The contribution of common and rare variants to autoimmunity in African Americans

描述（由申请人提供）：多发性硬化症（MS）是一种常见且严重的中枢神经系统疾病，其特征是髓磷脂丢失、慢性炎症、轴突和少突胶质细胞病理以及进行性神经功能障碍。虽然MS的确切病因尚不清楚，但它的发病机制有一个明确的，尽管是部分的遗传贡献。尽管经过长期的努力，对MS遗传学的了解仍然不完整。我们的总体目标是通过对非裔美国人的基因研究来促进对MS发病机制的理解。该人群独特的遗传结构，以及非裔美国人和欧洲人之间MS风险（和表型）的差异，为获得疾病易感性和病因学的宝贵见解提供了独特的机会。这一建议建立在最近获得的大量数据的基础上，这些数据导致了罕见的基因组变异有助于疾病风险的假设。它包括三个主要的研究目标，将基因组筛选与功能研究联系起来：在Specific Aim 1中，我们将生成和分析高覆盖序列信息（调控区域，外显子和外显子侧翼区域），这些基因在代表性非裔美国人MS和对照基因组中具有强烈的关联证据。从这个数据集中，大约500个变异将在一个验证队列中进行基因分型，以全面描述等位基因异质性和发现群体特异性相关的罕见变异。在Specific Aim 2中，我们建议以40倍的分辨率对一个多代、多病例家族的基因组进行测序，并寻找血统相同的DNA片段（IBD），目的是识别与该特定家族疾病表达相关的罕见等位基因变异。此外，我们将使用高覆盖率RNAseq对患病和未患病家族成员的CD4+、CD8+和B细胞的MS转录组进行综合分析。最后，EVI5 （ch.1p22.1）是一个经过充分验证的易感基因，在非裔美国人中显示出MHC外最强的相关性。在Specific Aim 3中，我们的目标是确定EVI5的等位基因差异如何影响免疫突触的形成，从而影响MS的易感性。如本文所述，大量且具有良好特征的样本集的可用性，加上高性能实验室技术的帮助，为鉴定和表征ms相关基因提供了绝佳的机会。这些信息可能转化为临床有用的遗传生物标志物，并揭示新的治疗靶点。

DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is a common and severe CNS disorder that is characterized by myelin loss, chronic inflammation, axonal and oligodendrocyte pathology, and progressive neurological dysfunction. While the exact cause of MS is unknown, there is an unequivocal, albeit partial, genetic contribution to its pathogenesis. In spite of intensive long-standing efforts, the knowledge of MS genetics remains incomplete. Our overall goal is to contribute to the understanding of MS pathogenesis by means of genetic research in African Americans. The distinct genetic architecture of this population, together with the differences in MS risk (and phenotypes) between African Americans and Europeans, provide a unique opportunity to gain valuable insights into disease susceptibility and etiology. This proposal builds on a large body of recently acquired data leading to the hypothesis that rare genomic variants contribute to disease risk. It includes three main research goals that bridge genomic screens with functional research: In Specific Aim 1 we will generate and analyze high-coverage sequence information (regulatory regions, exons, and exon-flanking regions) for genes with strong evidence of association in representative African American MS and control genomes. From this dataset, approximately 500 variants will be genotyped in a validation cohort for the full description of allelic heterogeneity and the discovery of population-specific associated rare variants. In Specific Aim 2 we propose to sequence the genome of a multi-generational, multi-case family at 40x resolution and search for DNA segments identical by descent (IBD) with the goal of identifying rare allelic variants linked to disease expression in this particular family. In addition, we will use high coverage RNAseq to comprehensive analyze the MS transcriptome of CD4+, CD8+ and B cells in affected and unaffected family members. Finally, EVI5 (ch.1p22.1) is a well-validated susceptibility gene, and showed the strongest association outside the MHC in African Americans. In Specific Aim 3 our goal is to determine how allelic differences in EVI5 contribute to altered formation of the immunological synapse, thus contributing to MS susceptibility. The availability of a large and well characterized sample-set as described here, coupled with the aid of high-powered laboratory technologies, provide an outstanding opportunity to identify and characterize MS-related genes. This information may translate into clinically useful genetic biomarkers and reveal novel targets for therapy.