Collaborative analysis of alpha-synuclein gene promoter variability and Parkinson disease.
BACKGROUND
Identification and replication of susceptibility genes for Parkinson disease at the population level have been hampered by small studies with potential biases. Alpha-synuclein (SNCA) has been one of the most promising susceptibility genes, but large-scale studies have been lacking.


OBJECTIVE
To determine whether allele-length variability in the dinucleotide repeat sequence (REP1) of the SNCA gene promoter is associated with Parkinson disease susceptibility, whether SNCA promoter haplotypes are associated with Parkinson disease, and whether REP1 variability modifies age at onset.


METHODS
We performed a collaborative analysis of individual-level data on SNCA REP1 and flanking markers in patients with Parkinson disease and controls. Study site recruitment, data collection, and analyses were performed between April 5, 2004, and December 31, 2005. Eighteen participating sites of a global genetics consortium provided clinical data. Genotyping was performed for SNCA REP1, -770, and -116 markers at individual sites; however, each site also provided 20 DNA samples for regenotyping centrally.


METHODS
Measures included estimations of Hardy-Weinberg equilibrium in controls; a test of heterogeneity; analyses for association of single variants or haplotypes; and survival analyses for age at onset.


RESULTS
Of the 18 sites, 11 met stringent criteria for concordance with Hardy-Weinberg equilibrium and low genotyping error rate. These 11 sites provided complete data for 2692 cases and 2652 controls. There was no heterogeneity across studies (P>.60). The SNCA REP1 alleles differed in frequency for cases and controls (P<.001). Genotypes defined by the 263 base-pair allele were associated with Parkinson disease (odds ratio, 1.43; 95% confidence interval, 1.22-1.69; P<.001 for trend). Multilocus haplotypes differed in frequency for cases and controls (global score statistic, P<.001). Two-loci haplotypes were associated with Parkinson disease only when they included REP1 as one of the loci. However, genotypes defined by REP1 alleles did not modify age at onset (P = .55).


CONCLUSIONS
This large-scale collaborative analysis demonstrates that SNCA REP1 allele-length variability is associated with an increased risk of Parkinson disease.
Maraganore
Demetrius M
DM
Department of Neurology, Mayo Clinic College of Medicine, Rochester, Minn 55905, USA. dmaraganore@mayo.edu
de Andrade
Mariza
M
Elbaz
Alexis
A
Farrer
Matthew J
MJ
Ioannidis
John P
JP
Krüger
Rejko
R
Rocca
Walter A
WA
Schneider
Nicole K
NK
Lesnick
Timothy G
TG
Lincoln
Sarah J
SJ
Hulihan
Mary M
MM
Aasly
Jan O
JO
Ashizawa
Tetsuo
T
Chartier-Harlin
Marie-Christine
MC
Checkoway
Harvey
H
Ferrarese
Carlo
C
Hadjigeorgiou
Georgios
G
Hattori
Nobutaka
N
Kawakami
Hideshi
H
Lambert
Jean-Charles
JC
Lynch
Timothy
T
Mellick
George D
GD
Papapetropoulos
Spiridon
S
Parsian
Abbas
A
Quattrone
Aldo
A
Riess
Olaf
O
Tan
Eng-King
EK
Van Broeckhoven
Christine
C
D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D018900:Dinucleotide Repeats; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D010300:Parkinson Disease / Q000453:epidemiology / Q000235:genetics*; D011401:Promoter Regions, Genetic; D051844:alpha-Synuclein / Q000235:genetics*
D051844:alpha-Synuclein