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


Shatunov, Aleksey, Mok, Kin, Newhouse, Stephen, Weale, Michael E, Smith, Bradley, Vance, Caroline, Johnson, Lauren, Veldink, Jan H, van Es, Michael A, van den Berg, Leonard H., Robberecht, Wim, Van Damme, Philip, Hardiman, Orla, Farmer, Anne E, Lewis, Cathryn M, Butler, Amy W, Abel, Olubunmi, Andersen, Peter M, Fogh, Isabella, Silani, Vincenzo, Chiò, Adriano, Traynor, Bryan J, Melki, Judith, Meininger, Vincent, Landers, John E, McGuffin, Peter, Glass, Jonathan D, Pall, Hardev, Leigh, P Nigel, Hardy, John, Brown, Robert H, Powell, John F, Orrell, Richard W, Morrison, Karen E, Shaw, Pamela J, Shaw, Christopher E, Al-Chalabi, Ammar


The Lancet. Neurology, Volume: 9, No.: 10, Pages.: 986-994

Year of Publication



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.; Copyright © 2010 Elsevier Ltd. All rights reserved.

Bibtex Citation

@article{Shatunov_2010, doi = {10.1016/s1474-4422(10)70197-6}, url = {}, year = 2010, month = {oct}, publisher = {Elsevier {BV}}, volume = {9}, number = {10}, pages = {986--994}, author = {Aleksey Shatunov and Kin Mok and Stephen Newhouse and Michael E Weale and Bradley Smith and Caroline Vance and Lauren Johnson and Jan H Veldink and Michael A van Es and Leonard H van den Berg and Wim Robberecht and Philip Van Damme and Orla Hardiman and Anne E Farmer and Cathryn M Lewis and Amy W Butler and Olubunmi Abel and Peter M Andersen and Isabella Fogh and Vincenzo Silani and Adriano Chi{`{o}} and Bryan J Traynor and Judith Melki and Vincent Meininger and John E Landers and Peter McGuffin and Jonathan D Glass and Hardev Pall and P Nigel Leigh and John Hardy and Robert H Brown and John F Powell and Richard W Orrell and Karen E Morrison and Pamela J Shaw and Christopher E Shaw and Ammar Al-Chalabi}, title = {Chromosome 9p21 in sporadic amyotrophic lateral sclerosis in the {UK} and seven other countries: a genome-wide association study}, journal = {The Lancet Neurology} }


aged, aged, 80 and over, amyotrophic lateral sclerosis, chromosomes human pair 9, cohort studies, epidemiology, europe, frontotemporal dementia, genetics, genomewide association study, great britain, humans, internationality, methods, middle aged, polymorphism single nucleotide, united states

Countries of Study


Types of Dementia

Fronto Temporal (also known as Pick’s Disease)

Types of Study


Type of Outcomes

Risk reduction (of dementia and co-morbidities)

Type of Interventions

Risk Factor Modification

Risk Factor Modifications

At risk population

Diagnostic Targets

Genetic Testing