The role of variation at AβPP, PSEN1, PSEN2, and MAPT in late onset Alzheimer's disease.
Rare mutations in AβPP, PSEN1, and PSEN2 cause uncommon early onset forms of Alzheimer's disease (AD), and common variants in MAPT are associated with risk of other neurodegenerative disorders. We sought to establish whether common genetic variation in these genes confer risk to the common form of AD which occurs later in life (>65 years). We therefore tested single-nucleotide polymorphisms at these loci for association with late-onset AD (LOAD) in a large case-control sample consisting of 3,940 cases and 13,373 controls. Single-marker analysis did not identify any variants that reached genome-wide significance, a result which is supported by other recent genome-wide association studies. However, we did observe a significant association at the MAPT locus using a gene-wide approach (p = 0.009). We also observed suggestive association between AD and the marker rs9468, which defines the H1 haplotype, an extended haplotype that spans the MAPT gene and has previously been implicated in other neurodegenerative disorders including Parkinson's disease, progressive supranuclear palsy, and corticobasal degeneration. In summary common variants at AβPP, PSEN1, and PSEN2 and MAPT are unlikely to make strong contributions to susceptibility for LOAD. However, the gene-wide effect observed at MAPT indicates a possible contribution to disease risk which requires further study.
MRC Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, UK.
Amy
A
Gerrish
Giancarlo
G
Russo
Alexander
A
Richards
Valentina
V
Moskvina
Dobril
D
Ivanov
Denise
D
Harold
Rebecca
R
Sims
Richard
R
Abraham
Paul
P
Hollingworth
Jade
J
Chapman
Marian
M
Hamshere
Jaspreet Singh
JS
Pahwa
Kimberley
K
Dowzell
Amy
A
Williams
Nicola
N
Jones
Charlene
C
Thomas
Alexandra
A
Stretton
Angharad R
AR
Morgan
Simon
S
Lovestone
John
J
Powell
Petroula
P
Proitsi
Michelle K
MK
Lupton
Carol
C
Brayne
David C
DC
Rubinsztein
Michael
M
Gill
Brian
B
Lawlor
Aoibhinn
A
Lynch
Kevin
K
Morgan
Kristelle S
KS
Brown
Peter A
PA
Passmore
David
D
Craig
Bernadette
B
McGuinness
Stephen
S
Todd
Janet A
JA
Johnston
Clive
C
Holmes
David
D
Mann
A David
AD
Smith
Seth
S
Love
Patrick G
PG
Kehoe
John
J
Hardy
Simon
S
Mead
Nick
N
Fox
Martin
M
Rossor
John
J
Collinge
Wolfgang
W
Maier
Frank
F
Jessen
Heike
H
Kölsch
Reinhard
R
Heun
Britta
B
Schürmann
Hendrik
H
van den Bussche
Isabella
I
Heuser
Johannes
J
Kornhuber
Jens
J
Wiltfang
Martin
M
Dichgans
Lutz
L
Frölich
Harald
H
Hampel
Michael
M
Hüll
Dan
D
Rujescu
Alison M
AM
Goate
John S K
JS
Kauwe
Carlos
C
Cruchaga
Petra
P
Nowotny
John C
JC
Morris
Kevin
K
Mayo
Gill
G
Livingston
Nicholas J
NJ
Bass
Hugh
H
Gurling
Andrew
A
McQuillin
Rhian
R
Gwilliam
Panagiotis
P
Deloukas
Gail
G
Davies
Sarah E
SE
Harris
John M
JM
Starr
Ian J
IJ
Deary
Ammar
A
Al-Chalabi
Christopher E
CE
Shaw
Magda
M
Tsolaki
Andrew B
AB
Singleton
Rita
R
Guerreiro
Thomas W
TW
Mühleisen
Markus M
MM
Nöthen
Susanne
S
Moebus
Karl-Heinz
KH
Jöckel
Norman
N
Klopp
H-Erich
HE
Wichmann
Minerva M
MM
Carrasquillo
V Shane
VS
Pankratz
Steven G
SG
Younkin
Lesley
L
Jones
Peter A
PA
Holmans
Michael C
MC
O'Donovan
Michael J
MJ
Owen
Julie
J
Williams
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D015201:Meta-Analysis as Topic; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D053764:Presenilin-1 / Q000235:genetics*; D053766:Presenilin-2 / Q000235:genetics*; D016875:tau Proteins / Q000235:genetics*
D016564:Amyloid beta-Protein Precursor; C054369:MAPT protein, human; C508853:PSEN1 protein, human; D053764:Presenilin-1; D053766:Presenilin-2; D016875:tau Proteins