Functional Genomics of Alopecia Areata

 描述（由申请人提供）：斑秃（AA）是美国最常见的自身免疫性疾病之一，终生风险为1.7%，影响所有种族群体中约530万人。我们最近进行了一项全基因组关联研究（GWAS），以确定导致AA风险的常见等位基因，并确定了几个含有潜在易感基因的基因组区域。在我们的初步研究中，我们使用几种方法在斑秃患者样本中产生了重要和独特的基因组和遗传数据集资源，包括>1000个个体的GWAS基因分型，>400个个体的免疫芯片，>50个家族的连锁分析，>100个个体的基因表达谱，124个个体的GWAS区域的靶向重测序，对10个以上连锁家系中的斑秃先证者进行全外显子测序。这些强大的和高度集成的数据集提供了丰富的基础，从其中询问AA候选基因中的变异的功能意义，在这种创新的建议的背景下。 作为理解这些结果的生物学意义的第一步，我们现在必须在这些区域进行深度测序分析，以确定驱动tagSNP关联的因果变异。常见疾病的遗传结构的新图景包含了常见和罕见变异的小生境，这些变异独立或协同作用以影响表型。了解这些变异在疾病发病机制中的影响是迈向AA新疗法的第一个关键步骤。这些研究非常及时，将使我们能够将AA置于GWAS和深度测序已经进行的其他自身免疫性疾病的背景下。 我们推测，候选基因的因果变异是AA易感性的基础。这项资助的重点是进行深度测序研究，以确定候选基因中的新变体，然后在几种体外环境中进行变体的功能基因组学研究，这将使我们能够确定：1）有助于AA易感性的特定变量的性质;以及2）它们有助于疾病发病机制的机制。 在这项提案中，我们将在我们以前的GWAS区域进行外显子组加测序，以鉴定致病变异。然后，我们将询问在毛囊和免疫细胞中表达的候选基因内的变体的功能后果，重点是NKG 2D途径。

 DESCRIPTION (provided by applicant): Alopecia Areata (AA) is one of the most common autoimmune diseases in the US, with a lifetime risk of 1.7%, it affects approximately 5.3 million individuals across all ethnic groups. We recently carried out a genome-wide association study (GWAS) to identify common alleles that contribute to risk of AA, and identified several genomic regions harboring potential susceptibility genes. In our Preliminary Studies, we have generated a significant and unique resource of genomic and genetic datasets in alopecia areata patient samples using several approaches, including GWAS genotyping on >1000 individuals, ImmunoChip on >400 individuals, Linkage analysis on >50 families, Gene expression profiling on >100 individuals, Targeted resequencing in GWAS regions in 124 individuals, and Whole exome sequencing in >10 alopecia areata probands selected from linkage families. These robust and highly integrated datasets provide a rich foundation from which to interrogate the functional significance of variants in AA candidate genes in the context of this innovative proposal. As a first step towards understanding the biological significance of these results, we must now perform deep sequencing analysis in these regions to identify causal variants that are driving the association of tagSNPs. The emerging picture of the genetic architecture of common diseases contains niches for both common and rare variants acting independently or in concert to influence phenotypes. Understanding the impact of these variants in disease pathogenesis is the first key step in moving toward novel therapies for AA. These studies are extremely timely, and will allow us to place AA into the context of other autoimmune diseases in which GWAS and deep sequencing is already underway. We postulate that causal variants in candidate genes underlie the susceptibility to develop AA. This grant is focused on carrying out deep sequencing studies to identify new variants in candidate genes, followed by functional genomics of variants in several in vitro contexts, which will allow us to determine: 1) the nature of the specific variats contributing to AA susceptibility; and 2) the mechanism(s) by which they contribute to disease pathogenesis. In this proposal, we will carry out Exome-plus sequencing with enrichment in our previous GWAS regions to identify causal variants. We will then interrogate the functional consequences of variants within candidate genes expressed in both the hair follicle and immune cells, with an emphasis on the NKG2D pathway.