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Chromosome 9p21 in sporadic amyotrophic lateral sclerosis in the UK and seven other countries: a genome-wide association study
Aleksey Shatunov PhD a, Kin Mok MSc e, Stephen Newhouse PhD a, Michael E Weale PhD b, Bradley Smith PhD a, Caroline Vance PhD a, Lauren Johnson PhD a, Jan H Veldink MD f, Michael A van Es MD f, Prof Leonard H van den Berg MD f, Prof Wim Robberecht MD g, Philip Van Damme MD g, Prof Orla Hardiman MD h, Prof Anne E Farmer FRCPsych c, Prof Cathryn M Lewis PhD b c, Amy W Butler PhD c, Olubunmi Abel MSc a, Prof Peter M Andersen MD i, Isabella Fogh PhD a, Prof Vincenzo Silani MD j, Adriano Chiò MD k, Bryan J Traynor MD l, Prof Judith Melki MD m, Prof Vincent Meininger MD n, John E Landers PhD o, Prof Peter McGuffin FRCPsych c, Jonathan D Glass MD p, Hardev Pall MD q, Prof P Nigel Leigh FMedSci a, Prof John Hardy PhD e, Prof Robert H Brown DPhil o, John F Powell DPhil d, Richard W Orrell MD e, Prof Karen E Morrison DPhil q, Prof Pamela J Shaw MD r, Prof Christopher E Shaw MD a, Prof Ammar Al-Chalabi PhD a
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).
