title: C9ORF72 intermediate repeat copies are a significant risk factor for Parkinson disease.
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.
authors.affiliation: University of Miami, Miller School of Medicine, John P. Hussman Institute for Human Genomics, Biomedical Research building, 1501 NW 10th Ave, Miami, FL, 33136, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Nuytemans
authors.forename: Güney
authors.initials: G
authors.lastname: Bademci
authors.forename: Martin M
authors.initials: MM
authors.lastname: Kohli
authors.forename: Gary W
authors.initials: GW
authors.lastname: Beecham
authors.forename: Liyong
authors.initials: L
authors.lastname: Wang
authors.forename: Juan I
authors.initials: JI
authors.lastname: Young
authors.forename: Fatta
authors.initials: F
authors.lastname: Nahab
authors.forename: Eden R
authors.initials: ER
authors.lastname: Martin
authors.forename: John R
authors.initials: JR
authors.lastname: Gilbert
authors.forename: Michael
authors.initials: M
authors.lastname: Benatar
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Haines
authors.forename: William K
authors.initials: WK
authors.lastname: Scott
authors.forename: Stephan
authors.initials: S
authors.lastname: Züchner
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Pericak-Vance
authors.forename: Jeffery M
authors.initials: JM
authors.lastname: Vance
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000073885:C9orf72 Protein; D016022:Case-Control Studies; D002648:Child; D018628:Gene Dosage; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D010300:Parkinson Disease / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D011506:Proteins / Q000235:genetics*; D012091:Repetitive Sequences, Nucleic Acid; D012307:Risk Factors; D055815:Young Adult
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D011506:Proteins
keywords: C9ORF72 repeat; Parkinson disease; association; risk factor