Genome-wide analysis of genetic loci associated with Alzheimer disease.
BACKGROUND
Genome-wide association studies (GWAS) have recently identified CLU, PICALM, and CR1 as novel genes for late-onset Alzheimer disease (AD).


OBJECTIVE
To identify and strengthen additional loci associated with AD and confirm these in an independent sample and to examine the contribution of recently identified genes to AD risk prediction in a 3-stage analysis of new and previously published GWAS on more than 35,000 persons (8371 AD cases).


METHODS
In stage 1, we identified strong genetic associations (P < 10(-3)) in a sample of 3006 AD cases and 14,642 controls by combining new data from the population-based Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (1367 AD cases [973 incident]) with previously reported results from the Translational Genomics Research Institute and the Mayo AD GWAS. We identified 2708 single-nucleotide polymorphisms (SNPs) with P < 10(-3). In stage 2, we pooled results for these SNPs with the European AD Initiative (2032 cases and 5328 controls) to identify 38 SNPs (10 loci) with P < 10(-5). In stage 3, we combined data for these 10 loci with data from the Genetic and Environmental Risk in AD consortium (3333 cases and 6995 controls) to identify 4 SNPs with P < 1.7x10(-8). These 4 SNPs were replicated in an independent Spanish sample (1140 AD cases and 1209 controls). Genome-wide association analyses were completed in 2007-2008 and the meta-analyses and replication in 2009.


METHODS
Presence of Alzheimer disease.


RESULTS
Two loci were identified to have genome-wide significance for the first time: rs744373 near BIN1 (odds ratio [OR],1.13; 95% confidence interval [CI],1.06-1.21 per copy of the minor allele; P = 1.59x10(-11)) and rs597668 near EXOC3L2/BLOC1S3/MARK4 (OR, 1.18; 95% CI, 1.07-1.29; P = 6.45x10(-9)). Associations of these 2 loci plus the previously identified loci CLU and PICALM with AD were confirmed in the Spanish sample (P < .05). However, although CLU and PICALM were confirmed to be associated with AD in this independent sample, they did not improve the ability of a model that included age, sex, and APOE to predict incident AD (improvement in area under the receiver operating characteristic curve from 0.847 to 0.849 in the Rotterdam Study and 0.702 to 0.705 in the Cardiovascular Health Study).


CONCLUSIONS
Two genetic loci for AD were found for the first time to reach genome-wide statistical significance. These findings were replicated in an independent population. Two recently reported associations were also confirmed. These loci did not improve AD risk prediction. While not clinically useful, they may implicate biological pathways useful for future research.
Seshadri
Sudha
S
Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, USA.
Fitzpatrick
Annette L
AL
Ikram
M Arfan
MA
DeStefano
Anita L
AL
Gudnason
Vilmundur
V
Boada
Merce
M
Bis
Joshua C
JC
Smith
Albert V
AV
Carassquillo
Minerva M
MM
Lambert
Jean Charles
JC
Harold
Denise
D
Schrijvers
Elisabeth M C
EM
Ramirez-Lorca
Reposo
R
Debette
Stephanie
S
Longstreth
W T
WT
Janssens
A Cecile J W
AC
Pankratz
V Shane
VS
Dartigues
Jean François
JF
Hollingworth
Paul
P
Aspelund
Thor
T
Hernandez
Isabel
I
Beiser
Alexa
A
Kuller
Lewis H
LH
Koudstaal
Peter J
PJ
Dickson
Dennis W
DW
Tzourio
Christophe
C
Abraham
Richard
R
Antunez
Carmen
C
Du
Yangchun
Y
Rotter
Jerome I
JI
Aulchenko
Yurii S
YS
Harris
Tamara B
TB
Petersen
Ronald C
RC
Berr
Claudine
C
Owen
Michael J
MJ
Lopez-Arrieta
Jesus
J
Varadarajan
Badri N
BN
Becker
James T
JT
Rivadeneira
Fernando
F
Nalls
Michael A
MA
Graff-Radford
Neill R
NR
Campion
Dominique
D
Auerbach
Sanford
S
Rice
Kenneth
K
Hofman
Albert
A
Jonsson
Palmi V
PV
Schmidt
Helena
H
Lathrop
Mark
M
Mosley
Thomas H
TH
Au
Rhoda
R
Psaty
Bruce M
BM
Uitterlinden
Andre G
AG
Farrer
Lindsay A
LA
Lumley
Thomas
T
Ruiz
Agustin
A
Williams
Julie
J
Amouyel
Philippe
P
Younkin
Steve G
SG
Wolf
Philip A
PA
Launer
Lenore J
LJ
Lopez
Oscar L
OL
van Duijn
Cornelia M
CM
Breteler
Monique M B
MM
D017668:Age of Onset; D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics*; D016022:Case-Control Studies; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide
Circ Cardiovasc Genet. 2009 Feb;2(1):73-80
20031568
J Biol Chem. 2004 Feb 13;279(7):5915-23
14594945
Neuron. 2007 Jun 7;54(5):713-20
17553421
Nat Genet. 2009 Feb;41(2):192-8
19136949
Arch Neurol. 2008 Jan;65(1):45-53
17998437
Arch Gen Psychiatry. 2006 Feb;63(2):168-74
16461860
Am J Hum Genet. 2009 Jan;84(1):35-43
19118814
J Nutr Health Aging. 2009 Mar;13(3):214-9
19262956
J Biol Chem. 1997 Dec 12;272(50):31453-8
9395479
Nat Genet. 2009 Oct;41(10):1088-93
19734902
Neuron. 2002 Feb 28;33(5):789-804
11879655
Hum Mol Genet. 2008 Oct 15;17(R2):R166-73
18852206
Science. 2000 Dec 22;290(5500):2304-5
11125144
Am J Hum Genet. 2008 Nov;83(5):623-32
18976728
Genet Epidemiol. 2008 May;32(4):381-5
18348202
Neuroscience. 2008 Jun 26;154(3):1107-20
18495355
Neurol Clin. 2007 Aug;25(3):611-67, v
17659183
Genome Med. 2009 Feb 18;1(2):20
19341491
Am J Med Genet B Neuropsychiatr Genet. 2009 Jan 5;150B(1):50-5
18449908
Mol Psychiatry. 2010 Jul;15(7):756-66
19125160
Mol Biol Cell. 1997 Oct;8(10):2003-15
9348539
Neuroscience. 2007 Jun 15;147(1):60-70
17499934
J Clin Psychiatry. 2007 Apr;68(4):613-8
17474819
Neurology. 1984 Jul;34(7):939-44
6610841
Neuroreport. 2001 Dec 4;12(17):3759-61
11726789
Nature. 2009 Aug 6;460(7256):748-52
19571811
Lancet Neurol. 2007 Dec;6(12):1106-14
18031707
Neuroscience. 2006 Nov 17;143(1):83-94
16973293
Proteomics. 2009 Jun;9(12):3368-82
19562803
J Alzheimers Dis. 2009;18(4):751-4
19749441
Nat Genet. 2007 Jan;39(1):17-23
17192785
Nat Genet. 2009 Oct;41(10):1094-9
19734903
J Biol Chem. 2004 Jul 2;279(27):28393-401
15102850
Biol Psychiatry. 2008 Jan 1;63(1):24-31
17618940