Association of late-onset Alzheimer's disease with genetic variation in multiple members of the GAPD gene family.
Although several genes have been implicated in the development of the early-onset autosomal dominant form of Alzheimer's disease (AD), the genetics of late-onset AD (LOAD) is complex. Loci on several chromosomes have been linked to the disease, but so far only the apolipoprotein E gene has been consistently shown to be a risk factor. We have performed a large-scale single-nucleotide polymorphism (SNP)-based association study, across the region of linkage on chromosome 12, in multiple case-control series totaling 1,089 LOAD patients and 1,196 control subjects and report association with SNPs in the glyceraldehyde-3-phosphate dehydrogenase (GAPD) gene. Subsequent analysis of GAPD paralogs on other chromosomes demonstrated association with two other paralogs. A significant association between LOAD and a compound genotype of the three GAPD genes was observed in all three sample sets. Individually, these SNPs make differential contributions to disease risk in each of the casecontrol series, suggesting that variants in functionally similar genes may account for series-to-series heterogeneity of disease risk. Our observations raise the possibility that GAPD genes are AD risk factors, a hypothesis that is consistent with the role of GAPD in neuronal apoptosis.
Li
Yonghong
Y
Celera Diagnostics, Alameda, CA 94502, USA.
Nowotny
Petra
P
Holmans
Peter
P
Smemo
Scott
S
Kauwe
John S K
JS
Hinrichs
Anthony L
AL
Tacey
Kristina
K
Doil
Lisa
L
van Luchene
Ryan
R
Garcia
Veronica
V
Rowland
Charles
C
Schrodi
Steve
S
Leong
Diane
D
Gogic
Goran
G
Chan
Joanne
J
Cravchik
Anibal
A
Ross
David
D
Lau
Kit
K
Kwok
Shirley
S
Chang
Sheng-Yung
SY
Catanese
Joe
J
Sninsky
John
J
White
Thomas J
TJ
Hardy
John
J
Powell
John
J
Lovestone
Simon
S
Morris
John C
JC
Thal
Leon
L
Owen
Michael
M
Williams
Julie
J
Goate
Alison
A
Grupe
Andrew
A
D017668:Age of Onset; D000368:Aged; D000483:Alleles; D000544:Alzheimer Disease / Q000201:enzymology* / Q000209:etiology / Q000235:genetics*; D053327:Apolipoprotein E4; D001057:Apolipoproteins E / Q000235:genetics; D017209:Apoptosis; D001921:Brain / Q000201:enzymology; D016022:Case-Control Studies; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics; D015870:Gene Expression; D005787:Gene Frequency; D014644:Genetic Variation; D005838:Genotype; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000235:genetics*; D006801:Humans; D008875:Middle Aged; D005810:Multigene Family; D009410:Nerve Degeneration; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
D053327:Apolipoprotein E4; D001057:Apolipoproteins E; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases