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.
| Nicolas, Aude (see original citation for additional authors) (2018) Genome-wide Analyses Identify KIF5A as a Novel ALS Gene. Neuron 97:1268-1283.e6 |
| Goldstein, Orly; Nayshool, Omri; Nefussy, Beatrice et al. (2016) OPTN 691_692insAG is a founder mutation causing recessive ALS and increased risk in heterozygotes. Neurology 86:446-53 |
| Chiò, Adriano; Mora, Gabriele; Sabatelli, Mario et al. (2015) CHCH10 mutations in an Italian cohort of familial and sporadic amyotrophic lateral sclerosis patients. Neurobiol Aging 36:1767.e3-1767.e6 |
| Marangi, Giuseppe; Traynor, Bryan J (2015) Genetic causes of amyotrophic lateral sclerosis: new genetic analysis methodologies entailing new opportunities and challenges. Brain Res 1607:75-93 |
| Borghero, Giuseppe; Pugliatti, Maura; Marrosu, Francesco et al. (2015) ATXN2 is a modifier of phenotype in ALS patients of Sardinian ancestry. Neurobiol Aging 36:2906.e1-5 |
| Renton, Alan E; Pliner, Hannah A; Provenzano, Carlo et al. (2015) A genome-wide association study of myasthenia gravis. JAMA Neurol 72:396-404 |
| Chiò, Adriano; Traynor, Bryan J (2015) Motor neuron disease in 2014. Biomarkers for ALS--in search of the Promised Land. Nat Rev Neurol 11:72-4 |
| Chiò, Adriano; Mora, Gabriele; Sabatelli, Mario et al. (2015) HFE p.H63D polymorphism does not influence ALS phenotype and survival. Neurobiol Aging 36:2906.e7-11 |
| Singleton, Andrew B; Traynor, Bryan J (2015) Genetics. For complex disease genetics, collaboration drives progress. Science 347:1422-3 |
| Zhang, Ming; Xi, Zhengrui; Zinman, Lorne et al. (2015) Mutation analysis of CHCHD10 in different neurodegenerative diseases. Brain 138:e380 |
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