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

Jason L. Stein, Xue Hua, Jonathan H. Morra, Suh Lee, Derrek P. Hibar, April J. Ho, Alex D. Leow, Arthur W. Toga, Jae Hoon Sul, Hyun Min Kang, Eleazar Eskin, Andrew J. Saykin, Li Shen, Tatiana Foroud, Nathan Pankratz, Matthew J. Huentelman, David W. Craig, Jill D. Gerber, April N. Allen, Jason J. CorneveauxDietrich A. Stephan, Jennifer Webster, Bryan M. DeChairo, Steven G. Potkin, Clifford R. Jack, Michael W. Weiner, Paul M. Thompson

Research output: Contribution to journalArticlepeer-review

109 Scopus citations

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<5×10<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.

Original languageEnglish (US)
Pages (from-to)542-554
Number of pages13
JournalNeuroImage
Volume51
Issue number2
DOIs
StatePublished - Jun 2010

ASJC Scopus subject areas

  • Neurology
  • Cognitive Neuroscience

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