Genome wide SNP analysis in Amyotrophic Lateral Sclerosis

在过去的一年里，我们完成了三个旨在阐明ALS遗传发病机制的项目：在第一个项目中，我们试图通过对432名爱尔兰人进行全基因组相关性研究来确定ALS的致病变异。该岛群相对同源的遗传背景增强了其检测相关基因座的能力。在我们之前发表的北美数据集中复制之后，最强烈的关联是编码DPP6的基因的一个变异，DPP6是A型神经元跨膜钾通道的一种成分。 在第二个项目中，我们筛选了279例散发性ALS患者和806名神经学正常对照个体的TARDBP基因突变。TARDBP基因突变最近在ALS家系中被描述，但该基因在常见的散发性疾病发病机制中的重要性尚不清楚。在ALS病例中没有发现突变或致病结构变异，这表明该特定基因不是散发性运动神经元变性的常见原因。 在第三个项目中，我们进行了两个阶段的全基因组关联研究，以确定与ALS相关的基因：我们遵循了最初的全基因组关联研究，对553名ALS患者和2338名欧洲血统对照的545,066个SNPs进行了研究，在包括2160例病例和3008名对照的三个独立队列中测试了第一阶段最相关的7600个SNPs。联合分析显示，染色体7p13.3上相邻的两个SNP rs2708909和rs2708851与疾病显著相关(P值分别为5.47x10-7和7.22x10-7)。最相关的SNP，rs2708909，位于Sunc1的内含子3，编码一种已知与微管和动力蛋白相互作用的核膜蛋白。我们的研究结果表明，Sunc1变异体与散发性ALS的易感性有关。 总而言之，今年已经成功地利用候选基因方法和全基因组关联方法确定了在ALS发病机制中重要的遗传变异。这三项研究中的每一项都使用了大量的研究对象，并利用了Illumina基因分型平台和NIA神经遗传学实验室提供的测序设施。

In the last year, we have completed three projects designed to elucidate the genetic pathogenesis of ALS: In the first project, we sought to identify causative variants for ALS by conducting a genome-wide association study in a cohort of 432 Irish individuals. The relatively homogeneous genetic background of this island population enhances its power to detect relevant loci. Following replication in our previously published North American dataset, the strongest association was a variant in the gene encoding DPP6, a component of type A neuronal transmembrane potassium channels. In the second project, we screened the TARDBP gene for mutations in a cohort of 279 sporadic ALS cases and 806 neurologically normal control individuals. Mutations in the TARDBP gene have been recently described in families with ALS, but the importance of the gene in the pathogenesis of the commoner sporadic form of the disease was unknown. No mutations or pathogenic structural variants were found in the ALS cases suggesting that this particular gene is not a common cause of sporadic motor neuron degeneration. In the third project, we undertook a two-stage genome-wide association study to identify the genes involved in ALS: we followed our initial genome-wide association study of 545,066 SNPs in 553 individuals with ALS and 2,338 controls of European descent by testing the 7,600 most associated SNPs from the first stage in three independent cohorts consisting of 2,160 cases and 3,008 controls. Two adjacent SNPs on chromosome 7p13.3, rs2708909 and rs2708851, were significantly associated with disease in the combined joint analysis (P-value = 5.47x10-7 and 7.22x10-7). The most associated SNP, rs2708909, is located in intron 3 of SUNC1, which encodes a nuclear envelope protein known to interact with microtubules and dynein. Our findings suggest that SUNC1 variants contribute to susceptibility to sporadic ALS. In summary, the current year has been successful in identifying genetic variants important in the pathogenesis of ALS using both candidate gene approaches and genome-wide association methods. Each of the three studies employed large cohorts of research subjects, and utilized the Illumina genotyping platform and the sequencing facilities available within the Laboratory of Neurogenetics, NIA.