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    Neuroimage. 2010 Jun;51(2):542-54. doi: 10.1016/j.neuroimage.2010.02.068. Epub 2010 Mar 1.

    Genome-wide analysis reveals novel genes influencing temporal lobe structure with relevance to neurodegeneration in Alzheimer's disease.

    Stein JL, Hua X, Morra JH, Lee S, Hibar DP, Ho AJ, Leow AD, Toga AW, Sul JH, Kang HM, Eskin E, Saykin AJ, Shen L, Foroud T, Pankratz N, Huentelman MJ, Craig DW, Gerber JD, Allen AN, Corneveaux JJ, Stephan DA, Webster J, DeChairo BM, Potkin SG, Jack CR Jr, Weiner MW, Thompson PM; Alzheimer's Disease Neuroimaging Initiative.

    Source

    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.

    Abstract

    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.

    Copyright 2010 Elsevier Inc. All rights reserved.

    PMID:
    20197096
    [PubMed - indexed for MEDLINE]
    PMCID:
    PMC2856746
    Free PMC Article

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