Genetic Epidemiology of Multiple Sclerosis

多发性硬化症（MS）是一种使人衰弱的神经免疫和神经退行性疾病， 在美国有超过40万人。流行病学和遗传学研究已经产生了 压倒性的证据表明遗传因素对MS的风险有影响。 关联（与HLA-DRB 1 *1501等位基因）在20世纪70年代初被确定，额外的成功是没有 即将使用当时可用的分子和统计工具。2007年，由于 目前的资金，我们确定了第一个新的遗传协会在MS超过30年;我们证明， IL 7 RA基因中常见的非同义功能性SNP与MS风险增加相关。 自从有了这一发现，我们和其他人已经确定并证实了与其他几个基因的关联， 包括IL 2 RA、CLEC 16 A、CD 58、TYK 2、TNFRSF 1A、IRF 8、CD 6和CD 226。然而， 在MS中仍然没有答案的重要遗传问题。首先，这些基因只能解释MS的一小部分。 对MS的总体遗传影响。许多其他适度但重要影响的基因仍有待研究。 found.其次，所有这些工作都假设了常见疾病/常见变异假设，我们 争论只是故事的一部分。详细检查在两个核中具有更强影响的罕见变体， 和线粒体基因组尚未进行，并可能很好地解释了一个可测量的比例， 遗传对MS的影响。我们处于一个很好的位置，以进一步研究遗传在严重程度和 和MS的进展类型。我们的具体目标是：1）。确认IL 7 RA中的其他重要基因 途径; 2）.确认在原始MS GWAS的前5% SNP中鉴定的其他重要基因 分析; 3）。鉴定确认的非MHC基因（目前为IL 7 RA、IL 2 RA、CLEC 16 A、CD 58、 CD226）。我们将利用我们独特的大型多元化 家族数据集来对最有可能携带强效应的罕见变体的MS病例进行测序。

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.