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（MS）是一种常见且严重的CNS疾病，其特征在于髓鞘丢失、慢性炎症、轴突和少突胶质细胞病理学以及进行性神经功能障碍。虽然MS的确切原因尚不清楚，但其发病机制中存在明确的（尽管是部分的）遗传贡献。尽管长期以来一直在努力，但对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遗传学研究来促进对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，为获得对疾病易感性和病因学的有价值见解提供了独特的机会。该提案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基因组变异导致疾病风险的假设。它包括三个主要的研究目标，桥梁基因组筛选与功能研究：在具体目标1中，我们将生成和分析高覆盖率的序列信息（调控区，外显子和外显子侧翼区）的基因与代表性的非裔美国人MS和控制基因组的关联的强有力证据。根据该数据集，将在验证队列中对约500种变异进行基因分型，以全面描述等位基因异质性并发现人群特异性相关罕见变异。在具体目标2中，我们建议以40倍分辨率对多代、多病例家族的基因组进行测序，并搜索血统相同（IBD）的DNA片段，目的是鉴定与该特定家族中疾病表达相关的罕见等位基因变异。此外，我们还将使用高覆盖率的RNAseq，全面分析受影响和未受影响的家族成员的CD 4+、CD 8+和B细胞的MS转录组。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最强的MHC外关联。在具体目标3中，我们的目标是确定EVI5中的等位基因差异如何有助于改变免疫突触的形成，从而有助于MS易感性。这里描述的一个大的和良好表征的样品集的可用性，再加上高性能的实验室技术的帮助下，提供了一个很好的机会，以确定和表征MS相关基因。这些信息可以转化为临床上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.