title: Residual association at C9orf72 suggests an alternative amyotrophic lateral sclerosis-causing hexanucleotide repeat.
abstract: 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.
authors.affiliation: King's College London, Institute of Psychiatry, Department of Clinical Neuroscience, London, UK.
authors.forename: Ashley R
authors.initials: AR
authors.lastname: Jones
authors.forename: Ione
authors.initials: I
authors.lastname: Woollacott
authors.forename: Aleksey
authors.initials: A
authors.lastname: Shatunov
authors.forename: Johnathan
authors.initials: J
authors.lastname: Cooper-Knock
authors.forename: Vladimir
authors.initials: V
authors.lastname: Buchman
authors.forename: William
authors.initials: W
authors.lastname: Sproviero
authors.forename: Bradley
authors.initials: B
authors.lastname: Smith
authors.forename: Kirsten M
authors.initials: KM
authors.lastname: Scott
authors.forename: Rubika
authors.initials: R
authors.lastname: Balendra
authors.forename: Olubunmi
authors.initials: O
authors.lastname: Abel
authors.forename: Peter
authors.initials: P
authors.lastname: McGuffin
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Ellis
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Shaw
authors.forename: Karen E
authors.initials: KE
authors.lastname: Morrison
authors.forename: Anne
authors.initials: A
authors.lastname: Farmer
authors.forename: Cathryn M
authors.initials: CM
authors.lastname: Lewis
authors.forename: P Nigel
authors.initials: PN
authors.lastname: Leigh
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Shaw
authors.forename: John F
authors.initials: JF
authors.lastname: Powell
authors.forename: Ammar
authors.initials: A
authors.lastname: Al-Chalabi
mesh_terms: D000483:Alleles; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D000073885:C9orf72 Protein; D056426:Genetic Loci / Q000235:genetics*; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D009154:Mutation; D011506:Proteins / Q000235:genetics*; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D011506:Proteins