SNCA Variant Associated With Parkinson Disease and Plasma α-Synuclein Level

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 alpha-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 alpha-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 (alpha=.05). Of these, 4 were successfully replicated in tier 2. In the combined sample, the most significant marker was rs356219 (odds ratio, 1.41; 95% confidence interval, 1.28-1.55; P=1.6 x 10-12), located approximately 9 kilobases downstream from the gene. A regression model containing rs356219 alone best fit the data. The linkage disequilibrium correlation coefficient between this SNP and REP1 was low (r(2)=0.09). The risk-associated Callele of rs356219 was also correlated with higher transformed plasma alpha-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.