Genetic Variants of the α-Synuclein Gene SNCA Are Associated with Multiple System Atrophy

Ammar Al-Chalabi,Michael H Parkinson,Alexis Brice,Alan Renton,Sigurd D Sussmuth,Gilbert Bensimon,Bernhard G Landwehrmeyer,P Nigel Leigh,Karen E Morrison,Nicholas W Wood,Agnes Camuzat,Yves Agid,For The Nnipps Genetic Study Group ,Alexandra Dürr,Albert Ludolph,Jean-Sébastien Hulot

doi:10.1371/journal.pone.0007114

Abstract

BackgroundMultiple 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 α-synuclein-immunoreactive glial cytoplasmic inclusions. Genetic variants of the α-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/FindingsWe 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 = 8.7×10−4). The association with rs3822086 was replicated in the independent samples (P = 0.035).Conclusions/SignificanceWe report a genetic association between MSA and α-synuclein which has replicated in independent samples. The strongest association is with the cerebellar subtype of MSA.Trial RegistrationClinicalTrials.gov NCT00211224. [NCT00211224]

Highlights

Multiple system atrophy (MSA) is a rare progressive neurodegenerative disease characterized by parkinsonism, cerebellar dysfunction and dysautonomia corresponding to previous diagnostic appellations of striatonigral degeneration, olivopontocerebellar atrophy and ShyDrager syndrome
We repeated the analysis in the MSA-C subgroup for these two SNPs and found the association strengthened despite more than halving the number of cases: rs3822086 P = 0.0024, OR 2.153,; rs3775444 P = 0.0017, OR 4.386; step-wise whole gene permutation test P = 0.0084
We have found two positive associations in the SNCA gene with MSA, one with rs3822086 and the other with rs3775444, only one survives correction for multiple testing

Summary

Introduction

Multiple system atrophy (MSA) is a rare progressive neurodegenerative disease characterized by parkinsonism, cerebellar dysfunction and dysautonomia corresponding to previous diagnostic appellations of striatonigral degeneration, olivopontocerebellar atrophy and ShyDrager syndrome. 1.9 and 4.4 per 100,000 persons this may represent an underestimate as post-mortem studies have suggested that as many as 5% of cases of clinically diagnosed Parkinson’s disease may have MSA. We examined the association between SNCA variants and MSA using the DNA Bank of the NNIPPS cohort [1]. This cohort has a nearly 50% autopsy rate for MSA so that the criteria for diagnosis can be validated pathologically, and in individual cases we can be certain of the diagnosis. We found that genetic variants of SNCA were associated with MSA and with the subset of people who had cerebellar signs

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