therapeutic tools for this major cause of kidney failure. PUBLIC HEALTH RELEVANCE: Immunoglobulin A Nephropathy (IgAN, OMIM %161950), an understudied disease that is a major cause of kidney failure in the U.S. and worldwide. These genetic studies will provide insight into the pathogenesis of IgAN, providing novel opportunities for development of diagnostic and therapeutic tools for this major cause of kidney failure.