Department of Neurology, Helsinki University Central Hospital and Molecular Neurology Programme, Biomedicum, University of Helsinki, Helsinki, Finland.
Lancet Neurol. 2010 Oct;9(10):978-85. doi: 10.1016/S1474-4422(10)70184-8.
The genetic cause of amyotrophic lateral sclerosis (ALS) is not well understood. Finland is a well suited location for a genome-wide association study of ALS because 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 aimed to identify genetic risk factors for ALS in the Finnish population.
We did a genome-wide association study of Finnish patients with ALS and control individuals by use of Illumina genome-wide genotyping arrays. DNA was collected from patients who attended an ALS specialty clinic that receives referrals from neurologists throughout Finland. Control samples were from a population-based study of elderly Finnish individuals. Patients known to carry D90A alleles of the SOD1 gene (n=40) were included in the final analysis as positive controls to assess whether our genome-wide association study was able to detect an association signal at this locus.
We obtained samples from 442 patients with ALS and 521 control individuals. After quality control filters were applied, 318 167 single nucleotide polymorphisms (SNPs) from 405 people with ALS and 497 control individuals were available for analysis. We identified two association peaks that exceeded genome-wide significance. One was located on chromosome 21q22 (rs13048019, p=2·58×10(-8)), which corresponds to the autosomal recessive D90A allele of the SOD1 gene. The other was detected in a 232 kb block of linkage disequilibrium (rs3849942, p=9·11×10(-11)) in a region of chromosome 9p that was previously identified in linkage studies of families with ALS. Within this region, we defined a 42-SNP haplotype that was associated with significantly increased risk of ALS (p=7·47×10(-33) when people with familial ALS were compared with controls, odds ratio 21·0, 95% CI 11·2-39·1) and which overlapped with an association locus recently reported for frontotemporal dementia. For the 93 patients with familial ALS, the population attributable risk for the chromosome 9p21 locus was 37·9% (95% CI 27·7-48·1) and that for D90A homozygosity was 25·5% (16·9-34·1).
The chromosome 9p21 locus is a major cause of familial ALS in the Finnish population. Our data suggest the presence of a founder mutation for chromosome 9p21-linked ALS. Furthermore, the overlap with the risk haplotype recently reported for frontotemporal dementia provides further evidence of a shared genetic cause for these two neurodegenerative diseases.
National Institutes of Health and National Institute on Aging, Microsoft Research, ALS Association, Helsinki University Central Hospital, Finnish Academy, Finnish Medical Society Duodecim, and Kuopio University.
肌萎缩侧索硬化症（ALS）的遗传原因尚不清楚。芬兰是进行 ALS 全基因组关联研究的理想地点，因为该病的发病率是世界上最高的之一，而且芬兰人群的遗传同质性增强了检测风险基因座的能力。我们旨在确定芬兰人群中 ALS 的遗传风险因素。
我们通过使用 Illumina 全基因组基因分型阵列对芬兰 ALS 患者和对照个体进行了全基因组关联研究。从在芬兰各地的神经病学家处就诊的 ALS 专科诊所收集患者的 DNA。对照样本来自芬兰老年人群的基于人群的研究。将已知携带 SOD1 基因 D90A 等位基因的患者（n=40）纳入最终分析，作为阳性对照，以评估我们的全基因组关联研究是否能够在该基因座检测到关联信号。
我们获得了 442 名 ALS 患者和 521 名对照个体的样本。应用质量控制过滤器后，有 405 名 ALS 患者和 497 名对照个体的 318167 个单核苷酸多态性（SNP）可用于分析。我们发现了两个超过全基因组显著性的关联峰。一个位于 21q22 染色体上（rs13048019，p=2·58×10(-8)），对应于 SOD1 基因的常染色体隐性 D90A 等位基因。另一个在先前在 ALS 家族的连锁研究中发现的 9p 染色体的一个 232 kb 连锁不平衡块(rs3849942，p=9·11×10(-11))中被检测到。在该区域内，我们定义了一个 42-SNP 单倍型，该单倍型与 ALS 的显著风险增加相关（与家族性 ALS 患者相比，对照组为 7·47×10(-33)，优势比 21·0，95%CI 11·2-39·1），并且与最近报道的额颞叶痴呆的关联基因座重叠。对于 93 名家族性 ALS 患者，9p21 基因座的人群归因风险为 37.9%（95%CI 27.7-48.1），D90A 纯合子的风险为 25.5%（16.9-34.1）。
9p21 基因座是芬兰人群中家族性 ALS 的主要原因。我们的数据表明，9p21 连锁 ALS 存在一个创始突变。此外，与最近报道的额颞叶痴呆风险单倍型的重叠提供了这两种神经退行性疾病具有共同遗传原因的进一步证据。
美国国立卫生研究院和美国国家老龄化研究所、微软研究公司、肌萎缩侧索硬化症协会、赫尔辛基大学中心医院、芬兰科学院、芬兰医学学会 Duodecim 和库奥皮奥大学。
