Genetic Epidemiology of Multiple Sclerosis

多发性硬化症(MS)是一种衰弱的神经免疫和神经退行性疾病，影响更多的是 在美国有超过40万人。流行病学和遗传学研究已经产生了 基因对多发性硬化症风险影响的压倒性证据，而第一个确认多发性硬化症的基因 关联(与HLADRB1*1501等位基因)是在20世纪70年代初被发现的，S没有更多的成功 即将使用当时可用的分子和统计工具。2007年，并作为直接结果是 目前的资金，我们确定了30多年来在多发性硬化症中第一个新的基因关联；我们证明了 IL7RA基因中常见的非同义功能性SNP与MS的风险增加相关。 自从这一发现以来，我们和其他人已经确定并确认了与其他几个基因的关联， 包括IL2RA、CLEC16A、CD58、TYK2、TNFRSF1A、IRF8、CD6和CD226。然而，有非常多的 在MS中仍未得到解答的重大遗传学问题首先，这些基因只解释了 对多发性硬化症的总体遗传影响的许多其他基因的适度但重要的影响仍然是 找到了。其次，所有这些工作都假设了常见病/共同变异假说，我们认为 争辩只是故事的一部分。详细检查在两个核中都有更强影响的罕见变体 线粒体基因组尚未完成，这很好地解释了相当大比例的 基因对女士的影响我们处于有利地位，可以进一步研究基因在这两个严重程度上的作用 我们的具体目标是：1)。确认IL7RA中的其他重要基因 途径：2)。确认在原始MS GWAS的前5%的SNPs中发现的其他重要基因 分析；3)。确定已确认的非MHC基因(目前为IL7RA、IL2RA、CLEC16A、CD58、 CD226)使用高通量测序技术。我们将利用我们独特的大型影院 家系数据集对多发性硬化症病例进行排序，这些病例最有可能携带有强烈影响的罕见变异。

Multiple sclerosis (MS) is a debilitating neuroimmunological and neurodegenerative disorder affecting more than 400,000 individuals in the United States. Epidemiological and genetic studies have produced overwhelming evidence for a genetic influence on the risk of MS. While the first confirmed MS genetic association (with the HLA-DRB1*1501 allele) was identified in the early 1970's, additional success was not forthcoming using the then available molecular and statistical tools. In 2007, and as a direct result of the current funding, we identified the first new genetic association in MS in over 30 years; we demonstrated that a common non-synonymous functional SNP in the IL7RA gene was associated with an increased risk of MS. Since making this discovery, we and others have identified and confirmed associations to several other genes, including IL2RA, CLEC16A, CD58, TYK2, TNFRSF1A, IRF8, CD6, and CD226. However, there are very significant genetic questions that remain unanswered in MS. First, these genes explain only a small fraction of the overall genetic influence on MS. Numerous additional genes of modest yet important effect remain to be found. Second, all this work has assumed the common-disease/common-variant hypothesis, which we contend is only part of the story. Detailed examination for rarer variants of stronger effect in both the nuclear and mitochondrial genomes has yet to be performed and may well explain a measurable proportion of the genetic influence on MS. We are in an excellent position to further examine the genetic role in both severity and type of progression of MS. Our specific aims are to: 1). Confirm additional important genes in the IL7RA pathway; 2). Confirm additional important genes identified in the top 5% of SNPs from the original MS GWAS analysis; 3). Identify all variants in the confirmed non-MHC genes (currently IL7RA, IL2RA, CLEC16A, CD58, CD226) using high-throughput sequencing techniques. We will take advantage of our unique large multiplex family dataset to sequence MS cases most likely to carry rare variants of strong effect.