Candidate single-nucleotide polymorphisms from a genomewide association study of Alzheimer disease.
OBJECTIVE
To identify single-nucleotide polymorphisms (SNPs) associated with risk and age at onset of Alzheimer disease (AD) in a genomewide association study of 469 438 SNPs.


METHODS
Case-control study with replication.


METHODS
Memory referral clinics in Canada and the United Kingdom.


METHODS
The hypothesis-generating data set consisted of 753 individuals with AD by National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer's Disease and Related Disorders Association criteria recruited from 9 memory referral clinics in Canada and 736 ethnically matched control subjects; control subjects were recruited from nonbiological relatives, friends, or spouses of the patients and did not exhibit cognitive impairment by history or cognitive testing. The follow-up data set consisted of 418 AD cases and 249 nondemented control cases from the United Kingdom Medical Research Council Genetic Resource for Late-Onset AD recruited from clinics at Cardiff University, Cardiff, Wales, and King's College London, London, England.


METHODS
Odds ratios and 95% confidence intervals for association of SNPs with AD by logistic regression adjusted for age, sex, education, study site, and French Canadian ancestry (for the Canadian data set). Hazard ratios and 95% confidence intervals from Cox proportional hazards regression for age at onset with similar covariate adjustments.


RESULTS
Unadjusted, SNP RS4420638 within APOC1 was strongly associated with AD due entirely to linkage disequilibrium with APOE. In the multivariable adjusted analyses, 3 SNPs within the top 120 by P value in the logistic analysis and 1 in the Cox analysis of the Canadian data set provided additional evidence for association at P< .05 within the United Kingdom Medical Research Council data set: RS7019241 (GOLPH2), RS10868366 (GOLPH2), RS9886784 (chromosome 9), and RS10519262 (intergenic between ATP8B4 and SLC27A2).


CONCLUSIONS
Our genomewide association analysis again identified the APOE linkage disequilibrium region as the strongest genetic risk factor for AD. This could be a consequence of the coevolution of more than 1 susceptibility allele, such as APOC1, in this region. We also provide new evidence for additional candidate genetic risk factors for AD that can be tested in further studies.
Li
Hao
H
GlaxoSmithKline, Research Triangle Park, North Carolina, USA.
Wetten
Sally
S
Li
Li
L
St Jean
Pamela L
PL
Upmanyu
Ruchi
R
Surh
Linda
L
Hosford
David
D
Barnes
Michael R
MR
Briley
James David
JD
Borrie
Michael
M
Coletta
Natalie
N
Delisle
Richard
R
Dhalla
Daniella
D
Ehm
Margaret G
MG
Feldman
Howard H
HH
Fornazzari
Luis
L
Gauthier
Serge
S
Goodgame
Neil
N
Guzman
Danilo
D
Hammond
Sandra
S
Hollingworth
Paul
P
Hsiung
Ging-Yuek
GY
Johnson
Joan
J
Kelly
Devon D
DD
Keren
Ron
R
Kertesz
Andrew
A
King
Karen S
KS
Lovestone
Simon
S
Loy-English
Inge
I
Matthews
Paul M
PM
Owen
Michael J
MJ
Plumpton
Mary
M
Pryse-Phillips
William
W
Prinjha
Rab K
RK
Richardson
Jill C
JC
Saunders
Ann
A
Slater
Andrew J
AJ
St George-Hyslop
Peter H
PH
Stinnett
Sandra W
SW
Swartz
Jina E
JE
Taylor
Rachel L
RL
Wherrett
John
J
Williams
Julie
J
Yarnall
David P
DP
Gibson
Rachel A
RA
Irizarry
Michael C
MC
Middleton
Lefkos T
LT
Roses
Allen D
AD
D000367:Age Factors; D000368:Aged; D000544:Alzheimer Disease / Q000453:epidemiology* / Q000235:genetics*; D001057:Apolipoproteins E / Q000235:genetics; D002170:Canada / Q000453:epidemiology; D016022:Case-Control Studies; D016001:Confidence Intervals; D004493:Education; D005260:Female; D005602:France / Q000208:ethnology; D015894:Genome, Human / Q000235:genetics*; D005838:Genotype; D006801:Humans; D016015:Logistic Models; D008297:Male; D016017:Odds Ratio; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D016016:Proportional Hazards Models; D012042:Registries; D012737:Sex Factors; D006113:United Kingdom / Q000453:epidemiology
D001057:Apolipoproteins E