Genome wide SNP analysis in Amyotrophic Lateral Sclerosis

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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.