Journal
NEUROBIOLOGY OF AGING
Volume 34, Issue 9, Pages -Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.neurobiolaging.2013.03.003
Keywords
Amyotrophic lateral sclerosis; Genetics; C9orf72; Hexanucleotide repeat mutation; GWAS; Residual association
Categories
Funding
- Medical Research Council PhD studentship awarded through the MRC Centre for Neurodegeneration Research
- Motor Neuron Disease Association of Great Britain and Northern Ireland
- European Community's Health Seventh Framework Programme [259867]
- Welcome Trust [075615/Z/04/z]
- Motor Neurone Disease Association of Great Britain and Northern Ireland
- Wellcome Trust
- ALS Association
- Angel Fund
- ALS Therapy Alliance
- National Institute for Health Research (NIHR) Dementia Biomedical Research Unit at South London
- NIHR Biomedical Research Centre in Mental Health at South London
- Maudsley NHS Foundation Trust
- King's College London
- MRC [G0900688, MC_G1000733, G0701420, MR/K003771/1] Funding Source: UKRI
- Medical Research Council [MC_G1000733, G0900688, MR/K003771/1, G0500289B, G0701420] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0512-10082, ACF-2012-18-009] Funding Source: researchfish
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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 x 2] x 10(-6), rank 7/442,057; rs903603, p = [7 x 6] x 10(-8), rank 2/442,057). Removal of the mutation-carrying cases resulted in loss of association for rs3849942 (p = [2 x 6] x 10(-3), rank 1225/442,068), but had little effect on rs903603 (p = [1 x 9] x 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. (C) 2013 Elsevier Inc. All rights reserved.
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