The genetic cause of amyotrophic lateral sclerosis (ALS) is not well understood. Finland is a well suited 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 aimed to identify genetic risk factors for ALS in the Finnish population.
We did a genome-wide association study of Finnish patients with ALS and control individuals by use of Illumina genome-wide genotyping arrays. DNA was collected from patients who attended an ALS specialty clinic that receives referrals from neurologists throughout Finland. Control samples were from a population-based study of elderly Finnish individuals. Patients known to carry D90A alleles of the SOD1 gene (n=40) were included in the final analysis as positive controls to assess whether our genome-wide association study was able to detect an association signal at this locus.
We obtained samples from 442 patients with ALS and 521 control individuals. After quality control filters were applied, 318?167 single nucleotide polymorphisms (SNPs) from 405 people with ALS and 497 control individuals were available for analysis. We identified two association peaks that exceeded genome-wide significance. One was located on chromosome 21q22 (rs13048019, p=2·58×10(-8)), which corresponds to the autosomal recessive D90A allele of the SOD1 gene. The other was detected in a 232 kb block of linkage disequilibrium (rs3849942, p=9·11×10(-11)) 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 (p=7·47×10(-33) when people with familial ALS were compared with controls, odds ratio 21·0, 95% CI 11·2-39·1) 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).
The chromosome 9p21 locus is a major cause of familial ALS in the Finnish population. Our data suggest the presence of a founder mutation for chromosome 9p21-linked ALS. 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.
National Institutes of Health and National Institute on Aging, Microsoft Research, ALS Association, Helsinki University Central Hospital, Finnish Academy, Finnish Medical Society Duodecim, and Kuopio University.
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The chromosome 9p21 amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) locus contains one of the last major unidentified autosomal-dominant genes underlying these common neurodegenerative diseases. We have previously shown that a founder haplotype, covering the MOBKL2b, IFNK, and C9ORF72 genes, is present in the majority of cases linked to this region. Here we show that there is a large hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72 on the affected haplotype. This repeat expansion segregates perfectly with disease in the Finnish population, underlying 46.0% of familial ALS and 21.1% of sporadic ALS in that population. Taken together with the D90A SOD1 mutation, 87% of familial ALS in Finland is now explained by a simple monogenic cause. The repeat expansion is also present in one-third of familial ALS cases of outbred European descent, making it the most common genetic cause of these fatal neurodegenerative diseases identified to date.