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