title: Chromosome 9p21 in amyotrophic lateral sclerosis in Finland: a genome-wide association study.
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.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  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.
authors.affiliation: Department of Neurology, Helsinki University Central Hospital and Molecular Neurology Programme, Biomedicum, University of Helsinki, Helsinki, Finland.
authors.forename: Hannu
authors.initials: H
authors.lastname: Laaksovirta
authors.forename: Terhi
authors.initials: T
authors.lastname: Peuralinna
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Schymick
authors.forename: Sonja W
authors.initials: SW
authors.lastname: Scholz
authors.forename: Shaoi-Lin
authors.initials: SL
authors.lastname: Lai
authors.forename: Liisa
authors.initials: L
authors.lastname: Myllykangas
authors.forename: Raimo
authors.initials: R
authors.lastname: Sulkava
authors.forename: Lilja
authors.initials: L
authors.lastname: Jansson
authors.forename: Dena G
authors.initials: DG
authors.lastname: Hernandez
authors.forename: J Raphael
authors.initials: JR
authors.lastname: Gibbs
authors.forename: Michael A
authors.initials: MA
authors.lastname: Nalls
authors.forename: David
authors.initials: D
authors.lastname: Heckerman
authors.forename: Pentti J
authors.initials: PJ
authors.lastname: Tienari
authors.forename: Bryan J
authors.initials: BJ
authors.lastname: Traynor
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology / Q000453:epidemiology* / Q000235:genetics*; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D005387:Finland / Q000453:epidemiology; D056426:Genetic Loci / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000453:epidemiology / Q000235:genetics; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1; D055815:Young Adult
chemical_list: C000606290:SOD1 protein, human; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1
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