Background: A functional repeat polymorphism in the SNCA promoter (REP1) conveys susceptibility for Parkinson disease (PD). There is also increasing evidence that single-nucleotide polymorphisms (SNPs) elsewhere in the gene are associated with PD risk. Objectives: To further explore the association of common SNCA SNPs with PD susceptibility, to determine whether evidence of allelic heterogeneity exists, and to examine the correlation between PD-associated variants and plasma α-synuclein levels. Design: Two-tiered analysis. Setting: Academic research. Patients: Patients and control subjects from the NeuroGenetics Research Consortium. Main Outcome Measures: We performed a 2-tiered analysis of 1956 patients with PD and 2112 controls from the NeuroGenetics Research Consortium using a comprehensive tag SNP approach. Previously published REP1 genotypes were also included. Plasma α-synuclein was assayed in 86 patients with PD and 78 controls using a highly sensitive Luminex assay. Results: Five of 15 SNPs genotyped were associated with PD under an additive model in tier 1 (α=.05). Of these, 4 weresuccessfullyreplicatedintier2.Inthecombinedsample, themostsignificantmarkerwasrs356219 (odds ratio, 1.41; 95%confidence interval, 1.28-1.55;P=1.6×10-12), located approximately 9 kilobases downstream from the gene. A regressionmodelcontainingrs356219alonebest fitthedata. Thelinkage disequilibrium correlation coefficient between thisSNPand REP1 was low (r2=0.09). The risk-associated Callele of rs356219 was also correlated with higher transformed plasma α-synuclein levels in patients under an adjusted additive model (P=.005). Conclusions: Our data suggest that 1 or more unidentified functional SNCA variants modify risk for PD and that the effect is larger than and independent of REP1. This variant(s), tagged by rs356219, might act by upregulating SNCA expression in a dose-dependent manner. ©2010 American Medical Association. All rights reserved.