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


RESULTS
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
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.


BACKGROUND
ClinicalTrials.gov NCT00211224.
Al-Chalabi
Ammar
A
MRC Centre for Neurodegeneration Research, King's College London, Department of Clinical Neuroscience, Institute of Psychiatry, and NIHR Biomedical Research Centre, London, United Kingdom. ammar@iop.kcl.ac.uk
Dürr
Alexandra
A
Wood
Nicholas W
NW
Parkinson
Michael H
MH
Camuzat
Agnes
A
Hulot
Jean-Sébastien
JS
Morrison
Karen E
KE
Renton
Alan
A
Sussmuth
Sigurd D
SD
Landwehrmeyer
Bernhard G
BG
Ludolph
Albert
A
Agid
Yves
Y
Brice
Alexis
A
Leigh
P Nigel
PN
Bensimon
Gilbert
G
D000368:Aged; D016022:Case-Control Studies; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D019578:Multiple System Atrophy / Q000235:genetics* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D011786:Quality Control; D051844:alpha-Synuclein / Q000235:genetics* / Q000502:physiology
C497604:SNCA protein, human; D051844:alpha-Synuclein