King's College London, Medical Research Council Centre for Neurodegeneration Research, Department of Clinical Neuroscience, Institute of Psychiatry, London, UK.
Lancet Neurol. 2010 Oct;9(10):986-94. doi: 10.1016/S1474-4422(10)70197-6.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of motor neurons that results in progressive weakness and death from respiratory failure, commonly within about 3 years. Previous studies have shown association of a locus on chromosome 9p with ALS and linkage with ALS-frontotemporal dementia. We aimed to test whether this genomic region is also associated with ALS in an independent set of UK samples, and to identify risk factors associated with ALS in a further genome-wide association study that combined data from the independent analysis with those from other countries.
We collected samples from patients with sporadic ALS from 20 UK hospitals and obtained UK control samples from the control groups of the Depression Case Control study, the Bipolar Affective Case Control Study, and the British 1958 birth cohort DNA collection. Genotyping of DNA in this independent analysis was done with Illumina HumanHap550 BeadChips. We then undertook a joint genome-wide analysis that combined data from the independent set with published data from the UK, USA, Netherlands, Ireland, Italy, France, Sweden, and Belgium. The threshold for significance was p=0·05 in the independent analysis, because we were interested in replicating a small number of previously reported associations, whereas the Bonferroni-corrected threshold for significance in the joint analysis was p=2·20×10(-7)
After quality control, samples were available from 599 patients and 4144 control individuals in the independent set. In this analysis, two single nucleotide polymorphisms in a locus on chromosome 9p21.2 were associated with ALS: rs3849942 (p=2·22×10(-6); odds ratio [OR] 1·39, 95% CI 1·21-1·59) and rs2814707 (p=3·32×10(-6); 1·38, 1·20-1·58). In the joint analysis, which included samples from 4312 patients with ALS and 8425 control individuals, rs3849942 (p=4·64×10(-10); OR 1·22, 95% CI 1·15-1·30) and rs2814707 (p=4·72×10(-10); 1·22, 1·15-1·30) were associated with ALS.
We have found strong evidence of a genetic association of two single nucleotide polymorphisms on chromosome 9 with sporadic ALS, in line with findings from previous independent GWAS of ALS and linkage studies of ALS-frontotemporal dementia. Our findings together with these earlier findings suggest that genetic variation at this locus on chromosome 9 causes sporadic ALS and familial ALS-frontotemporal dementia. Resequencing studies and then functional analysis should be done to identify the defective gene.
肌萎缩性侧索硬化症（ALS）是一种运动神经元的神经退行性疾病，导致进行性无力，并通常在大约 3 年内因呼吸衰竭而死亡。先前的研究表明，9 号染色体上的一个基因座与 ALS 有关，并与 ALS-额颞叶痴呆有关。我们旨在测试该基因组区域是否也与英国独立样本中的 ALS 有关，并在进一步的全基因组关联研究中确定与 ALS 相关的风险因素，该研究将独立分析的数据与来自其他国家的数据相结合。
我们从 20 家英国医院的散发性 ALS 患者中收集样本，并从英国抑郁症病例对照研究、双相情感障碍病例对照研究和英国 1958 年出生队列 DNA 收集的对照组中获得英国对照样本。该独立分析中的 DNA 基因分型是使用 Illumina HumanHap550 BeadChips 进行的。然后，我们进行了一项联合全基因组分析，该分析将来自独立数据集的数据与来自英国、美国、荷兰、爱尔兰、意大利、法国、瑞典和比利时的已发表数据相结合。独立分析中显著水平的阈值为 p=0.05，因为我们有兴趣复制少数先前报道的关联，而联合分析中经 Bonferroni 校正的显著水平的阈值为 p=2.20×10(-7)。
经过质量控制，独立数据集的 599 名患者和 4144 名对照个体的样本可用。在该分析中，9 号染色体 9p21.2 上的两个单核苷酸多态性与 ALS 相关：rs3849942（p=2.22×10(-6)；优势比[OR]1.39，95%CI 1.21-1.59）和 rs2814707（p=3.32×10(-6)；1.38，1.20-1.58）。在包括 4312 名 ALS 患者和 8425 名对照个体的联合分析中，rs3849942（p=4.64×10(-10)；OR 1.22，95%CI 1.15-1.30）和 rs2814707（p=4.72×10(-10)；1.22，1.15-1.30）与 ALS 相关。
我们发现 9 号染色体上的两个单核苷酸多态性与散发性 ALS 有很强的遗传关联，与之前 ALS 的独立全基因组关联研究和 ALS-额颞叶痴呆的连锁研究结果一致。我们的发现以及这些早期发现表明，9 号染色体上该基因座的遗传变异导致了散发性 ALS 和家族性 ALS-额颞叶痴呆。应该进行重测序研究和功能分析以确定缺陷基因。
