Genome wide SNP analysis in Amyotrophic Lateral Sclerosis

在过去的一年中，我们已经完成了三个项目，旨在阐明ALS的遗传发病机制：在第一个项目中，我们试图通过在432名爱尔兰人的队列中进行全基因组关联研究来确定ALS的致病变体。这个岛屿人口的相对同质的遗传背景，提高了它的权力，以检测相关的基因座。在我们先前发表的北美数据集中进行复制后，最强的关联是编码DPP 6的基因的变体，DPP 6是A型神经元跨膜钾通道的一种成分。 在第二个项目中，我们在279例散发性ALS病例和806例神经学正常对照个体中筛选了TARDBP基因突变。最近在ALS家族中描述了TARDBP基因的突变，但该基因在该疾病的常见散发形式的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性结构变异，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，以确定参与ALS的基因：我们对553名ALS患者和2,338名欧洲血统对照者的545,066个SNP进行了初步的全基因组关联研究，通过在三个独立的队列中测试第一阶段的7,600个最相关的SNP，008控制。在联合分析中，染色体7p13.3上的两个相邻SNP rs 2708909和rs 2708851与疾病显著相关（P值= 5.47x10-7和7.22x10-7）。最相关的SNP，rs 2708909，位于SUNC 1的内含子3，其编码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，SUNC 1变异有助于散发性ALS的易感性。 总之，今年已经成功地确定了重要的ALS发病机制的候选基因的方法和全基因组关联方法的遗传变异。这三项研究中的每一项都采用了大量的研究对象，并利用了Illumina基因分型平台和NIA神经遗传学实验室内可用的测序设施。

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.