Chromosome 9p21 in amyotrophic lateral sclerosis in Finland: a genome-wide association study.
Chromosome 9p21 in amyotrophic lateral sclerosis in Finland: a genome-wide association study.
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DOI：
10.1016/s1474-4422(10)70184-8
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发表时间：
2010-10
期刊：
影响因子：
48
通讯作者：
Traynor, Bryan J.
中科院分区：
文献类型：
--
作者：
Laaksovirta, Hannu;Peuralinna, Terhi;Schymick, Jennifer C.;Scholz, Sonja W.;Lai, Shaoi-Lin;Myllykangas, Liisa;Sulkava, Raimo;Jansson, Lilja;Hernandez, Dena G.;Gibbs, J. Raphael;Nalls, Michael A.;Heckerman, David;Tienari, Pentti J.;Traynor, Bryan J.
肌萎缩侧索硬化症（ALS）的遗传病因学还不清楚。芬兰是ALS全基因组关联研究的理想地点，因为该疾病的发病率是世界上最高的国家之一，而且芬兰人口的遗传同质性增强了检测风险基因座的能力。我们使用Illumina全基因组基因分型阵列对442名诊断为ALS的芬兰患者和521名芬兰对照受试者进行了全基因组关联研究。DNA是从参加ALS专科诊所的患者中收集的，该诊所接受芬兰各地神经学家的转诊，而对照样本是从芬兰老年人的人群研究中获得的。将已知携带SOD1基因D90A等位基因的个体（n = 40）作为阳性对照纳入最终分析，以确定我们的GWAS是否能够检测到该基因座的关联信号。我们确定了两个超过全基因组显著性的关联峰。其中一个位于染色体21q22（rs13048019，p = 2·58 × 10 − 8），对应于SOD1基因的已知常染色体隐性D90A等位基因。另一个在染色体9p的一个232kb连锁不平衡区（rs3849942，p = 9·11 × 10 − 11）中检测到，该区域先前已通过ALS家族的连锁研究确定。在该区域内，我们定义了一个42-SNP单倍型，该单倍型显著增加了发生ALS的风险（在家族性病例中p = 4.2 × 10 − 33，比值比= 21.0，95%CI = 11.2 - 39.1），并且与最近报道的额颞叶痴呆（FTD）相关基因座重叠。基于纳入分析的93例家族性ALS病例，染色体9p21位点的群体归因风险百分比为37.9%（95%CI，27.7 - 48.1%），D90A纯合性的群体归因风险百分比为25.5%（95%CI，16.9 - 34.1%）。总之，我们提出的证据表明，染色体9p21 ALS-FTD基因座是芬兰人群中家族性ALS的主要原因。
The genetic etiology of amyotrophic lateral sclerosis (ALS) is not well understood. Finland is a well-suited location for a genome-wide association study of ALS, as the incidence of the disease is one of the highest in the world, and because the genetic homogeneity of the Finnish population enhances the ability to detect risk loci. We performed a genome-wide association study of 442 Finnish patients diagnosed with ALS, and 521 Finnish control subjects using Illumina genome-wide genotyping arrays. DNA was collected from patients attending an ALS specialty clinic that receives referrals from neurologists throughout Finland, whereas the control samples were obtained from a population-based study of elderly Finnish individuals. Individuals known to carry D90A alleles of the SOD1 gene (n = 40) were included in the final analysis as positive controls to determine if our GWAS was able to detect an association signal at this locus. We identified two association peaks that exceeded genome-wide significance. One of these was located on chromosome 21q22 (rs13048019, p = 2·58×10−8) that corresponded to the known autosomal recessive D90A allele of the SOD1 gene. The other was detected in a 232kb block of linkage disequilibrium (rs3849942, p = 9·11×10−11) in a region of chromosome 9p that has been previously identified by linkage studies of ALS families. Within this region, we defined a 42-SNP haplotype that significantly increased risk of developing ALS (p = 4·2×10−33 among familial cases, odds ratio = 21·0, 95% CI = 11·2–39·1), and which overlapped with an association locus recently reported for fronto-temporal dementia (FTD). Based on the 93 familial ALS cases included in the analysis, population attributable risk percent for the chromosome 9p21 locus was 37.9% (95% CI, 27·7 – 48·1%), and for D90A homozygosity was 25·5% (95% CI, 16·9 – 34·1%). In summary, we present evidence that the chromosome 9p21 ALS-FTD locus is a major cause of familial ALS in the Finnish population.