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

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

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)

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.

Figures

Figure 1
Figure 1
p values for association in the independent genome-wide association study
Figure 2
Figure 2
p values for association in the joint analysis
Figure 3
Figure 3
Genetic architecture of the associated region Circles=−log10 of the p value of association with amyotrophic lateral sclerosis for typed and imputed single nucleotide polymorphisms in the joint analysis, coloured according to linkage disequilibrium with rs3849942 (shown as a purple diamond) as measured by r. Blue lines=recombination rate across the locus based on the 1000 genomes project. Genes in the region are displayed below the graph. Arrows indicate the direction of transcription.

References

    1. Johnston CA, Stanton BR, Turner MR. Amyotrophic lateral sclerosis in an urban setting: a population based study of inner city London. J Neurol. 2006;253:1642–1643.
    1. Morita M, Al-Chalabi A, Andersen PM. A locus on chromosome 9p confers susceptibility to amyotrophic lateral sclerosis and frontotemporal dementia. Neurology. 2006;66:839–844.
    1. Vance C, Al-Chalabi A, Ruddy D. Familial amyotrophic lateral sclerosis with frontotemporal dementia is linked to a locus on chromosome 9p13.2-21.3. Brain. 2006;129:868–876.
    1. Boxer AL, Mackenzie IR, Boeve BF. Clinical, neuroimaging and neuropathological features of a new chromosome 9p-linked FTD-ALS family. J Neurol Neurosurg Psychiatry. 2010 doi: 10.1136/jnnp.2009.204081. published online June 20.
    1. Valdmanis PN, Dupre N, Bouchard JP. Three families with amyotrophic lateral sclerosis and frontotemporal dementia with evidence of linkage to chromosome 9p. Arch Neurol. 2007;64:240–245.
    1. Gijselinck I, Engelborghs S, Maes G. Identification of 2 loci at chromosomes 9 and 14 in a multiplex family with frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Arch Neurol. 2010;67:606–616.
    1. Benajiba L, Le Ber I, Camuzat A. TARDBP mutations in motoneuron disease with frontotemporal lobar degeneration. Ann Neurol. 2009;65:470–473.
    1. van Es MA, Veldink JH, Saris CG. Genome-wide association study identifies 19p13.3 (UNC13A) and 9p21.2 as susceptibility loci for sporadic amyotrophic lateral sclerosis. Nat Genet. 2009;41:1083–1087.
    1. Dunckley T, Huentelman MJ, Craig DW. Whole-genome analysis of sporadic amyotrophic lateral sclerosis. N Engl J Med. 2007;357:775–788.
    1. van Es MA, Van Vught PW, Blauw HM. ITPR2 as a susceptibility gene in sporadic amyotrophic lateral sclerosis: a genome-wide association study. Lancet Neurol. 2007;6:869–877.
    1. Cronin S, Berger S, Ding J. A genome-wide association study of sporadic ALS in a homogenous Irish population. Hum Mol Genet. 2008;17:768–774.
    1. van Es MA, van Vught PW, Blauw HM. Genetic variation in DPP6 is associated with susceptibility to amyotrophic lateral sclerosis. Nat Genet. 2008;40:29–31.
    1. Fogh I, D'Alfonso S, Gellera C. No association of DPP6 with amyotrophic lateral sclerosis in an Italian population. Neurobiol Aging. 2009 doi: 10.1016/j.neurobiolaging.2009.05.014. published online June 12.
    1. Lewis CM, Ng MY, Butler AW. Genome-wide association study of major recurrent depression in the UK population. Am J Psychiatry. 2010;167:949–957.
    1. Gaysina D, Cohen-Woods S, Chow PC. Association of the dystrobrevin binding protein 1 gene (DTNBP1) in a bipolar case-control study (BACCS) Am J Med Genet B Neuropsychiatr Genet. 2009;150B:836–844.
    1. Landers JE, Melki J, Meininger V. Reduced expression of the kinesin-associated protein 3 (KIFAP3) gene increases survival in sporadic amyotrophic lateral sclerosis. Proc Natl Acad Sci USA. 2009;106:9004–9009.
    1. Schymick JC, Scholz SW, Fung HC. Genome-wide genotyping in amyotrophic lateral sclerosis and neurologically normal controls: first stage analysis and public release of data. Lancet Neurol. 2007;6:322–328.
    1. Wroe R, Wai-Ling Butler A, Andersen PM, Powell JF, Al-Chalabi A. ALSOD: the amyotrophic lateral sclerosis online database. Amyotroph Lateral Scler. 2008;9:249–250.
    1. Purcell S, Cherny SS, Sham PC. Genetic power calculator: design of linkage and association genetic mapping studies of complex traits. Bioinformatics. 2003;19:149–150.
    1. Price AL, Patterson NJ, Plenge RM, Weinblatt ME, Shadick NA, Reich D. Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet. 2006;38:904–909.
    1. Patterson N, Price AL, Reich D. Population structure and eigenanalysis. PLoS Genet. 2006;2:e190.
    1. Purcell S, Neale B, Todd-Brown K. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007;81:559–575.
    1. Howie BN, Donnelly P, Marchini J. A flexible and accurate genotype imputation method for the next generation of genome-wide association studies. PLoS Genet. 2009;5:e1000529.
    1. International HapMap Consortium The international HapMap project. Nature. 2003;426:789–796.
    1. Marchini J, Howie B, Myers S, McVean G, Donnelly P. A new multipoint method for genome-wide association studies by imputation of genotypes. Nat Genet. 2007;39:906–913.
    1. Al-Chalabi A, Fang F, Hanby MF, et al. An estimate of amyotrophic lateral sclerosis heritability using twin data. J Neurol Neurosurg Psychiatry (in press).
    1. Ringholz GM, Appel SH, Bradshaw M, Cooke NA, Mosnik DM, Schulz PE. Prevalence and patterns of cognitive impairment in sporadic ALS. Neurology. 2005;65:586–590.
    1. Lomen-Hoerth C. Characterization of amyotrophic lateral sclerosis and frontotemporal dementia. Dement Geriatr Cogn Disord. 2004;17:337–341.
    1. Van Deerlin VM, Sleiman PM, Martinez-Lage M. Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions. Nat Genet. 2010;42:234–239.
    1. Dickson SP, Wang K, Krantz I, Hakonarson H, Goldstein DB. Rare variants create synthetic genome-wide associations. PLoS Biol. 2010;8:e1000294.
    1. Laaksovirta H, Peuralinna T, Schymick JC. Chromosome 9p21 in amyotrophic lateral sclerosis in Finland: a genome-wide association study. Lancet Neurol. 2010 doi: 10.1016/S1474-4422(10)70184-8. published online Aug 31.
    1. Beaver JE, Tasan M, Gibbons FD, Tian W, Hughes TR, Roth FP. FuncBase: a resource for quantitative gene function annotation. Bioinformatics. 2010;26:1806–1807.
    1. Wain LV, Pedroso I, Landers JE. The role of copy number variation in susceptibility to amyotrophic lateral sclerosis: genome-wide association study and comparison with published loci. PLoS ONE. 2009;4:e8175.
    1. Cronin S, Blauw HM, Veldink JH. Analysis of genome-wide copy number variation in Irish and Dutch amyotrophic lateral sclerosis populations. Hum Mol Genet. 2008;17:3392–3398.
    1. Blauw HM, Veldink JH, van Es MA. Copy-number variation in sporadic amyotrophic lateral sclerosis: a genome-wide screen. Lancet Neurol. 2008;7:319–326.

Source: PubMed

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