A scan of chromosome 10 identifies a novel locus showing strong association with late-onset Alzheimer disease.
Strong evidence of linkage to late-onset Alzheimer disease (LOAD) has been observed on chromosome 10, which implicates a wide region and at least one disease-susceptibility locus. Although significant associations with several biological candidate genes on chromosome 10 have been reported, these findings have not been consistently replicated, and they remain controversial. We performed a chromosome 10-specific association study with 1,412 gene-based single-nucleotide polymorphisms (SNPs), to identify susceptibility genes for developing LOAD. The scan included SNPs in 677 of 1,270 known or predicted genes; each gene contained one or more markers, about half (48%) of which represented putative functional mutations. In general, the initial testing was performed in a white case-control sample from the St. Louis area, with 419 LOAD cases and 377 age-matched controls. Markers that showed significant association in the exploratory analysis were followed up in several other white case-control sample sets to confirm the initial association. Of the 1,397 markers tested in the exploratory sample, 69 reached significance (P < .05). Five of these markers replicated at P < .05 in the validation sample sets. One marker, rs498055, located in a gene homologous to RPS3A (LOC439999), was significantly associated with Alzheimer disease in four of six case-control series, with an allelic P value of .0001 for a meta-analysis of all six samples. One of the case-control samples with significant association to rs498055 was derived from the linkage sample (P = .0165). These results indicate that variants in the RPS3A homologue are associated with LOAD and implicate this gene, adjacent genes, or other functional variants (e.g., noncoding RNAs) in the pathogenesis of this disorder.
Grupe
Andrew
A
Celera Diagnostics, Alameda, CA, USA.
Li
Yonghong
Y
Rowland
Charles
C
Nowotny
Petra
P
Hinrichs
Anthony L
AL
Smemo
Scott
S
Kauwe
John S K
JS
Maxwell
Taylor J
TJ
Cherny
Sara
S
Doil
Lisa
L
Tacey
Kristina
K
van Luchene
Ryan
R
Myers
Amanda
A
Wavrant-De Vrièze
Fabienne
F
Kaleem
Mona
M
Hollingworth
Paul
P
Jehu
Luke
L
Foy
Catherine
C
Archer
Nicola
N
Hamilton
Gillian
G
Holmans
Peter
P
Morris
Chris M
CM
Catanese
Joseph
J
Sninsky
John
J
White
Thomas J
TJ
Powell
John
J
Hardy
John
J
O'Donovan
Michael
M
Lovestone
Simon
S
Jones
Lesley
L
Morris
John C
JC
Thal
Leon
L
Owen
Michael
M
Williams
Julie
J
Goate
Alison
A
D000483:Alleles; D000544:Alzheimer Disease / Q000235:genetics*; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics*; D008040:Genetic Linkage; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008923:Missouri; D020641:Polymorphism, Single Nucleotide; D012269:Ribosomal Proteins / Q000235:genetics*; D044465:White People / Q000235:genetics
D005819:Genetic Markers; C031016:RPS3A protein, human; D012269:Ribosomal Proteins