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Comparative Study
. 2010 Oct;9(10):978-85.
doi: 10.1016/S1474-4422(10)70184-8.

Chromosome 9p21 in amyotrophic lateral sclerosis in Finland: a genome-wide association study

Hannu Laaksovirta  1 , Terhi Peuralinna, Jennifer C Schymick, Sonja W Scholz, Shaoi-Lin Lai, Liisa Myllykangas, Raimo Sulkava, Lilja Jansson, Dena G Hernandez, J Raphael Gibbs, Michael A Nalls, David Heckerman, Pentti J Tienari, Bryan J Traynor
Affiliations
Comparative Study

Chromosome 9p21 in amyotrophic lateral sclerosis in Finland: a genome-wide association study

Hannu Laaksovirta et al. Lancet Neurol. 2010 Oct.

Abstract

Background: 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.

Methods: 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.

Findings: 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).

Interpretation: 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.

Funding: 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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Conflict of interest statement

Conflicts of interest

David Heckerman is Senior Director of the eScience Research Group at Microsoft Research. Hannu Laaksovirta has received payment from Sanofi-Aventis and Rhone-Poulenc Rorer for development of educational presentations including services on speakers’ bureaus, as well as travel and accommodation expenses from Rhone-Poulenc-Rorer. None of the other authors have any conflicts of interest.

Figures

Figure 1
Figure 1
Graphical representation of p-values from genome-wide association study of 405 Finnish ALS cases and 497 elderly Finnish controls. P-values are log transformed (y-axis) and plotted against chromosomes (x-axis). The red dotted line indicates the Bonferroni threshold. Signals indicated in red are on chromosome 9p21 and chromosome 21q22 and surpass the Bonferroni threshold for genome-wide significance.
Figure 2
Figure 2
Graphical representation of p-values from genome-wide association study of (A) 93 familial ALS cases and 497 Finnish controls, and (B) 312 sporadic ALS cases and 497 Finnish controls. P-values are log transformed (y-axis) and plotted against chromosomes (x-axis). The red dotted line indicates the Bonferroni threshold. Signals indicated in red are on chromosome 9p21 and chromosome 21q22 and surpass the Bonferroni threshold for genome-wide significance.
Figure 3
Figure 3
Graphical representation of the association results, recombination rates and linkage disequilibrium (LD) across the chromosome 9p21 locus in the Finnish cohort. −log10 p-values are shown for genotyped SNPs (blue). Recombination rates from phase 2 CEPH samples of HapMap are represented by the blue line. Annotated transcripts are shown across the bottom of the plot. Red dotted line indicates the threshold for genome-wide significance. LD structure in the region is shown on the bottom and was generated using data from the Finnish ALS cases carrying the 42-SNP risk haplotype.
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