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Collaborative Analysis of  -Synuclein Gene Promoter Variability and Parkinson Disease
Demetrius M. Maraganore, MD;
Mariza de Andrade, PhD;
Alexis Elbaz, MD, PhD;
Matthew J. Farrer, PhD;
John P. Ioannidis, MD;
Rejko Krüger, MD;
Walter A. Rocca, MD, MPH;
Nicole K. Schneider, BA;
Timothy G. Lesnick, MS;
Sarah J. Lincoln, BS;
Mary M. Hulihan, MPH;
Jan O. Aasly, MD;
Tetsuo Ashizawa, MD;
Marie-Christine Chartier-Harlin, PhD;
Harvey Checkoway, PhD;
Carlo Ferrarese, MD, PhD;
Georgios Hadjigeorgiou, MD;
Nobutaka Hattori, MD, PhD;
Hideshi Kawakami, MD, PhD;
Jean-Charles Lambert, PhD;
Timothy Lynch, BSc, FRCPI, FRCP;
George D. Mellick, PhD;
Spiridon Papapetropoulos, MD, PhD;
Abbas Parsian, PhD;
Aldo Quattrone, MD;
Olaf Riess, MD;
Eng-King Tan, MD, MRCP, FAMS;
Christine Van Broeckhoven, PhD, DSc; for the Genetic Epidemiology of Parkinson's Disease (GEO-PD) Consortium
JAMA. 2006;296:661-670.
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.
Author Affiliations: Departments of Neurology (Drs Maraganore and Rocca) and Health Sciences Research (Drs de Andrade and Rocca and Ms Schneider and Mr Lesnick), Mayo Clinic College of Medicine, Rochester, Minn; Institut National de la Santé et de la Recherche Médicale Unit 708, Université Pierre et Marie Curie, Paris, France (Dr Elbaz); Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Fla (Dr Farrer and Mss Lincoln and Hulihan); Biomedical Research Institute, Foundation for Research and Technology-Hellas and Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece (Dr Ioannidis); Center of Neurology and Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany (Dr Krüger); Department of Neurology, University Hospital, Trondheim, Norway (Dr Aasly); University of Texas Medical Branch, Galveston, (Dr Ashizawa); Institut de Recherche sur le Cancer, Lille, France (Dr Chartier-Harlin); Department of Environmental and Occupational Health Sciences, University of Washington, Seattle (Dr Checkoway); Department of Neurology, University of Milano-Bicocca, Monza, Italy (Dr Ferrarese); University of Thessaly, School of Medicine, Larissa, Greece (Dr Hadjigeorgiou); Juntendo University School of Medicine, Tokyo, Japan (Dr Hattori); Department of Epidemiology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan (Dr Kawakami); Institut National de la Santé et de la Recherche Médicale Unit 744, Institut Pasteur de Lille, Université de Lille 2, Lille, France (Dr Lambert); Department of Neurology, Mater Misericordiae University Hospital and Conway Institute, University College Dublin, Dublin, Ireland (Dr Lynch); Department of Neurology, University of Queensland, Brisbane, Australia (Dr Mellick); Department of Neurology, University of Miami, Miami, Fla (Dr Papapetropoulos); Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock (Dr Parsian); Institute of Neurological Sciences, National Research Council, Cosenza, and Institute of Neurology, University Magna Graecia, Catanzaro, Italy (Dr Quattrone); Department of Medical Genetics, University of Tübingen, Tübingen, Germany (Dr Riess); Department of Neurology, Singapore General Hospital, Singapore, Singapore (Dr Tan); Neurodegenerative Brain Diseases Group, Flanders Interuniversity Institute of Biotechnology, University of Antwerp, Antwerpen, Belgium (Dr Van Broeckhoven).
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