Multiple regions of alpha-synuclein are associated with Parkinson's disease.
alpha-Synuclein is considered to play an important role in the pathogenesis of both the rare familial and the common sporadic forms of Parkinson's disease. Previous reports primarily have tested the association of alpha-synuclein promoter polymorphisms with idiopathic Parkinson's disease, but results are controversial. We first characterized the linkage disequilibrium structure of the alpha-synuclein gene region with a dense set of 56 genetic markers and subsequently performed two independent case-control association analyses using tagging markers. We could distinguish two large linkage disequilibrium blocks spanning the alpha-synuclein gene. Several markers within the 3'-block around exons 5 and 6 showed strong association with Parkinson's disease (p = 0.00009). Effects of the associated variants might be mediated by regulatory elements in this highly conserved region or by a frequency shift in a previously described splice variant lacking exon 5. A direct association with promoter polymorphisms could not be replicated in our sample set. A second set of markers in the 5'-block of the gene were also significantly associated with Parkinson's disease, when young patients and female subjects were analyzed separately. These findings indicate locus heterogeneity for the pathogenesis of Parkinson's disease in different genetic or physiological environments, related to sex and age.
Mueller
Jakob C
JC
Institute for Human Genetics, GSF-National Research Centre for Environment and Health, Neuherberg, Germany.
Fuchs
Julia
J
Hofer
Anne
A
Zimprich
Alexander
A
Lichtner
Peter
P
Illig
Thomas
T
Berg
Daniela
D
Wüllner
Ullrich
U
Meitinger
Thomas
T
Gasser
Thomas
T
D000367:Age Factors; D000818:Animals; D005260:Female; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010300:Parkinson Disease / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012737:Sex Factors; D013045:Species Specificity; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D051843:Synucleins; D051844:alpha-Synuclein
D009419:Nerve Tissue Proteins; C497604:SNCA protein, human; D051843:Synucleins; D051844:alpha-Synuclein