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

• Published in: Neurobiology of aging Vol. 34; no. 5; pp. 1519.e5 - 1519.e12
• Main Authors: Kohli, Martin A, John-Williams, Krista, Rajbhandary, Ruchita, Naj, Adam, Whitehead, Patrice, Hamilton, Kara, Carney, Regina M, Wright, Clinton, Crocco, Elizabeth, Gwirtzman, Harry E, Lang, Rosalyn, Beecham, Gary, Martin, Eden R, Gilbert, John, Benatar, Michael, Small, Gary W, Mash, Deborah, Byrd, Goldie, Haines, Jonathan L, Pericak-Vance, Margaret A, Züchner, Stephan
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.05.2013
• Subjects: Aged; Aged, 80 and over; Alzheimer disease; Alzheimer Disease - ethnology; Alzheimer Disease - genetics; C9ORF72; C9orf72 Protein; Comorbidity; DNA Repeat Expansion - genetics; European Continental Ancestry Group - statistics & numerical data; Female; Frontotemporal Dementia - ethnology; Frontotemporal Dementia - genetics; Genetic association; Genetic Markers - genetics; Genetic Predisposition to Disease - ethnology; Genetic Predisposition to Disease - genetics; Genetic Testing - statistics & numerical data; Humans; Internal Medicine; Male; Middle Aged; Neurology; Prevalence; Proteins - genetics; Repeat expansion; Repeat-primed PCR; Risk Factors; Spectrum of neurodegenerative phenotypes; United States - epidemiology; Repeat expansion; Repeat-primed PCR; Spectrum of neurodegenerative phenotypes; Genetic association; Alzheimer disease; C9ORF72
• ISSN: 0197-4580; 1558-1497
• DOI: 10.1016/j.neurobiolaging.2012.10.003

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.