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Chromosome 9p21 Tied to ALS Across Multiple Populations

Genetic variations linked to familial and sporadic ALS, overlap with frontotemporal dementia

WEDNESDAY, Sept. 1 (HealthDay News) -- A major cause of familial amyotrophic lateral sclerosis (ALS) in the Finnish population is the chromosome 9p21 locus that overlaps with a haplotype recently reported to be associated with frontotemporal dementia, according to research published online Aug. 31 in The Lancet Neurology. A second study published in the same issue found strong evidence of a genetic association of two single nucleotide polymorphisms (SNPs) on chromosome 9 with sporadic ALS.

Hannu Laaksovirta, M.D., of the University of Helsinki in Finland, and colleagues conducted a genome-wide association study of Finnish patients with ALS and non-ALS controls. Two significant association peaks were identified, one on chromosome 21q22 and the other a previously identified linkage disequilibrium on chromosome 9p, where a 42-SNP haplotype was significantly associated with a substantially increased risk of ALS (odds ratio [OR], 21.0); this region overlapped a recently identified locus associated with frontotemporal dementia. At least one of these variations was found in more than 70 percent of patients with a family history of ALS, suggesting a 'founder' mutation in the Finnish population, and explaining many cases of familial ALS in Finland.

Aleksey Shatunov, Ph.D., of King's College London, and colleagues found strong evidence of a genetic association of sporadic ALS with two SNPs on chromosome 9. First studying an independent sample of sporadic ALS patients and controls from the United Kingdom, and then combining these data with a larger data set of ALS patients and controls from several countries, the researchers confirmed a significant association of two SNPs in a locus on chromosome 9p21.2 with sporadic ALS: rs3849942 (ORs, 1.39 in the independent analysis and 1.22 in the joint analysis) and rs2814707 (ORs, 1.38 and 1.22, respectively).

"Although the results presented here must be interpreted with caution, both studies identified a linkage disequilibrium block in the chromosome 9p21 locus, suggesting that a variant in this genomic interval might have a role in ALS and possibly frontotemporal dementia," write the authors of an accompanying editorial. "However, because patients with familial chromosome 9p-linked ALS frontotemporal dementia do not all share a common haplotype, multiple variations, and thus multiple founders, are probably involved."

One author of the first study has financial ties to Sanofi-Aventis and Rhone-Poulenc Rorer; another author is a senior director of the eScience Research Group at Microsoft Research, which provided funding for the study. Several authors of the second study disclosed financial relationships with pharmaceutical companies, and two authors have submitted patents for therapeutic molecules for either ALS or neurodegeneration.

Abstract - Laaksovirta
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Abstract - Shatunov
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