title: Repeat expansions in the C9ORF72 gene contribute to Alzheimer's disease in Caucasians.
abstract: Recently, a hexanucleotide repeat expansion in the C9ORF72 gene has been identified to account for a significant portion of Caucasian families affected by frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Given the clinical overlap of FTD with Alzheimer's disease (AD), we hypothesized that C9ORF72 expansions might contribute to AD. In Caucasians, we found C9ORF72 expansions in the pathogenic range of FTD/ALS (>30 repeats) at a proportion of 0.76% in AD cases versus 0 in control subjects (p = 3.3E-03; 1182 cases, 1039 controls). In contrast, no large expansions were detected in individuals of African American ethnicity (291 cases, 620 controls). However, in the range of normal variation of C9ORF72 expansions (0-23 repeat copies), we detected significant differences in distribution and mean repeat counts between Caucasians and African Americans. Clinical and pathological re-evaluation of identified C9ORF72 expansion carriers revealed 9 clinical and/or autopsy confirmed AD and 2 FTD final diagnoses. Thus, our results support the notion that large C9ORF72 expansions lead to a phenotypic spectrum of neurodegenerative disease including AD.
authors.affiliation: John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL 33136, USA. mkohli@med.miami.edu
authors.forename: Martin A
authors.initials: MA
authors.lastname: Kohli
authors.forename: Krista
authors.initials: K
authors.lastname: John-Williams
authors.forename: Ruchita
authors.initials: R
authors.lastname: Rajbhandary
authors.forename: Adam
authors.initials: A
authors.lastname: Naj
authors.forename: Patrice
authors.initials: P
authors.lastname: Whitehead
authors.forename: Kara
authors.initials: K
authors.lastname: Hamilton
authors.forename: Regina M
authors.initials: RM
authors.lastname: Carney
authors.forename: Clinton
authors.initials: C
authors.lastname: Wright
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Crocco
authors.forename: Harry E
authors.initials: HE
authors.lastname: Gwirtzman
authors.forename: Rosalyn
authors.initials: R
authors.lastname: Lang
authors.forename: Gary
authors.initials: G
authors.lastname: Beecham
authors.forename: Eden R
authors.initials: ER
authors.lastname: Martin
authors.forename: John
authors.initials: J
authors.lastname: Gilbert
authors.forename: Michael
authors.initials: M
authors.lastname: Benatar
authors.forename: Gary W
authors.initials: GW
authors.lastname: Small
authors.forename: Deborah
authors.initials: D
authors.lastname: Mash
authors.forename: Goldie
authors.initials: G
authors.lastname: Byrd
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Haines
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Pericak-Vance
authors.forename: Stephan
authors.initials: S
authors.lastname: Züchner
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000208:ethnology* / Q000235:genetics*; D000073885:C9orf72 Protein; D015897:Comorbidity; D042622:DNA Repeat Expansion / Q000235:genetics*; D005260:Female; D057180:Frontotemporal Dementia / Q000208:ethnology* / Q000235:genetics*; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000208:ethnology / Q000235:genetics; D005820:Genetic Testing / Q000706:statistics & numerical data; D006801:Humans; D008297:Male; D008875:Middle Aged; D015995:Prevalence; D011506:Proteins / Q000235:genetics*; D012307:Risk Factors; D014481:United States / Q000453:epidemiology; D044465:White People / Q000706:statistics & numerical data*
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D005819:Genetic Markers; D011506:Proteins