C9ORF72 intermediate repeat copies are a significant risk factor for Parkinson disease

Ann Hum Genet. 2013 Sep;77(5):351-63. doi: 10.1111/ahg.12033. Epub 2013 Jul 12.

Abstract

We set out to determine whether expansions in the C9ORF72 repeat found in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) families are associated with Parkinson disease (PD). We determined the repeat size in a total of 889 clinically ascertained patients (including PD and essential tremor plus Parkinsonism (ETP)) and 1144 controls using a repeat-primed PCR assay. We found that large C9ORF72 repeat expansions (>30 repeats) were not contributing to PD risk. However, PD and ETP cases had a significant increase in intermediate (>20 to 30+) repeat copies compared to controls. Overall, 14 cases (13 PD, 1 ETP) and three controls had >20 repeat copies (Fisher's exact test p = 0.002). Further, seven cases and no controls had >23 repeat copies (p = 0.003). Our results suggest that intermediate copy numbers of the C9ORF72 repeat contribute to risk for PD and ETP. This also suggests that PD, ALS and FTD share some pathophysiological mechanisms of disease. Further studies are needed to elucidate the contribution of the C9ORF72 repeat in the overall PD population and to determine whether other common genetic risk factors exist between these neurodegenerative disorders.

Keywords: C9ORF72 repeat; Parkinson disease; association; risk factor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • C9orf72 Protein
  • Case-Control Studies
  • Child
  • Gene Dosage*
  • Genetic Predisposition to Disease
  • Genotype
  • Humans
  • Middle Aged
  • Parkinson Disease / genetics*
  • Pedigree
  • Phenotype
  • Proteins / genetics*
  • Repetitive Sequences, Nucleic Acid*
  • Risk Factors
  • Young Adult

Substances

  • C9orf72 Protein
  • C9orf72 protein, human
  • Proteins