Genome wide SNP analysis in Amyotrophic Lateral Sclerosis

在上个财政年度，我们完成了两个与额颞部痴呆(FTD)直接相关的项目。在第一个项目中，TARDBP基因编码的TAR DNA结合蛋白43被鉴定为伴有或不伴有肌萎缩侧索硬化症(ALS)和散发性ALS的FTD的主要病理蛋白。随后，在2%至3%的ALS患者(家族性和散发性ALS)中检测到TARDBP基因突变。然而，据我们所知，只有一种描述两名FTD和TARDBP基因突变的患者后来发展为运动神经元疾病。与我们的意大利同事合作，我们对36名家族性肌萎缩侧索硬化症患者和280名健康对照进行了遗传、神经心理学和神经影像分析。我们鉴定了3例家族性ALS患者，携带TARDBP基因P.Ala382Thr错义突变，并伴有FTD的临床、神经影像和神经心理学特征。在3个有DNA可用的家庭中，所有受影响的成员都存在这种病毒。这3个家系的所有受累成员都在ALS发病后发展为FTLD，经神经心理测试和正电子发射断层扫描和计算机断层扫描评估额叶关联区的低代谢证实。 在第二个项目中，我们进行了芬兰ALS的全基因组关联研究。芬兰是进行肌萎缩侧索硬化症全基因组关联研究的理想地点，因为这种疾病的发病率是世界上最高的之一，而且芬兰人口的遗传同质性提高了检测风险基因座的能力。我们确定了两个关联峰，它们超过了全基因组的意义。其中一个位于染色体21q22上，对应于SOD1基因的常染色体隐性D90A等位基因。另一个是在染色体9p区域232kb的连锁不平衡区块中检测到的，该区域以前在ALS家系的连锁研究中发现。在这个区域内，我们定义了一个与ALS风险显著增加相关的42-SNP单倍型，该单倍型与最近报道的额颞叶痴呆相关基因座重叠。在93例家族性ALS患者中，9p21基因座的人群归因危险度为37.9%(95%可信区间为27.7~48.1)，D90A纯合子的人群归因危险度为25.5%(16.9~34.1)。这些数据清楚地表明，染色体9p21基因座是芬兰人家族性ALS的主要原因。此外，与最近报道的额颞部痴呆风险单倍型的重叠进一步证明了这两种神经退行性疾病的共同遗传原因。这篇论文发表在《柳叶刀神经学》杂志上。 综上所述，今年已经成功地利用候选基因和全基因组方法确定了在FTD发病机制中重要的遗传变异。这两项研究中的每一项都使用了大量的研究对象，并利用了NIA神经遗传学实验室提供的测序和基因分型设施。

During the last fiscal year, we have completed two projects that are directly relevant to frontotemporal dementia (FTD). In the first project, TAR DNA-binding protein 43, encoded by the TARDBP gene, has been identified as the major pathological protein of FTD with or without amyotrophic lateral sclerosis (ALS) and sporadic ALS. Subsequently, mutations in the TARDBP gene have been detected in 2% to 3% of patients with ALS (both familial and sporadic ALS). However, to our knowledge, there is only one description of two patients with FTD and TARDBP gene mutations who later developed motor neuron disease. In collaboration with our Italian colleagues, we undertook genetic, neuropsychological, and neuroimaging analyses in 36 patients with familial ALS and 280 healthy controls. We identified 3 index cases of familial ALS carrying the p.Ala382Thr missense mutation of the TARDBP gene and with clinical, neuroimaging, and neuropsychological features of FTD. It was present in all affected members of the 3 families for whom DNA was available. All affected members of the 3 families developed FTLD after the onset of ALS, confirmed by neuropsychological testing and hypometabolism in frontal associative areas assessed with positron emission tomography and computed tomography. In the second project, we undertook a genome-wide association study of ALS in Finland. Finland is an ideal 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 identified two association peaks that exceeded genome-wide significance. One was located on chromosome 21q22, which corresponds to the autosomal recessive D90A allele of the SOD1 gene. The other was detected in a 232kb block of linkage disequilibrium 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, 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). These data clearly show that the chromosome 9p21 locus is a major cause of familial ALS in the Finnish population. 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. This paper was published in Lancet Neurology. In summary, the current year has been successful in identifying genetic variants important in the pathogenesis of FTD using candidate gene and genome-wide approaches. Each of the two studies employed large cohorts of research subjects, and utilized the sequencing and genotyping facilities available within the Laboratory of Neurogenetics, NIA.