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Chromosome 9p21 in sporadic amyotrophic lateral sclerosis in the UK and seven other countries: a genome-wide association study

Authors :
Bradley N. Smith
Cathryn M. Lewis
John Hardy
Wim Robberecht
Christopher Shaw
Stephen Newhouse
Adriano Chiò
Isabella Fogh
Aleksey Shatunov
Richard W. Orrell
Olubunmi Abel
Vincenzo Silani
Peter M. Andersen
Michael A van Es
Peter McGuffin
P. Nigel Leigh
John Powell
Karen E. Morrison
Leonard H. van den Berg
Jonathan D. Glass
Caroline Vance
Kin Y. Mok
Robert H. Brown
Pamela J. Shaw
John Landers
Jan H. Veldink
Ammar Al-Chalabi
Bryan J. Traynor
Anne Farmer
Lauren Johnson
Hardev Pall
Vincent Meininger
Orla Hardiman
Michael E. Weale
Philip Van Damme
Amy W. Butler
Judith Melki
Source :
Lancet Neurology, Shatunov, A, Mok, K, Newhouse, S, Weale, M E, Smith, B, Vance, C, Johnson, L, Veldink, J H, van Es, M A, van den Berg, L H, Robberecht, W, Van Damme, P, Hardiman, O, Farmer, A E, Lewis, C M, Butler, A W, Abel, O, Andersen, P M, Fogh, I, Silani, V, Chiò, A, Traynor, B J, Melki, J, Meininger, V, Landers, J E, McGuffin, P, Glass, J D, Pall, H, Leigh, P N, Hardy, J, Brown, R H, Powell, J F, Orrell, R W, Morrison, K E, Shaw, P J, Shaw, C E & Al-Chalabi, A 2010, ' Chromosome 9p21 in sporadic amyotrophic lateral sclerosis in the UK and seven other countries : a genome-wide association study ', Lancet Neurology, vol. 9, no. 10, pp. 986-94 . https://doi.org/10.1016/S1474-4422(10)70197-6
Publication Year :
2010
Publisher :
Elsevier BV, 2010.

Abstract

Summary 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 Findings 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. Interpretation 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. Funding ALS Therapy Alliance, the Angel Fund, the Medical Research Council, the Motor Neurone Disease Association of Great Britain and Northern Ireland, the Wellcome Trust, and the National Institute for Health Research Dementias and Neurodegenerative Diseases Research Network (DeNDRoN).

Details

ISSN :
14744422
Volume :
9
Database :
OpenAIRE
Journal :
The Lancet Neurology
Accession number :
edsair.doi.dedup.....d6f49011e47a3d731c1d1a93bf661bb4