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

Research output: Contribution to journalArticlepeer-review


  • Ashley R. Jones
  • Ione Woollacott
  • Aleksey Shatunov
  • Johnathan Cooper-knock
  • Vladimir Buchman
  • And 15 others
  • William Sproviero
  • Bradley Smith
  • Kirsten M. Scott
  • Rubika Balendra
  • Olubunmi Abel
  • Peter Mcguffin
  • Catherine M. Ellis
  • Pamela J. Shaw
  • Karen E. Morrison
  • Anne Farmer
  • Cathryn M. Lewis
  • P. Nigel Leigh
  • Christopher E. Shaw
  • John F. Powell
  • Ammar Al-chalabi

Colleges, School and Institutes


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 × 2] × 10−6, rank 7/442,057; rs903603, p = [7 × 6] × 10−8, rank 2/442,057). Removal of the mutation-carrying cases resulted in loss of association for rs3849942 (p = [2 × 6] × 10−3, rank 1225/442,068), but had little effect on rs903603 (p = [1 × 9] × 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.


Original languageEnglish
Pages (from-to)2234.e1-2234.e7
JournalNeurobiology of Aging
Issue number9
Early online date12 Apr 2013
Publication statusPublished - 1 Sep 2013


  • Amyotrophic lateral sclerosis, Genetics, C9orf72, Hexanucleotide repeat mutation, GWAS, Residual association