title: Ataxin-2 repeat-length variation and neurodegeneration.
abstract: Expanded glutamine repeats of the ataxin-2 (ATXN2) protein cause spinocerebellar ataxia type 2 (SCA2), a rare neurodegenerative disorder. More recent studies have suggested that expanded ATXN2 repeats are a genetic risk factor for amyotrophic lateral sclerosis (ALS) via an RNA-dependent interaction with TDP-43. Given the phenotypic diversity observed in SCA2 patients, we set out to determine the polymorphic nature of the ATXN2 repeat length across a spectrum of neurodegenerative disorders. In this study, we genotyped the ATXN2 repeat in 3919 neurodegenerative disease patients and 4877 healthy controls and performed logistic regression analysis to determine the association of repeat length with the risk of disease. We confirmed the presence of a significantly higher number of expanded ATXN2 repeat carriers in ALS patients compared with healthy controls (OR = 5.57; P= 0.001; repeat length >30 units). Furthermore, we observed significant association of expanded ATXN2 repeats with the development of progressive supranuclear palsy (OR = 5.83; P= 0.004; repeat length >30 units). Although expanded repeat carriers were also identified in frontotemporal lobar degeneration, Alzheimer's and Parkinson's disease patients, these were not significantly more frequent than in controls. Of note, our study identified a number of healthy control individuals who harbor expanded repeat alleles (31-33 units), which suggests caution should be taken when attributing specific disease phenotypes to these repeat lengths. In conclusion, our findings confirm the role of ATXN2 as an important risk factor for ALS and support the hypothesis that expanded ATXN2 repeats may predispose to other neurodegenerative diseases, including progressive supranuclear palsy.
authors: Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
authors: Owen A
authors: OA
authors: Ross
authors: Nicola J
authors: NJ
authors: Rutherford
authors: Matt
authors: M
authors: Baker
authors: Alexandra I
authors: AI
authors: Soto-Ortolaza
authors: Minerva M
authors: MM
authors: Carrasquillo
authors: Mariely
authors: M
authors: DeJesus-Hernandez
authors: Jennifer
authors: J
authors: Adamson
authors: Ma
authors: M
authors: Li
authors: Kathryn
authors: K
authors: Volkening
authors: Elizabeth
authors: E
authors: Finger
authors: William W
authors: WW
authors: Seeley
authors: Kimmo J
authors: KJ
authors: Hatanpaa
authors: Catherine
authors: C
authors: Lomen-Hoerth
authors: Andrew
authors: A
authors: Kertesz
authors: Eileen H
authors: EH
authors: Bigio
authors: Carol
authors: C
authors: Lippa
authors: Bryan K
authors: BK
authors: Woodruff
authors: David S
authors: DS
authors: Knopman
authors: Charles L
authors: CL
authors: White
authors: Jay A
authors: JA
authors: Van Gerpen
authors: James F
authors: JF
authors: Meschia
authors: Ian R
authors: IR
authors: Mackenzie
authors: Kevin
authors: K
authors: Boylan
authors: Bradley F
authors: BF
authors: Boeve
authors: Bruce L
authors: BL
authors: Miller
authors: Michael J
authors: MJ
authors: Strong
authors: Ryan J
authors: RJ
authors: Uitti
authors: Steven G
authors: SG
authors: Younkin
authors: Neill R
authors: NR
authors: Graff-Radford
authors: Ronald C
authors: RC
authors: Petersen
authors: Zbigniew K
authors: ZK
authors: Wszolek
authors: Dennis W
authors: DW
authors: Dickson
authors: Rosa
authors: R
authors: Rademakers
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