The role of variation at AβPP, PSEN1, PSEN2, and MAPT in late onset Alzheimer's disease.

TY - JOUR

T1 - The role of variation at AβPP, PSEN1, PSEN2, and MAPT in late onset Alzheimer's disease.

AU - Gerrish, Amy

AU - Russo, Giancarlo

AU - Richards, Alexander

AU - Moskvina, Valentina

AU - Ivanov, Dobril

AU - Harold, Denise

AU - Sims, Rebecca

AU - Abraham, Richard

AU - Hollingworth, Paul

AU - Chapman, Jade

AU - Hamshere, Marian

AU - Pahwa, Jaspreet Singh

AU - Dowzell, Kimberley

AU - Williams, Amy

AU - Jones, Nicola

AU - Thomas, Charlene

AU - Stretton, Alexandra

AU - Morgan, Angharad R

AU - Lovestone, Simon

AU - Powell, John

AU - Proitsi, Petroula

AU - Lupton, Michelle K

AU - Brayne, Carol

AU - Rubinsztein, David C

AU - Gill, Michael

AU - Lawlor, Brian

AU - Lynch, Aoibhinn

AU - Morgan, Kevin

AU - Brown, Kristelle S

AU - Passmore, Peter A

AU - Craig, David

AU - McGuinness, Bernadette

AU - Todd, Stephen

AU - Johnston, Janet A

AU - Holmes, Clive

AU - Mann, David

AU - Smith, A David

AU - Love, Seth

AU - Kehoe, Patrick G

AU - Hardy, John

AU - Mead, Simon

AU - Fox, Nick

AU - Rossor, Martin

AU - Collinge, John

AU - Maier, Wolfgang

AU - Jessen, Frank

AU - Kölsch, Heike

AU - Heun, Reinhard

AU - Schürmann, Britta

AU - Bussche van den, Hendrik

AU - Heuser, Isabella

AU - Kornhuber, Johannes

AU - Wiltfang, Jens

AU - Dichgans, Martin

AU - Frölich, Lutz

AU - Hampel, Harald

AU - Hüll, Michael

AU - Rujescu, Dan

AU - Goate, Alison M

AU - Kauwe, John S K

AU - Cruchaga, Carlos

AU - Nowotny, Petra

AU - Morris, John C

AU - Mayo, Kevin

AU - Livingston, Gill

AU - Bass, Nicholas J

AU - Gurling, Hugh

AU - McQuillin, Andrew

AU - Gwilliam, Rhian

AU - Deloukas, Panagiotis

AU - Davies, Gail

AU - Harris, Sarah E

AU - Starr, John M

AU - Deary, Ian J

AU - Al-Chalabi, Ammar

AU - Shaw, Christopher E

AU - Tsolaki, Magda

AU - Singleton, Andrew B

AU - Guerreiro, Rita

AU - Mühleisen, Thomas W

AU - Nöthen, Markus M

AU - Moebus, Susanne

AU - Jöckel, Karl-Heinz

AU - Klopp, Norman

AU - Wichmann, H-Erich

AU - Carrasquillo, Minerva M

AU - Pankratz, V Shane

AU - Younkin, Steven G

AU - Jones, Lesley

AU - Holmans, Peter A

AU - O'Donovan, Michael C

AU - Owen, Michael J

AU - Williams, Julie

PY - 2012

Y1 - 2012

N2 - Rare mutations in A?PP, 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 A?PP, 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.

AB - Rare mutations in A?PP, 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 A?PP, 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.

KW - Humans

KW - Male

KW - Aged

KW - Female

KW - Aged, 80 and over

KW - Meta-Analysis as Topic

KW - Genotype

KW - Odds Ratio

KW - Genome-Wide Association Study

KW - Alzheimer Disease/genetics

KW - Polymorphism, Single Nucleotide/genetics

KW - Genetic Predisposition to Disease

KW - Amyloid beta-Protein Precursor/genetics

KW - Presenilin-1/genetics

KW - Presenilin-2/genetics

KW - tau Proteins/genetics

KW - Humans

KW - Male

KW - Aged

KW - Female

KW - Aged, 80 and over

KW - Meta-Analysis as Topic

KW - Genotype

KW - Odds Ratio

KW - Genome-Wide Association Study

KW - Alzheimer Disease/genetics

KW - Polymorphism, Single Nucleotide/genetics

KW - Genetic Predisposition to Disease

KW - Amyloid beta-Protein Precursor/genetics

KW - Presenilin-1/genetics

KW - Presenilin-2/genetics

KW - tau Proteins/genetics

M3 - SCORING: Journal article

VL - 28

SP - 377

EP - 387

JO - J ALZHEIMERS DIS

JF - J ALZHEIMERS DIS

SN - 1387-2877

IS - 2

M1 - 2

ER -