Genome-wide analysis reveals novel genes influencing temporal lobe structure with relevance to neurodegeneration in Alzheimer's disease.
In a genome-wide association study of structural brain degeneration, we mapped the 3D profile of temporal lobe volume differences in 742 brain MRI scans of Alzheimer's disease patients, mildly impaired, and healthy elderly subjects. After searching 546,314 genomic markers, 2 single nucleotide polymorphisms (SNPs) were associated with bilateral temporal lobe volume (P<5 x 10(-7)). One SNP, rs10845840, is located in the GRIN2B gene which encodes the N-methyl-d-aspartate (NMDA) glutamate receptor NR2B subunit. This protein - involved in learning and memory, and excitotoxic cell death - has age-dependent prevalence in the synapse and is already a therapeutic target in Alzheimer's disease. Risk alleles for lower temporal lobe volume at this SNP were significantly over-represented in AD and MCI subjects vs. controls (odds ratio=1.273; P=0.039) and were associated with mini-mental state exam scores (MMSE; t=-2.114; P=0.035) demonstrating a negative effect on global cognitive function. Voxelwise maps of genetic association of this SNP with regional brain volumes, revealed intense temporal lobe effects (FDR correction at q=0.05; critical P=0.0257). This study uses large-scale brain mapping for gene discovery with implications for Alzheimer's disease.
Stein
Jason L
JL
Laboratory of Neuro Imaging, Department of Neurology, UCLA School of Medicine, Neuroscience Research Building 225E, 635 Charles Young Drive, Los Angeles, CA 90095-1769, USA.
Hua
Xue
X
Morra
Jonathan H
JH
Lee
Suh
S
Hibar
Derrek P
DP
Ho
April J
AJ
Leow
Alex D
AD
Toga
Arthur W
AW
Sul
Jae Hoon
JH
Kang
Hyun Min
HM
Eskin
Eleazar
E
Saykin
Andrew J
AJ
Shen
Li
L
Foroud
Tatiana
T
Pankratz
Nathan
N
Huentelman
Matthew J
MJ
Craig
David W
DW
Gerber
Jill D
JD
Allen
April N
AN
Corneveaux
Jason J
JJ
Stephan
Dietrich A
DA
Webster
Jennifer
J
DeChairo
Bryan M
BM
Potkin
Steven G
SG
Jack
Clifford R
CR
Weiner
Michael W
MW
Thompson
Paul M
PM
D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D007090:Image Interpretation, Computer-Assisted; D008279:Magnetic Resonance Imaging; D009410:Nerve Degeneration / Q000235:genetics* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics*; D013702:Temporal Lobe / Q000473:pathology*
C121001:NR2B NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate