Genetic variants of the alpha-synuclein gene SNCA are associated with multiple system atrophy

Abstract

Background: Multiple system atrophy (MSA) is a progressive neurodegenerative disorder characterized by parkinsonism, cerebellar ataxia and autonomic dysfunction. Pathogenic mechanisms remain obscure but the neuropathological hallmark is the presence of alpha-synuclein-immunoreactive glial cytoplasmic inclusions. Genetic variants of the alpha-synuclein gene, SNCA, are thus strong candidates for genetic association with MSA. One follow-up to a genome-wide association of Parkinson's disease has identified association of a SNP in SNCA with MSA.

Methodology/findings: We evaluated 32 SNPs in the SNCA gene in a European population of 239 cases and 617 controls recruited as part of the Neuroprotection and Natural History in Parkinson Plus Syndromes (NNIPPS) study. We used 161 independently collected samples for replication. Two SNCA SNPs showed association with MSA: rs3822086 (P = 0.0044), and rs3775444 (P = 0.012), although only the first survived correction for multiple testing. In the MSA-C subgroup the association strengthened despite more than halving the number of cases: rs3822086 P = 0.0024, OR 2.153, (95% CI 1.3-3.6); rs3775444 P = 0.0017, OR 4.386 (95% CI 1.6-11.7). A 7-SNP haplotype incorporating three SNPs either side of rs3822086 strengthened the association with MSA-C further (best haplotype, P = 8.7 x 10(-4)). The association with rs3822086 was replicated in the independent samples (P = 0.035).

Conclusions/significance: We report a genetic association between MSA and alpha-synuclein which has replicated in independent samples. The strongest association is with the cerebellar subtype of MSA.

Trial registration: ClinicalTrials.gov NCT00211224.

Figure 1. The genetic architecture of the SNCA gene and the markers genotyped.

The base pair position along chromosome 4 is shown by the top ruler. The position of the α-synuclein gene is shown in the next row down, with exons represented by vertical lines and introns by lines connecting them. The relative positions of the genotyped markers are shown below, with vertical lines connecting position to the linkage disequilibrium map. Asterisks show the two markers demonstrating association in MSA-C. Only the left-most marker showed association with MSA as a whole. (For a list of markers genotyped and P-values, see Table 3). The coloured triangle is the linkage disequilibrium heat map showing the strength of association between pairs of markers as measured by D′. Red is high and blue low with the other colours intermediate. The two associated SNPs are in different linkage disequilibrium blocks and are not in linkage disequilibrium with each other.