title: 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.
  
  
  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.
authors.affiliation: 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
authors.forename: Ammar
authors.initials: A
authors.lastname: Al-Chalabi
authors.forename: Alexandra
authors.initials: A
authors.lastname: Dürr
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Wood
authors.forename: Michael H
authors.initials: MH
authors.lastname: Parkinson
authors.forename: Agnes
authors.initials: A
authors.lastname: Camuzat
authors.forename: Jean-Sébastien
authors.initials: JS
authors.lastname: Hulot
authors.forename: Karen E
authors.initials: KE
authors.lastname: Morrison
authors.forename: Alan
authors.initials: A
authors.lastname: Renton
authors.forename: Sigurd D
authors.initials: SD
authors.lastname: Sussmuth
authors.forename: Bernhard G
authors.initials: BG
authors.lastname: Landwehrmeyer
authors.forename: Albert
authors.initials: A
authors.lastname: Ludolph
authors.forename: Yves
authors.initials: Y
authors.lastname: Agid
authors.forename: Alexis
authors.initials: A
authors.lastname: Brice
authors.forename: P Nigel
authors.initials: PN
authors.lastname: Leigh
authors.forename: Gilbert
authors.initials: G
authors.lastname: Bensimon
mesh_terms: 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
chemical_list: C497604:SNCA protein, human; D051844:alpha-Synuclein