Collaborative Analysis of alpha-Synuclein Gene Promoter Variability and Parkinson Disease

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Title Collaborative Analysis of alpha-Synuclein Gene Promoter Variability and Parkinson Disease
Author Maraganore, Demetrius M.; Andrade, Mariza de; Elbaz, Alexis; Farrer, Matthew J.; Ioannidis, John P.; Kruger, Rejko; Rocca, Walter A.; Schneider, Nicole K.; Lesnick, Timothy G.; Lincoln, Sarah J.; Hulihan, Mary M.; Aasly, Jan O.; Ashizawa, Tetsuo; Chartier-Harlin, Marie-Christine; Checkoway, Harvey; Ferrarese, Carlo; Hadjigeorgiou, Georgios; Hattori, Nobutaka; Kawakami, Hideshi; Lambert, Jean-Charles; Lynch, Timothy; Mellick, George; Papapetropoulos, Spiridon; Parsian, Abbas; Quattrone, Aldo; Riess, Olaf; Tan, Eng-King; Broeckhoven, Christine Van
Journal Name Journal of American Medical Association
Editor Catherine D DeAngelis
Year Published 2006
Place of publication United States
Publisher American Medical Association
Abstract Context Identification and replication of susceptibility genes for Parkinson disease at the population level have been hampered by small studies with potential biases. -Synuclein (SNCA) has been one of the most promising susceptibility genes, but large-scale studies have been lacking. Objective To determine whether allele-length variability in the dinucleotide repeat sequence (REP1) of the SNCA gene promoter is associated with Parkinson disease susceptibility, whether SNCA promoter haplotypes are associated with Parkinson disease, and whether REP1 variability modifies age at onset. Design, Setting, and Participants We performed a collaborative analysis of individual-level data on SNCA REP1 and flanking markers in patients with Parkinson disease and controls. Study site recruitment, data collection, and analyses were performed between April 5, 2004, and December 31, 2005. Eighteen participating sites of a global genetics consortium provided clinical data. Genotyping was performed for SNCA REP1, –770, and –116 markers at individual sites; however, each site also provided 20 DNA samples for regenotyping centrally. Main Outcome Measures Measures included estimations of Hardy-Weinberg equilibrium in controls; a test of heterogeneity; analyses for association of single variants or haplotypes; and survival analyses for age at onset. Results Of the 18 sites, 11 met stringent criteria for concordance with Hardy-Weinberg equilibrium and low genotyping error rate. These 11 sites provided complete data for 2692 cases and 2652 controls. There was no heterogeneity across studies (P>.60). The SNCA REP1 alleles differed in frequency for cases and controls (P<.001). Genotypes defined by the 263 base-pair allele were associated with Parkinson disease (odds ratio, 1.43; 95% confidence interval, 1.22-1.69; P<.001 for trend). Multilocus haplotypes differed in frequency for cases and controls (global score statistic, P<.001). Two-loci haplotypes were associated with Parkinson disease only when they included REP1 as one of the loci. However, genotypes defined by REP1 alleles did not modify age at onset (P = .55). Conclusion This large-scale collaborative analysis demonstrates that SNCA REP1 allele-length variability is associated with an increased risk of Parkinson disease.
Peer Reviewed Yes
Published Yes
Publisher URI http://jama.ama-assn.org/
Alternative URI http://jama.ama-assn.org/cgi/content/full/296/6/661
Copyright Statement Copyright 2006 American Medical Association. Self-archiving of the author-manuscript version is not yet supported by this publisher. Please refer to the journal link for access to the definitive, published version or contact the author for more information.
Volume 296
Issue Number 6
Page from 661
Page to 670
ISSN 0098-7484
Date Accessioned 2007-03-15
Language en_AU
Research Centre Eskitis Institute for Drug Discovery
Faculty Faculty of Science, Environment, Engineering and Technology
Subject PRE2009-Central Nervous System
URI http://hdl.handle.net/10072/14359
Publication Type Journal Articles (Refereed Article)
Publication Type Code c1

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