Association of alpha-, beta-, and gamma-Synuclein with diffuse lewy body disease.
OBJECTIVE
To determine the association of the genes that encode alpha-, beta-, and gamma-synuclein (SNCA, SNCB, and SNCG, respectively) with diffuse Lewy body disease (DLBD).


METHODS
Case-control study. Subjects A total of 172 patients with DLBD consistent with a clinical diagnosis of Parkinson disease dementia/dementia with Lewy bodies and 350 clinically and 97 pathologically normal controls.


METHODS
Sequencing of SNCA, SNCB, and SNCG and genotyping of single-nucleotide polymorphisms performed on an Applied Biosystems capillary sequencer and a Sequenom MassArray pLEX platform, respectively. Associations were determined using chi(2) or Fisher exact tests.


RESULTS
Initial sequencing studies of the coding regions of each gene in 89 patients with DLBD did not detect any pathogenic substitutions. Nevertheless, genotyping of known polymorphic variability in sequence-conserved regions detected several single-nucleotide polymorphisms in the SNCA and SNCG genes that were significantly associated with disease (P = .05 to <.001). Significant association was also observed for 3 single-nucleotide polymorphisms located in SNCB when comparing DLBD cases and pathologically confirmed normal controls (P = .03-.01); however, this association was not significant for the clinical controls alone or the combined clinical and pathological controls (P > .05). After correction for multiple testing, only 1 single-nucleotide polymorphism in SNCG (rs3750823) remained significant in all of the analyses (P = .05-.009).


CONCLUSIONS
These findings suggest that variants in all 3 members of the synuclein gene family, particularly SNCA and SNCG, affect the risk of developing DLBD and warrant further investigation in larger, pathologically defined data sets as well as clinically diagnosed Parkinson disease/dementia with Lewy bodies case-control series.
Nishioka
Kenya
K
Department of Neuroscience, Mayo Clinic Florida, 4500 San Pablo Rd, Jacksonville, FL 32224, USA.
Wider
Christian
C
Vilariño-Güell
Carles
C
Soto-Ortolaza
Alexandra I
AI
Lincoln
Sarah J
SJ
Kachergus
Jennifer M
JM
Jasinska-Myga
Barbara
B
Ross
Owen A
OA
Rajput
Alex
A
Robinson
Christopher A
CA
Ferman
Tanis J
TJ
Wszolek
Zbigniew K
ZK
Dickson
Dennis W
DW
Farrer
Matthew J
MJ
D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D005075:Biological Evolution; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D020961:Lewy Body Disease / Q000235:genetics*; D015810:Linkage Disequilibrium; D008297:Male; D010802:Phylogeny; D020641:Polymorphism, Single Nucleotide; D051844:alpha-Synuclein / Q000235:genetics*; D051846:beta-Synuclein / Q000235:genetics*; D051845:gamma-Synuclein / Q000235:genetics*
D051844:alpha-Synuclein; D051846:beta-Synuclein; D051845:gamma-Synuclein