Genome-wide association with MRI atrophy measures as a quantitative trait locus for Alzheimer's disease.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder with considerable evidence suggesting an initiation of disease in the entorhinal cortex and hippocampus and spreading thereafter to the rest of the brain. In this study, we combine genetics and imaging data obtained from the Alzheimer's Disease Neuroimaging Initiative and the AddNeuroMed study. To identify genetic susceptibility loci for AD, we conducted a genome-wide study of atrophy in regions associated with neurodegeneration in this condition. We identified one single-nucleotide polymorphism (SNP) with a disease-specific effect associated with entorhinal cortical volume in an intron of the ZNF292 gene (rs1925690; P-value=2.6 × 10(-8); corrected P-value for equivalent number of independent quantitative traits=7.7 × 10(-8)) and an intergenic SNP, flanking the ARPP-21 gene, with an overall effect on entorhinal cortical thickness (rs11129640; P-value=5.6 × 10(-8); corrected P-value=1.7 × 10(-7)). Gene-wide scoring also highlighted PICALM as the most significant gene associated with entorhinal cortical thickness (P-value=6.7 × 10(-6)).
National Institute for Health Research Biomedical Research Centre for Mental Health, Institute of Psychiatry, King's College London, London, UK.
S J
SJ
Furney
A
A
Simmons
G
G
Breen
I
I
Pedroso
K
K
Lunnon
P
P
Proitsi
A
A
Hodges
J
J
Powell
L-O
LO
Wahlund
I
I
Kloszewska
P
P
Mecocci
H
H
Soininen
M
M
Tsolaki
B
B
Vellas
C
C
Spenger
M
M
Lathrop
L
L
Shen
S
S
Kim
A J
AJ
Saykin
M W
MW
Weiner
S
S
Lovestone
D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology; D053327:Apolipoprotein E4 / Q000235:genetics; D001284:Atrophy; D001921:Brain / Q000473:pathology*; D002352:Carrier Proteins / Q000235:genetics; D018450:Disease Progression; D018728:Entorhinal Cortex / Q000473:pathology; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D007438:Introns; D015810:Linkage Disequilibrium; D008279:Magnetic Resonance Imaging; D008297:Male; D034041:Monomeric Clathrin Assembly Proteins / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics; D009929:Organ Size; D010750:Phosphoproteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D012307:Risk Factors
D053327:Apolipoprotein E4; D002352:Carrier Proteins; D034041:Monomeric Clathrin Assembly Proteins; D009419:Nerve Tissue Proteins; C439003:PICALM protein, human; D010750:Phosphoproteins; C570380:ZNF292 protein, human; C061368:cyclic AMP-regulated phosphoprotein ARPP-21