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

Jones AR, Woollacott I, Shatunov A, Cooper-Knock J, Buchman V, Sproviero W, Smith B, Scott KM, Balendra R, Abel O, McGuffin P, Ellis CM, Shaw PJ, Morrison KE, Farmer A, Lewis CM, Leigh PN, Shaw CE, Powell JF, Al-Chalabi A - Neurobiol. Aging (2013)

Bottom Line: Single-nucleotide polymorphism rs3849942 is associated with ALS, tagging a hexanucleotide repeat mutation in the C9orf72 gene.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).These results indicate residual association at the C9orf72 locus suggesting a second disease-causing repeat mutation.

View Article: PubMed Central - PubMed

Affiliation: King's College London, Institute of Psychiatry, Department of Clinical Neuroscience, London, UK.

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Relationship between rs3849942 alleles and repeat length in nonmutation cases. The risk allele is strongly associated with longer repeat lengths, suggesting it might lie on a haplotype promoting repeat length instability.
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fig1: Relationship between rs3849942 alleles and repeat length in nonmutation cases. The risk allele is strongly associated with longer repeat lengths, suggesting it might lie on a haplotype promoting repeat length instability.

Mentions: We examined the relationship between the hexanucleotide repeat length of phased cases without the mutation (n = 448) and the allelic frequency and distribution of ALS-associated SNPs to explore the linkage disequilibrium pattern of the locus. The mutation-tagging SNP rs3849942 risk allele was associated with increased hexanucleotide repeat numbers for the larger allele in linear regression (β = 5.711; p = 3.02 × 10−84) (Supplementary Table 4). Allele frequency distributions of the repeat length stratified by rs3849942 alleles showed a marked difference between those with 6 or less against 7 or more (Fig. 1). Nonmutation samples with 7 or more repeats (n = 208) showed the strongest genome-wide association with ALS when compared with control samples (n = 4142; OR, 4.99; p = 1.35 × 10−43) (Supplementary Table 5).


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

Jones AR, Woollacott I, Shatunov A, Cooper-Knock J, Buchman V, Sproviero W, Smith B, Scott KM, Balendra R, Abel O, McGuffin P, Ellis CM, Shaw PJ, Morrison KE, Farmer A, Lewis CM, Leigh PN, Shaw CE, Powell JF, Al-Chalabi A - Neurobiol. Aging (2013)

Relationship between rs3849942 alleles and repeat length in nonmutation cases. The risk allele is strongly associated with longer repeat lengths, suggesting it might lie on a haplotype promoting repeat length instability.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3753508&req=5

fig1: Relationship between rs3849942 alleles and repeat length in nonmutation cases. The risk allele is strongly associated with longer repeat lengths, suggesting it might lie on a haplotype promoting repeat length instability.
Mentions: We examined the relationship between the hexanucleotide repeat length of phased cases without the mutation (n = 448) and the allelic frequency and distribution of ALS-associated SNPs to explore the linkage disequilibrium pattern of the locus. The mutation-tagging SNP rs3849942 risk allele was associated with increased hexanucleotide repeat numbers for the larger allele in linear regression (β = 5.711; p = 3.02 × 10−84) (Supplementary Table 4). Allele frequency distributions of the repeat length stratified by rs3849942 alleles showed a marked difference between those with 6 or less against 7 or more (Fig. 1). Nonmutation samples with 7 or more repeats (n = 208) showed the strongest genome-wide association with ALS when compared with control samples (n = 4142; OR, 4.99; p = 1.35 × 10−43) (Supplementary Table 5).

Bottom Line: Single-nucleotide polymorphism rs3849942 is associated with ALS, tagging a hexanucleotide repeat mutation in the C9orf72 gene.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).These results indicate residual association at the C9orf72 locus suggesting a second disease-causing repeat mutation.

View Article: PubMed Central - PubMed

Affiliation: King's College London, Institute of Psychiatry, Department of Clinical Neuroscience, London, UK.

Show MeSH
Related in: MedlinePlus