Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease.
We undertook a two-stage genome-wide association study (GWAS) of Alzheimer's disease (AD) involving over 16,000 individuals, the most powerful AD GWAS to date. In stage 1 (3,941 cases and 7,848 controls), we replicated the established association with the apolipoprotein E (APOE) locus (most significant SNP, rs2075650, P = 1.8 x 10(-157)) and observed genome-wide significant association with SNPs at two loci not previously associated with the disease: at the CLU (also known as APOJ) gene (rs11136000, P = 1.4 x 10(-9)) and 5' to the PICALM gene (rs3851179, P = 1.9 x 10(-8)). These associations were replicated in stage 2 (2,023 cases and 2,340 controls), producing compelling evidence for association with Alzheimer's disease in the combined dataset (rs11136000, P = 8.5 x 10(-10), odds ratio = 0.86; rs3851179, P = 1.3 x 10(-9), odds ratio = 0.86).
Harold
Denise
D
Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, UK.
Abraham
Richard
R
Hollingworth
Paul
P
Sims
Rebecca
R
Gerrish
Amy
A
Hamshere
Marian L
ML
Pahwa
Jaspreet Singh
JS
Moskvina
Valentina
V
Dowzell
Kimberley
K
Williams
Amy
A
Jones
Nicola
N
Thomas
Charlene
C
Stretton
Alexandra
A
Morgan
Angharad R
AR
Lovestone
Simon
S
Powell
John
J
Proitsi
Petroula
P
Lupton
Michelle K
MK
Brayne
Carol
C
Rubinsztein
David C
DC
Gill
Michael
M
Lawlor
Brian
B
Lynch
Aoibhinn
A
Morgan
Kevin
K
Brown
Kristelle S
KS
Passmore
Peter A
PA
Craig
David
D
McGuinness
Bernadette
B
Todd
Stephen
S
Holmes
Clive
C
Mann
David
D
Smith
A David
AD
Love
Seth
S
Kehoe
Patrick G
PG
Hardy
John
J
Mead
Simon
S
Fox
Nick
N
Rossor
Martin
M
Collinge
John
J
Maier
Wolfgang
W
Jessen
Frank
F
Schürmann
Britta
B
Heun
Reinhard
R
van den Bussche
Hendrik
H
Heuser
Isabella
I
Kornhuber
Johannes
J
Wiltfang
Jens
J
Dichgans
Martin
M
Frölich
Lutz
L
Hampel
Harald
H
Hüll
Michael
M
Rujescu
Dan
D
Goate
Alison M
AM
Kauwe
John S K
JS
Cruchaga
Carlos
C
Nowotny
Petra
P
Morris
John C
JC
Mayo
Kevin
K
Sleegers
Kristel
K
Bettens
Karolien
K
Engelborghs
Sebastiaan
S
De Deyn
Peter P
PP
Van Broeckhoven
Christine
C
Livingston
Gill
G
Bass
Nicholas J
NJ
Gurling
Hugh
H
McQuillin
Andrew
A
Gwilliam
Rhian
R
Deloukas
Panagiotis
P
Al-Chalabi
Ammar
A
Shaw
Christopher E
CE
Tsolaki
Magda
M
Singleton
Andrew B
AB
Guerreiro
Rita
R
Mühleisen
Thomas W
TW
Nöthen
Markus M
MM
Moebus
Susanne
S
Jöckel
Karl-Heinz
KH
Klopp
Norman
N
Wichmann
H-Erich
HE
Carrasquillo
Minerva M
MM
Pankratz
V Shane
VS
Younkin
Steven G
SG
Holmans
Peter A
PA
O'Donovan
Michael
M
Owen
Michael J
MJ
Williams
Julie
J
D000544:Alzheimer Disease / Q000235:genetics*; D002877:Chromosomes, Human; D051152:Clusterin / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D055106:Genome-Wide Association Study; D006801:Humans; D034041:Monomeric Clathrin Assembly Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide
C495242:CLU protein, human; D051152:Clusterin; D034041:Monomeric Clathrin Assembly Proteins; C439003:PICALM protein, human