Cronin Simon, Blauw Hylke M, Veldink Jan H, van Es Michael A, Ophoff Roel A, Bradley Daniel G, van den Berg Leonard H, Hardiman Orla
Department of Clinical Neurological Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland.
Hum Mol Genet. 2008 Nov 1;17(21):3392-8. doi: 10.1093/hmg/ddn233. Epub 2008 Aug 7.
Amyotrophic lateral sclerosis (ALS) is an unrelenting neurodegenerative condition characterized by adult-onset loss of motor neurons. Genetic risk factors have been implicated in ALS susceptibility. Copy number variants (CNVs) account for more inter-individual genetic variation than SNPs and have the capacity to alter gene dose and phenotype. We sought to identify the contribution both of commonly polymorphic CNVs and rare ALS-specific CNVs to sporadic ALS (SALS). Using high-density genome-wide data from 408 Irish individuals and 868 Dutch individuals and the QuantiSNP CNV-detection algorithm, we showed that no common CNV locus is significantly associated with ALS risk. However, we identified 39 recurrent CNV loci and 16 replicated ALS-specific gene dose alterations that occur exclusively in patients with ALS and do not occur in more than 11 000 previously identified CNVs in the Database of Genomic Variation. Ataxin genes and the hereditary haemochromatosis locus were implicated along with ENSG00000176605, an uncharacterized gene on chromosome 14. Our data support the hypothesis that multiple rare CNVs may contribute risk for SALS. Future work should seek to profile the contribution of CNVs located in regions not covered on the present SNP platforms.
肌萎缩侧索硬化症（ALS）是一种无情的神经退行性疾病，其特征为成年期运动神经元丧失。遗传风险因素与ALS易感性有关。拷贝数变异（CNV）比单核苷酸多态性（SNP）导致更多的个体间遗传变异，并且有能力改变基因剂量和表型。我们试图确定常见多态性CNV和罕见的ALS特异性CNV对散发性ALS（SALS）的影响。利用来自408名爱尔兰人和868名荷兰人的高密度全基因组数据以及QuantiSNP CNV检测算法，我们发现没有常见的CNV位点与ALS风险显著相关。然而，我们确定了39个复发性CNV位点和16个重复性ALS特异性基因剂量改变，这些改变仅发生在ALS患者中，在基因组变异数据库中超过11000个先前鉴定的CNV中未出现。共济失调基因和遗传性血色素沉着症位点以及14号染色体上一个未表征的基因ENSG00000176605也被牵涉其中。我们的数据支持这样一种假设，即多个罕见的CNV可能会增加SALS的风险。未来的工作应该致力于分析位于当前SNP平台未覆盖区域的CNV的影响。
