title: Chromosome 9p21 in sporadic amyotrophic lateral sclerosis in the UK and seven other countries: a genome-wide association study.
abstract: BACKGROUND
  Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of motor neurons that results in progressive weakness and death from respiratory failure, commonly within about 3 years. Previous studies have shown association of a locus on chromosome 9p with ALS and linkage with ALS-frontotemporal dementia. We aimed to test whether this genomic region is also associated with ALS in an independent set of UK samples, and to identify risk factors associated with ALS in a further genome-wide association study that combined data from the independent analysis with those from other countries.
  
  
  METHODS
  We collected samples from patients with sporadic ALS from 20 UK hospitals and obtained UK control samples from the control groups of the Depression Case Control study, the Bipolar Affective Case Control Study, and the British 1958 birth cohort DNA collection. Genotyping of DNA in this independent analysis was done with Illumina HumanHap550 BeadChips. We then undertook a joint genome-wide analysis that combined data from the independent set with published data from the UK, USA, Netherlands, Ireland, Italy, France, Sweden, and Belgium. The threshold for significance was p=0·05 in the independent analysis, because we were interested in replicating a small number of previously reported associations, whereas the Bonferroni-corrected threshold for significance in the joint analysis was p=2·20×10(-7)
  
  
  RESULTS
  After quality control, samples were available from 599 patients and 4144 control individuals in the independent set. In this analysis, two single nucleotide polymorphisms in a locus on chromosome 9p21.2 were associated with ALS: rs3849942 (p=2·22×10(-6); odds ratio [OR] 1·39, 95% CI 1·21-1·59) and rs2814707 (p=3·32×10(-6); 1·38, 1·20-1·58). In the joint analysis, which included samples from 4312 patients with ALS and 8425 control individuals, rs3849942 (p=4·64×10(-10); OR 1·22, 95% CI 1·15-1·30) and rs2814707 (p=4·72×10(-10); 1·22, 1·15-1·30) were associated with ALS.
  
  
  CONCLUSIONS
  We have found strong evidence of a genetic association of two single nucleotide polymorphisms on chromosome 9 with sporadic ALS, in line with findings from previous independent GWAS of ALS and linkage studies of ALS-frontotemporal dementia. Our findings together with these earlier findings suggest that genetic variation at this locus on chromosome 9 causes sporadic ALS and familial ALS-frontotemporal dementia. Resequencing studies and then functional analysis should be done to identify the defective gene.
authors.affiliation: King's College London, Medical Research Council Centre for Neurodegeneration Research, Department of Clinical Neuroscience, Institute of Psychiatry, London, UK.
authors.forename: Aleksey
authors.initials: A
authors.lastname: Shatunov
authors.forename: Kin
authors.initials: K
authors.lastname: Mok
authors.forename: Stephen
authors.initials: S
authors.lastname: Newhouse
authors.forename: Michael E
authors.initials: ME
authors.lastname: Weale
authors.forename: Bradley
authors.initials: B
authors.lastname: Smith
authors.forename: Caroline
authors.initials: C
authors.lastname: Vance
authors.forename: Lauren
authors.initials: L
authors.lastname: Johnson
authors.forename: Jan H
authors.initials: JH
authors.lastname: Veldink
authors.forename: Michael A
authors.initials: MA
authors.lastname: van Es
authors.forename: Leonard H
authors.initials: LH
authors.lastname: van den Berg
authors.forename: Wim
authors.initials: W
authors.lastname: Robberecht
authors.forename: Philip
authors.initials: P
authors.lastname: Van Damme
authors.forename: Orla
authors.initials: O
authors.lastname: Hardiman
authors.forename: Anne E
authors.initials: AE
authors.lastname: Farmer
authors.forename: Cathryn M
authors.initials: CM
authors.lastname: Lewis
authors.forename: Amy W
authors.initials: AW
authors.lastname: Butler
authors.forename: Olubunmi
authors.initials: O
authors.lastname: Abel
authors.forename: Peter M
authors.initials: PM
authors.lastname: Andersen
authors.forename: Isabella
authors.initials: I
authors.lastname: Fogh
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Silani
authors.forename: Adriano
authors.initials: A
authors.lastname: Chiò
authors.forename: Bryan J
authors.initials: BJ
authors.lastname: Traynor
authors.forename: Judith
authors.initials: J
authors.lastname: Melki
authors.forename: Vincent
authors.initials: V
authors.lastname: Meininger
authors.forename: John E
authors.initials: JE
authors.lastname: Landers
authors.forename: Peter
authors.initials: P
authors.lastname: McGuffin
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Glass
authors.forename: Hardev
authors.initials: H
authors.lastname: Pall
authors.forename: P Nigel
authors.initials: PN
authors.lastname: Leigh
authors.forename: John
authors.initials: J
authors.lastname: Hardy
authors.forename: Robert H
authors.initials: RH
authors.lastname: Brown
authors.forename: John F
authors.initials: JF
authors.lastname: Powell
authors.forename: Richard W
authors.initials: RW
authors.lastname: Orrell
authors.forename: Karen E
authors.initials: KE
authors.lastname: Morrison
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Shaw
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Shaw
authors.forename: Ammar
authors.initials: A
authors.lastname: Al-Chalabi
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000690:Amyotrophic Lateral Sclerosis / Q000453:epidemiology* / Q000235:genetics*; D016022:Case-Control Studies; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics*; D015331:Cohort Studies; D005060:Europe / Q000453:epidemiology; D057180:Frontotemporal Dementia / Q000453:epidemiology / Q000235:genetics; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D038622:Internationality; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D006113:United Kingdom / Q000453:epidemiology; D014481:United States / Q000453:epidemiology
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