Chromosome 9p21 in sporadic amyotrophic lateral sclerosis in the UK and seven other countries: a genome-wide association study.
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.
Shatunov
Aleksey
A
King's College London, Medical Research Council Centre for Neurodegeneration Research, Department of Clinical Neuroscience, Institute of Psychiatry, London, UK.
Mok
Kin
K
Newhouse
Stephen
S
Weale
Michael E
ME
Smith
Bradley
B
Vance
Caroline
C
Johnson
Lauren
L
Veldink
Jan H
JH
van Es
Michael A
MA
van den Berg
Leonard H
LH
Robberecht
Wim
W
Van Damme
Philip
P
Hardiman
Orla
O
Farmer
Anne E
AE
Lewis
Cathryn M
CM
Butler
Amy W
AW
Abel
Olubunmi
O
Andersen
Peter M
PM
Fogh
Isabella
I
Silani
Vincenzo
V
Chiò
Adriano
A
Traynor
Bryan J
BJ
Melki
Judith
J
Meininger
Vincent
V
Landers
John E
JE
McGuffin
Peter
P
Glass
Jonathan D
JD
Pall
Hardev
H
Leigh
P Nigel
PN
Hardy
John
J
Brown
Robert H
RH
Powell
John F
JF
Orrell
Richard W
RW
Morrison
Karen E
KE
Shaw
Pamela J
PJ
Shaw
Christopher E
CE
Al-Chalabi
Ammar
A
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
Nat Genet. 2008 Jan;40(1):29-31
18084291
Lancet Neurol. 2008 Apr;7(4):319-26
18313986
Bioinformatics. 2010 Jul 15;26(14):1806-7
20495000
Lancet Neurol. 2007 Apr;6(4):322-8
17362836
PLoS Genet. 2009 Jun;5(6):e1000529
19543373
Nat Genet. 2006 Aug;38(8):904-9
16862161
Amyotroph Lateral Scler. 2008 Aug;9(4):249-50
18608099
J Neurol. 2006 Dec;253(12):1642-3
17219036
PLoS Biol. 2010 Jan 26;8(1):e1000294
20126254
Ann Neurol. 2009 Apr;65(4):470-3
19350673
Am J Psychiatry. 2010 Aug;167(8):949-57
20516156
Neurology. 2005 Aug 23;65(4):586-90
16116120
J Neurol Neurosurg Psychiatry. 2011 Feb;82(2):196-203
20562461
Lancet Neurol. 2007 Oct;6(10):869-77
17827064
Dement Geriatr Cogn Disord. 2004;17(4):337-41
15178949
J Neurol Neurosurg Psychiatry. 2010 Dec;81(12):1324-6
20861059
Neurology. 2006 Mar 28;66(6):839-44
16421333
Lancet Neurol. 2010 Oct;9(10):978-85
20801718
Neurobiol Aging. 2011 May;32(5):966-7
19525032
PLoS One. 2009 Dec 04;4(12):e8175
19997636
Nat Genet. 2010 Mar;42(3):234-9
20154673
Arch Neurol. 2010 May;67(5):606-16
20457961
N Engl J Med. 2007 Aug 23;357(8):775-88
17671248
Brain. 2006 Apr;129(Pt 4):868-76
16495328
PLoS Genet. 2006 Dec;2(12):e190
17194218
Am J Med Genet B Neuropsychiatr Genet. 2009 Sep 5;150B(6):836-44
19089808
Bioinformatics. 2003 Jan;19(1):149-50
12499305
Am J Hum Genet. 2007 Sep;81(3):559-75
17701901
Hum Mol Genet. 2008 Mar 1;17(5):768-74
18057069
Arch Neurol. 2007 Feb;64(2):240-5
17296840
Nature. 2003 Dec 18;426(6968):789-96
14685227
Nat Genet. 2007 Jul;39(7):906-13
17572673
Proc Natl Acad Sci U S A. 2009 Jun 2;106(22):9004-9
19451621
Nat Genet. 2009 Oct;41(10):1083-7
19734901
Hum Mol Genet. 2008 Nov 1;17(21):3392-8
18689356