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

• Published in: JAMA : the journal of the American Medical Association 2006-08, Vol.296 (6), p.661-670
• Main Authors: Maraganore, Demetrius M, de Andrade, Mariza, Elbaz, Alexis, Farrer, Matthew J, Ioannidis, John P, Krüger, 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 D, Papapetropoulos, Spiridon, Parsian, Abbas, Quattrone, Aldo, Riess, Olaf, Tan, Eng-King, Van Broeckhoven, Christine, Genetic Epidemiology of Parkinson's Disease (GEO-PD) Consortium, for the
• Format: Article
• Language: English
• Subjects: Adult; Age of Onset; Aged; Aged, 80 and over; Alleles; alpha-Synuclein; alpha-Synuclein - genetics; Biological and medical sciences; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Dinucleotide Repeats; Female; General aspects; Genes; Genetic Predisposition to Disease; Genetic Variation; Genotype; Haplotypes; Humans; Life Sciences; Male; Medical sciences; Middle Aged; Nervous system (semeiology, syndromes); Nervous system as a whole; Neurology; Neurons and Cognition; Parkinson Disease; Parkinson Disease - epidemiology; Parkinson Disease - genetics; Parkinson's disease; Promoter Regions (Genetics); Promoter Regions, Genetic; Risk factors; Santé publique et épidémiologie; Variation (Genetics)
• ISSN: 0098-7484; 1538-3598
• DOI: 10.1001/jama.296.6.661

CONTEXT Identification and replication of susceptibility genes for Parkinson disease at the population level have been hampered by small studies with potential biases. α-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