SNCA variant associated with Parkinson disease and plasma alpha-synuclein level.
BACKGROUND
A functional repeat polymorphism in the SNCA promoter (REP1) conveys susceptibility for Parkinson disease (PD). There is also increasing evidence that single-nucleotide polymorphisms (SNPs) elsewhere in the gene are associated with PD risk.


OBJECTIVE
To further explore the association of common SNCA SNPs with PD susceptibility, to determine whether evidence of allelic heterogeneity exists, and to examine the correlation between PD-associated variants and plasma α-synuclein levels.


METHODS
Two-tiered analysis.


METHODS
Academic research.


METHODS
Patients and control subjects from the NeuroGenetics Research Consortium.


METHODS
We performed a 2-tiered analysis of 1956 patients with PD and 2112 controls from the NeuroGenetics Research Consortium using a comprehensive tag SNP approach. Previously published REP1 genotypes were also included. Plasma α-synuclein was assayed in 86 patients with PD and 78 controls using a highly sensitive Luminex assay.


RESULTS
Five of 15 SNPs genotyped were associated with PD under an additive model in tier 1 (α = .05). Of these, 4 were successfully replicated in tier 2. In the combined sample, the most significant marker was rs356219 (odds ratio, 1.41; 95% confidence interval, 1.28-1.55; P = 1.6 × 10(-12)), located approximately 9 kilobases downstream from the gene. A regression model containing rs356219 alone best fit the data. The linkage disequilibrium correlation coefficient between this SNP and REP1 was low (r(2) = 0.09). The risk-associated C allele of rs356219 was also correlated with higher transformed plasma α-synuclein levels in patients under an adjusted additive model (P = .005).


CONCLUSIONS
Our data suggest that 1 or more unidentified functional SNCA variants modify risk for PD and that the effect is larger than and independent of REP1. This variant(s), tagged by rs356219, might act by upregulating SNCA expression in a dose-dependent manner.
Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Mailstop S-182, 1660 S Columbian Way, Seattle, WA 98108, USA.
Ignacio F
IF
Mata
Min
M
Shi
Pinky
P
Agarwal
Kathryn A
KA
Chung
Karen L
KL
Edwards
Stewart A
SA
Factor
Douglas R
DR
Galasko
Carmen
C
Ginghina
Alida
A
Griffith
Donald S
DS
Higgins
Denise M
DM
Kay
Hojoong
H
Kim
James B
JB
Leverenz
Joseph F
JF
Quinn
John W
JW
Roberts
Ali
A
Samii
Katherine W
KW
Snapinn
Debby W
DW
Tsuang
Dora
D
Yearout
Jing
J
Zhang
Haydeh
H
Payami
Cyrus P
CP
Zabetian
D000483:Alleles; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D056726:Genetic Association Studies; D018740:Genetic Heterogeneity; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D016015:Logistic Models; D008297:Male; D016017:Odds Ratio; D010300:Parkinson Disease / Q000097:blood* / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D051844:alpha-Synuclein / Q000097:blood* / Q000235:genetics*
D051844:alpha-Synuclein