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Residual association at C9orf72 suggests an alternative amyotrophic lateral sclerosis-causing hexanucleotide repeat

Residual association at C9orf72 suggests an alternative amyotrophic lateral sclerosis-causing hexanucleotide repeat
Residual association at C9orf72 suggests an alternative amyotrophic lateral sclerosis-causing hexanucleotide repeat
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of motor neurons. Single-nucleotide polymorphism rs3849942 is associated with ALS, tagging a hexanucleotide repeat mutation in the C9orf72 gene. It is possible that there is more than 1 disease-causing genetic variation at this locus, in which case association might remain after removal of cases carrying the mutation. DNA from patients with ALS was therefore tested for the mutation. Genome-wide association testing was performed first using all samples, and then restricting the analysis to samples not carrying the mutation. rs3849942 and rs903603 were strongly associated with ALS when all samples were included (rs3849942, p = [3 × 2] × 10?6, rank 7/442,057; rs903603, p = [7 × 6] × 10?8, rank 2/442,057). Removal of the mutation-carrying cases resulted in loss of association for rs3849942 (p = [2 × 6] × 10?3, rank 1225/442,068), but had little effect on rs903603 (p = [1 × 9] × 10?5, rank 8/442,068). Those with a risk allele of rs903603 had an excess of apparent homozygosity for wild type repeat alleles, consistent with polymerase chain reaction failure of 1 allele because of massive repeat expansion. These results indicate residual association at the C9orf72 locus suggesting a second disease-causing repeat mutation.
2234.e1-2234.e7
Jones, Ashley R.
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Woollacott, Ione
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Shatunov, Aleksey
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Cooper-Knock, Johnathan
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Buchman, Vladimir
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Sproviero, William
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Smith, Bradley
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Scott, Kirsten M.
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Balendra, Rubika
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Abel, Olubunmi
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McGuffin, Peter
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Ellis, Catherine M.
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Shaw, Pamela J.
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Morrison, Karen E.
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Farmer, Anne
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Lewis, Cathryn M.
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Leigh, P. Nigel
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Shaw, Christopher E.
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Powell, John F.
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Al-Chalabi, Ammar
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Jones, Ashley R.
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Woollacott, Ione
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Shatunov, Aleksey
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Cooper-Knock, Johnathan
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Buchman, Vladimir
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Sproviero, William
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Smith, Bradley
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Scott, Kirsten M.
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Balendra, Rubika
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Abel, Olubunmi
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McGuffin, Peter
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Ellis, Catherine M.
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Shaw, Pamela J.
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Morrison, Karen E.
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Farmer, Anne
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Lewis, Cathryn M.
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Leigh, P. Nigel
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Shaw, Christopher E.
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Powell, John F.
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Al-Chalabi, Ammar
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Jones, Ashley R., Woollacott, Ione, Shatunov, Aleksey, Cooper-Knock, Johnathan, Buchman, Vladimir, Sproviero, William, Smith, Bradley, Scott, Kirsten M., Balendra, Rubika, Abel, Olubunmi, McGuffin, Peter, Ellis, Catherine M., Shaw, Pamela J., Morrison, Karen E., Farmer, Anne, Lewis, Cathryn M., Leigh, P. Nigel, Shaw, Christopher E., Powell, John F. and Al-Chalabi, Ammar (2013) Residual association at C9orf72 suggests an alternative amyotrophic lateral sclerosis-causing hexanucleotide repeat. Neurobiology of Aging, 34 (9), 2234.e1-2234.e7. (doi:10.1016/j.neurobiolaging.2013.03.003). (PMID:23587638)

Record type: Article

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of motor neurons. Single-nucleotide polymorphism rs3849942 is associated with ALS, tagging a hexanucleotide repeat mutation in the C9orf72 gene. It is possible that there is more than 1 disease-causing genetic variation at this locus, in which case association might remain after removal of cases carrying the mutation. DNA from patients with ALS was therefore tested for the mutation. Genome-wide association testing was performed first using all samples, and then restricting the analysis to samples not carrying the mutation. rs3849942 and rs903603 were strongly associated with ALS when all samples were included (rs3849942, p = [3 × 2] × 10?6, rank 7/442,057; rs903603, p = [7 × 6] × 10?8, rank 2/442,057). Removal of the mutation-carrying cases resulted in loss of association for rs3849942 (p = [2 × 6] × 10?3, rank 1225/442,068), but had little effect on rs903603 (p = [1 × 9] × 10?5, rank 8/442,068). Those with a risk allele of rs903603 had an excess of apparent homozygosity for wild type repeat alleles, consistent with polymerase chain reaction failure of 1 allele because of massive repeat expansion. These results indicate residual association at the C9orf72 locus suggesting a second disease-causing repeat mutation.

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Accepted/In Press date: 11 March 2013
e-pub ahead of print date: 12 April 2013
Published date: September 2013
Organisations: Medical Education

Identifiers

Local EPrints ID: 398461
URI: http://eprints.soton.ac.uk/id/eprint/398461
PURE UUID: b8321ed8-46dc-48f9-83ff-4560f2a8ccb2
ORCID for Karen E. Morrison: ORCID iD orcid.org/0000-0003-0216-5717

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Date deposited: 25 Jul 2016 13:29
Last modified: 29 Oct 2019 01:34

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Contributors

Author: Ashley R. Jones
Author: Ione Woollacott
Author: Aleksey Shatunov
Author: Johnathan Cooper-Knock
Author: Vladimir Buchman
Author: William Sproviero
Author: Bradley Smith
Author: Kirsten M. Scott
Author: Rubika Balendra
Author: Olubunmi Abel
Author: Peter McGuffin
Author: Catherine M. Ellis
Author: Pamela J. Shaw
Author: Anne Farmer
Author: Cathryn M. Lewis
Author: P. Nigel Leigh
Author: Christopher E. Shaw
Author: John F. Powell
Author: Ammar Al-Chalabi

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