Genetic association between alpha-synuclein and idiopathic Parkinson's disease.
Point mutations and copy number variations in SNCA, the gene encoding alpha-synuclein, cause familial Parkinson's disease (PD). A dinucleotide polymorphism (REP1) in the SNCA promoter may be a risk factor for common forms of PD. We studied 1,802 PD patients and 2,129 controls from the NeuroGenetics Research Consortium, using uniform, standardized protocols for diagnosis, subject recruitment, data collection, genotyping, and data analysis. Three common REP1 alleles (257, 259, and 261 bp, with control frequencies of 0.28, 0.65, and 0.06) and several rare alleles (combined frequency <0.01) were detected. We confirmed association of REP1 with PD risk [odds ratio (OR) = 0.86, P = 0.006 for 257-carriers; OR = 1.25, P = 0.022 for 261-carriers]. Using a normalization procedure, we showed that the 257 and 261 alleles are both independently associated with PD risk (for 257, P = 0.002 in overall data, 0.003 in non-familial PD, 0.001 in early-onset PD; for 261, P = 0.056 in overall data, 0.024 in non-familial PD, 0.052 in early-onset PD). The 257-associated risk was consistent with a dominant model [hazard ratio (HR) = 0.99, P = 0.91 for 257/257 vs. 257/X where X denotes all other common alleles; HR = 1.16, P = 0.004 for X/X vs. 257/X]. The 261-associated risk was consistent with a recessive model (HR = 1.89, P = 0.026 for 261/261 vs. 261/X; HR = 0.95, P = 0.42 for X/X vs. 261/X). Genotype-specific mean onset ages (+/-SD) ranged from 54.8 +/- 12.1 for 261/261 to 59.4 +/- 11.5 for 257/257, displaying a trend of decreasing onset age with increasing allele size (P = 0.055). Genetic variation in SNCA and its regulatory regions play an important role in both familial and sporadic PD.
Kay
Denise M
DM
New York State Department of Health, Division of Genetic Disorders, Wadsworth Center, Albany, New York 12208, USA.
Factor
Stewart A
SA
Samii
Ali
A
Higgins
Donald S
DS
Griffith
Alida
A
Roberts
John W
JW
Leis
Berta C
BC
Nutt
John G
JG
Montimurro
Jennifer S
JS
Keefe
Robert G
RG
Atkins
April J
AJ
Yearout
Dora
D
Zabetian
Cyrus P
CP
Payami
Haydeh
H
D000328:Adult; D017668:Age of Onset; D000368:Aged; D000483:Alleles; D016022:Case-Control Studies; D005192:Family Health; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D008875:Middle Aged; D010300:Parkinson Disease / Q000235:genetics*; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic / Q000235:genetics; D051844:alpha-Synuclein / Q000235:genetics*
D051844:alpha-Synuclein