Genome Wide Association Studies in Alopecia Areata

斑秃的全基因组关联研究

• 批准号: 7590170
• 负责人: Angela M Christiano
• 金额: $ 68.82万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-19 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7590170
• 关键词: Admixture; Affect; Age; Alleles; Alopecia Areata; Animal Model; Autoimmune Diseases; Biological Assay; Candidate Disease Gene; Case-Control Studies; Caucasians; Caucasoid Race; Code; Communities; Complex; Control Groups; Custom; Data; Data Set; Databases; Depth; Dermatologic; Disease; Disease Association; Disease Pathway; Environmental Risk Factor; Ethnic group; European; Family; Female; First Degree Relative; Frequencies; Gene Frequency; Genes; Genetic; Genetic Variation; Genome; Genotype; Goals; Hair; Hair follicle structure; Haplotypes; Heritability; Human; Incidence; Individual; International; Investigation; Israel; Japan; Lead; Letters; Life; Link; Linkage Disequilibrium; Localized; Lod Score; Measurement; Measures; Messenger RNA; Microsatellite Repeats; Morbidity - disease rate; Numbers; Pathogenesis; Patient Self-Report; Patients; Pattern; Phenotype; Population; Predisposition; Process; Public Health; Publishing; Quality of life; Range; Registries; Reporting; Research; Research Design; Risk; Rodent Model; Sampling; Scalp structure; Site; Source; Study models; Time; United States; Variant; base; case control; cohort; cost; design; genetic association; genetic linkage analysis; genetic pedigree; genetic risk factor; genetic variant; genome wide association study; human disease; interest; lifetime risk; male; mouse model; novel strategies; novel therapeutics; protein expression; skin disorder; success; therapeutic target; time use; trait

DESCRIPTION (provided by applicant): The long-term goal of this Project is to identify the genetic variation contributing to the risk of developing Alopecia Areata (AA). AA is one of the most common human autoimmune diseases, with a lifetime risk of approximately 2%. It affects approximately 4.6 million individuals in the United States alone, including males and females of all ages and ethnic groups. AA fits the paradigm of a complex or multifactorial trait, in which combinations of genetic and environmental factors combine to give rise to the final phenotype. Our lab has focused on using unbiased genome-wide approaches to identify susceptibility loci for AA. We recently pioneered the use of genome-wide family-based linkage as applied to AA for the first time, and identified four susceptibility loci in a small cohort of large, multiplex pedigrees. This study was designed to identify rare alleles with relatively large effects. In this Project, we now seek to do the converse. Here, we propose to carry out a genome-wide association study (GWAS) to identify common alleles with small effect that contribute to risk of AA, using 1000 cases and 3000 controls. All of these cases and a proportion of the controls were collected from the Alopecia Areata Registry and will be genotyped with the Illumina 550K SNP array. We will utilize a strategy that has proved successful with other GWAS and obtain the majority of our control samples from a database of shared controls. We will perform replication studies in an additional 3 independent samples of cases and controls. Each of these four studies will be analyzed independently and jointly, greatly increasing our power to detect association of disease alleles with moderate genetic effects. Once susceptibility alleles for AA have been identified, candidate genes containing the SNPs of interest will be prioritized using mRNA and protein expression patterns in the hair follicle. The positional information will be cross-referenced with information derived from expression studies in mouse models for AA. Finally, should some of the variants identified be coding-sequence SNPs, we will then analyze these candidate genes in depth, to look at mRNA and protein expression, and to formulate mechanistic links to the human disease. We expect that identification of SNPs that confer susceptibility to AA will uncover the network of pathways of disease pathogenesis and lead to new approaches for treating this disorder. PUBLIC HEALTH RELEVANCE. The long-term goal of this Application is to identify the genetic variation contributing to the risk of developing Alopecia Areata (AA). AA is a form of hair loss in which the body attacks the growing hair follicle, and can result in hair loss ranging from patches on the scalp to complete hair loss over the body. AA is one of the most common human autoimmune diseases, with a lifetime risk of approximately 2%. AA affects approximately 4.6 million individuals in the United States alone, including males and females of all ages and ethnic groups. While AA is a non-lethal skin disease, its impact as measured in the Burden of Skin Disease Report is profound as it relates to quality-of-life measures. Ultimately, it is anticipated that discovery and modulation of the genes for AA will provide novel therapeutic targets, and eventually eliminate this psychologically devastating dermatologic disorder. The studies outlined in this Application aim to systematically pinpoint common susceptibility alleles for human AA for the first time.

描述（由申请人提供）：该项目的长期目标是确定导致脱发Areata（AA）风险的遗传变异。 AA是人类最常见的自身免疫性疾病之一，终生风险约为2％。仅在美国，它就会影响约460万人，包括各个年龄段和种族的男性和女性。 AA符合复杂或多因素性状的范式，其中遗传和环境因素的组合结合起来产生最终表型。我们的实验室专注于使用无偏基因组的方法来识别AA的易感基因座。我们最近首次率先使用了对AA的全基因组链接的使用，并在一小部分大型多重谱系中鉴定了四个易感位点。这项研究旨在鉴定具有相对较大效果的稀有等位基因。在这个项目中，我们现在寻求进行匡威。在这里，我们建议进行全基因组关联研究（GWAS），以使用1000例和3000例对照来识别具有造成AA风险的较小影响的常见等位基因。所有这些病例和一部分对照均从脱发型注册表中收集，并将用Illumina 550K SNP阵列进行基因分型。我们将利用一种证明与其他GWAS成功的策略，并从共享控件数据库中获取我们的大多数控制样本。我们将在其他3个独立的病例和对照样本中进行复制研究。这四个研究中的每一项都将独立和共同分析，从而大大增加了我们检测疾病等位基因与中等遗传作用的关联的能力。一旦确定了AA的敏感性等位基因，将使用毛囊中的mRNA和蛋白质表达模式优先考虑包含感兴趣SNP的候选基因。位置信息将与AA小鼠模型中的表达研究得出的信息交叉引用。最后，如果确定的一些变体是编码序列SNP，我们将深入分析这些候选基因，以查看mRNA和蛋白质表达，并建立与人类疾病的机械联系。我们期望鉴定SNP具有对AA敏感性的SNP将发现疾病发病机理的途径网络，并导致治疗这种疾病的新方法。 公共卫生相关性。该应用的长期目标是确定导致脱发Areata（AA）风险的遗传变异。 AA是一种脱发的一种形式，可以在体内攻击毛囊不断增长的毛囊，并可能导致脱发范围从头皮上的斑块到完全脱发。 AA是人类最常见的自身免疫性疾病之一，终生风险约为2％。仅在美国，AA就会影响大约460万人，包括各个年龄段和种族的男性和女性。虽然AA是一种非致命的皮肤病，但在皮肤病负担报告中衡量的影响很大，因为它与生活质量措施有关。最终，可以预料，对AA基因的发现和调节将提供新颖的治疗靶标，并最终消除这种心理上毁灭性的皮肤病学障碍。该应用中概述的研究旨在系统地确定对人AA的共同敏感性等位基因。