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
Related in: MedlinePlus
Mentions: The association of risk alleles with greater than 2 hexanucleotide repeats suggests that residual association SNPs might predispose to instability, and therefore a repeat mutation, as has been postulated previously for the rs3849942 haplotypic background. Thus, 1 possible explanation of the residual association is an interrupted or alternative repeat sequence, also pathologically expanded, but not detected by repeat-primed PCR targeted at (GGGGCC)n (Fig. 4). In that situation one would expect a similar problem to that reported by DeJesus-Hernandez et al. (2011): that cases appear homozygous because their larger repeat allele is too expanded to amplify. Most cases (93.8%; 15/16 cases) with greater than 2 repeats and the rs903603 risk allele were apparently homozygous for the hexanucleotide repeat allele, breaking Hardy–Weinberg equilibrium. In comparison, 66% (150/266) of cases with the same risk allele were heterozygous for the repeat and we found only 4% (3/83) of cases with the risk allele homozygous for 2 repeats (Table 3). We did not observe this >2 repeat homozygosity bias for any other SNPs. For example, 37% of cases with the mutation-specific risk alleles had homozygosity for repeat alleles of length greater than 2, which satisfied Hardy–Weinberg equilibrium.
Affiliation: King's College London, Institute of Psychiatry, Department of Clinical Neuroscience, London, UK.