Genome wide SNP analysis in Amyotrophic Lateral Sclerosis

在上一财政年度，我们完成了两个与额颞叶痴呆（FTD）直接相关的项目。在第一个项目中，由TARDBP基因编码的TAR dna结合蛋白43被确定为伴有或不伴有肌萎缩性侧索硬化症（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，两名FTD和TARDBP基因突变的患者后来发展为运动神经元疾病，只有一种描述。我们与意大利同事合作，对36名家族性ALS患者和280名健康对照者进行了遗传、神经心理学和神经影像学分析。我们发现3例家族性ALS患者携带p.a ala382thr TARDBP基因错义突变，并具有FTD的临床、神经影像学和神经心理学特征。这3个家庭中DNA可用的所有受影响成员都存在这种情况。3个家族的所有受影响成员在ALS发病后均出现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联合区代谢低下证实。

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.