Repeat expansions in the C9ORF72 gene contribute to Alzheimer's disease in Caucasians.

TitleRepeat expansions in the C9ORF72 gene contribute to Alzheimer's disease in Caucasians.
Publication TypeJournal Article
Year of Publication2013
AuthorsKohli MA, John-Williams K, Rajbhandary R, Naj A, Whitehead P, Hamilton K, Carney RM, Wright C, Crocco E, Gwirtzman HE, Lang R, Beecham G, Martin ER, Gilbert J, Benatar M, Small GW, Mash D, Byrd G, Haines JL, Pericak-Vance MA, Züchner S
JournalNeurobiol Aging
Volume34
Issue5
Pagination1519.e5-12
Date Published2013 May
ISSN1558-1497
KeywordsAged, Aged, 80 and over, Alzheimer Disease, C9orf72 Protein, Comorbidity, DNA Repeat Expansion, European Continental Ancestry Group, Female, Frontotemporal Dementia, Genetic Markers, Genetic Predisposition to Disease, Genetic Testing, Humans, Male, Middle Aged, Prevalence, Proteins, Risk Factors, United States
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.

DOI10.1016/j.neurobiolaging.2012.10.003
Alternate JournalNeurobiol. Aging
PubMed ID23107433
PubMed Central IDPMC3586789
Grant ListRC2 AG036528 / AG / NIA NIH HHS / United States
U24 AG021886 / AG / NIA NIH HHS / United States
R01 AG019085 / AG / NIA NIH HHS / United States
U01 AG032984 / AG / NIA NIH HHS / United States
UL1 TR000124 / TR / NCATS NIH HHS / United States
R01 AG028786 / AG / NIA NIH HHS / United States
R01 AG028786-02 / AG / NIA NIH HHS / United States
RC2AG036528 / AG / NIA NIH HHS / United States
5R01 AG028786-04 / AG / NIA NIH HHS / United States
R01 AG027944 / AG / NIA NIH HHS / United States