Common genetic variability around the α-synuclein gene influences risk for Parkinson’s disease
Introduction. Mutations in the alpha-synuclein gene (SNCA) lead to familial forms of Parkinson's disease (PD). Considerable evidence also links alpha-synuclein to sporadic PD. A polymorphic genetic variable (REP1, D4S3481) 10kb upstream from SNCA is associated with sporadic PD. However, the mechanisms for how common genetic variability around SNCA alters risk for PD remain elusive. Aim. To provide a comprehensive analysis of common genetic variability around SNCA using a haplotype tagging approach in a newly ascertained PD case-control sample recruited as part of the Australian Parkinson's Project. Methods. PD cases (n=326) were and unaffected control subjects (n=306) were recruited from three specialist clinics in Brisbane and the Australian Electoral Roll. Common genetic variables around SNCA, including 8 potential haplotype tagging single nucleotide polymorphisms (htSNPs) and the REP1 microsatellite, were genotyped in all subjects using standard methods. Haplotypes were inferred by implementing the expectation-maximization algorithm using the program EH. Statistical analyses were performed using SPSS. Results. Three out of the eight SNPs proved redundant in our sample (correlated with another selected SNP with r^2>0.9). The REP1 locus showed modest correlation with several of the selected SNPs. Seven common haplotypes described >90% of the variability around this region. There was a significant difference in haplotype distribution between the case and control groups (p=0.003). The most common haplotype (designated 1ATATT) was more frequent in the PD group (Odds Ratio (OR) = 1.40, 95% CI=1.09-1.80); several haplotypes were more frequent in the controls. Independent analysis of SNPs rs10005233 (p=0.03) and rs3910104 (p=0.05) revealed significant associations with PD. We also independently confirmed the previously reported association between the REP1 locus and PD (p=0.02). Logistic regression analysis confirmed that variables other than REP1 contribute to the association. Conclusion. Our analysis provides evidence that multiple common functional variables around SNCA may contribute to differential risk of sporadic PD.
Proceedings of IBRO Satellite Meeting: New frontiers in basic and clinical research in Parkinson's disease and other synucleinopathies