Residual association at C9orf72 suggests an alternative amyotrophic lateral sclerosis-causing hexanucleotide repeat.
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.
Affiliation: King's College London, Institute of Psychiatry, Department of Clinical Neuroscience, London, UK.Show MeSH
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Mentions: A similar relationship between risk alleles and hexanucleotide repeat length was observed for the SNPs showing residual association. Repeat numbers greater than 2 (the minimum length) for the larger allele were significantly associated with risk alleles at all of the 3 SNPs showing residual association (Fig. 2). Modeling repeat length as a quantitative variable in a linear regression confirmed that these SNPs were significant predictors of having greater than 2 repeats (example SNP rs10812611; β = 5.835; p = 1.50 × 10−52) (Supplementary Table 4). Again, association testing of samples with repeat length greater than 2 (n = 385) against all controls (n = 4142) showed that SNPs showing residual association were most significantly associated with ALS; rs903603: OR, 0.39; p = 2.21 × 10−28; rs10812611: OR, 2.78; p = 6.96 × 10−33; and rs10967976: OR, 2.82; p = 1.19 × 10−33 (Supplementary Table 6).
Affiliation: King's College London, Institute of Psychiatry, Department of Clinical Neuroscience, London, UK.