Meta-analysis confirms CR1, CLU, and PICALM as alzheimer disease risk loci and reveals interactions with APOE genotypes.
OBJECTIVE
To determine whether genotypes at CLU, PICALM, and CR1 confer risk for Alzheimer disease (AD) and whether risk for AD associated with these genes is influenced by apolipoprotein E (APOE) genotypes.


METHODS
Association study of AD and CLU, PICALM, CR1, and APOE genotypes.


METHODS
Academic research institutions in the United States, Canada, and Israel.


METHODS
Seven thousand seventy cases with AD, 3055 with autopsies, and 8169 elderly cognitively normal controls, 1092 with autopsies, from 12 different studies, including white, African American, Israeli-Arab, and Caribbean Hispanic individuals.


RESULTS
Unadjusted, CLU (odds ratio [OR], 0.91; 95% confidence interval [CI], 0.85-0.96 for single-nucleotide polymorphism [SNP] rs11136000), CR1 (OR, 1.14; 95% CI, 1.07-1.22; SNP rs3818361), and PICALM (OR, 0.89; 95% CI, 0.84-0.94, SNP rs3851179) were associated with AD in white individuals. None were significantly associated with AD in the other ethnic groups. APOE ε4 was significantly associated with AD (ORs, 1.80-9.05) in all but 1 small white cohort and in the Arab cohort. Adjusting for age, sex, and the presence of at least 1 APOE ε4 allele greatly reduced evidence for association with PICALM but not CR1 or CLU. Models with the main SNP effect, presence or absence of APOE ε4, and an interaction term showed significant interaction between presence or absence of APOE ε4 and PICALM.


CONCLUSIONS
We confirm in a completely independent data set that CR1, CLU, and PICALM are AD susceptibility loci in European ancestry populations. Genotypes at PICALM confer risk predominantly in APOE ε4-positive subjects. Thus, APOE and PICALM synergistically interact.
Jun
Gyungah
G
Department of Medicine, Boston University, USA.
Naj
Adam C
AC
Beecham
Gary W
GW
Wang
Li-San
LS
Buros
Jacqueline
J
Gallins
Paul J
PJ
Buxbaum
Joseph D
JD
Ertekin-Taner
Nilufer
N
Fallin
M Daniele
MD
Friedland
Robert
R
Inzelberg
Rivka
R
Kramer
Patricia
P
Rogaeva
Ekaterina
E
St George-Hyslop
Peter
P
Cantwell
Laura B
LB
Dombroski
Beth A
BA
Saykin
Andrew J
AJ
Reiman
Eric M
EM
Bennett
David A
DA
Morris
John C
JC
Lunetta
Kathryn L
KL
Martin
Eden R
ER
Montine
Thomas J
TJ
Goate
Alison M
AM
Blacker
Deborah
D
Tsuang
Debby W
DW
Beekly
Duane
D
Cupples
L Adrienne
LA
Hakonarson
Hakon
H
Kukull
Walter
W
Foroud
Tatiana M
TM
Haines
Jonathan
J
Mayeux
Richard
R
Farrer
Lindsay A
LA
Pericak-Vance
Margaret A
MA
Schellenberg
Gerard D
GD
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics*; D001057:Apolipoproteins E / Q000235:genetics*; D051152:Clusterin / Q000235:genetics*; D015331:Cohort Studies; D016001:Confidence Intervals; D005260:Female; D005787:Gene Frequency; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D015201:Meta-Analysis as Topic; D034041:Monomeric Clathrin Assembly Proteins / Q000235:genetics*; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017463:Receptors, Complement 3b / Q000235:genetics*; D012307:Risk Factors; D044465:White People
D001057:Apolipoproteins E; C495242:CLU protein, human; C509991:CR1 protein, human; D051152:Clusterin; D034041:Monomeric Clathrin Assembly Proteins; C439003:PICALM protein, human; D017463:Receptors, Complement 3b