Genome-wide analysis reveals novel genes influencing temporal lobe structure with relevance to neurodegeneration in Alzheimer’s disease
Open accessAbstract
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.
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A large number of novel loci and genes have been nominated by imaging GWAS analyses.
“a large number of novel loci and genes have been nominated by these analyses [222, 229–231]”
From Genetic architecture of Alzheimer's disease (2020) · cites this paper as [231]
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- Authors
- Stein, J. L., Hua, X., Morra, J. H., Lee, S., Hibar, D. P., Ho, A. J., Leow, A. D., Toga, A. W., Sul, J. H., Kang, H. M., Eskin, E., Saykin, A. J., Shen, L., Foroud, T., Pankratz, N., Huentelman, M. J., Craig, D. W., Gerber, J. D., Allen, A. N., Corneveaux, J. J., Stephan, D. A., Webster, J., DeChairo, B. M., Potkin, S. G., Jack, C. R., Weiner, M. W., & Thompson, P. M.
- Affiliations
- University of California, Los Angeles (US)
- University of Michigan (US)
- Indiana University Indianapolis (US)
- Indiana University School of Medicine (US)
- Translational Genomics Research Institute (US)
- Pfizer (United States) (US)
- University of California, Irvine (US)
- Mayo Clinic (US)
- San Francisco VA Medical Center (US)
- Corresponding author
- Thompson, Paul M.
- ORCID
- Venue
- NeuroImage
- Publisher
- Elsevier BV
- Published
- 2010-06
- Volume
- 51
- Issue
- 2
- Pages
- 542-554
- ISSN
- 1053-8119 (ISSN-L)
- PMC
- PMC2856746
- OpenAlex
- W1994029270
- Cited by
- 145
- References
- 67
- Citations by year
- 2025: 1 · 2024: 4 · 2023: 5 · 2022: 5 · 2021: 9 · 2020: 2 · 2019: 4 · 2018: 6 · 2017: 6 · 2016: 8 · 2015: 13 · 2014: 16 · 2013: 22 · 2012: 15
- FWCI
- 14.43
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- NeuroImage (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- IUScholarWorks (Indiana University) (submittedVersion)
- Funders
- ADNI (U01 AG024904)
- National Institutes of Health (U54 RR021813)
- National Center for Research Resources (NCRR) (P41 RR013642, M01 RR000865)
- NIBIB (R01 EB007813, R01 EB008281, R01 EB008432)
- NICHHD (R01 HD050735)
- NIA (R01 AG020098)
- NIH/NIDA (1-T90-DA022768:02)
- ARCS foundation
- NIMH (1F31MH087061)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- Alzheimer's disease, temporal lobe volume, NR2B subunit, single nucleotide polymorphisms, mild cognitive impairment, cognitive function, genetic risk factors, brain MRI, gene discovery
- MeSH terms
- Aged, Alzheimer Disease, Genotype, Humans, Image Interpretation, Computer-Assisted, Magnetic Resonance Imaging, Nerve Degeneration, Temporal Lobe, Receptors, N-Methyl-D-Aspartate, Polymorphism, Single Nucleotide, Genome-Wide Association Study
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