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Genetic Control of Human Brain Transcript Expression in Alzheimer Disease
Open accessAbstract
We recently surveyed the relationship between the human brain transcriptome and genome in a series of neuropathologically normal postmortem samples. We have now analyzed additional samples with a confirmed pathologic diagnosis of late-onset Alzheimer disease (LOAD; final n = 188 controls, 176 cases). Nine percent of the cortical transcripts that we analyzed had expression profiles correlated with their genotypes in the combined cohort, and approximately 5% of transcripts had SNP-transcript relationships that could distinguish LOAD samples. Two of these transcripts have been previously implicated in LOAD candidate-gene SNP-expression screens. This study shows how the relationship between common inherited genetic variants and brain transcript expression can be used in the study of human brain disorders. We suggest that studying the transcriptome as a quantitative endo-phenotype has greater power for discovering risk SNPs influencing expression than the use of discrete diagnostic categories such as presence or absence of disease.
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“Among the DEGs identified in our snRNA-seq analysis, 1,113 and 764 genes were significantly differentially expressed in the microarray data from the prefrontal cortex and temporal cortex, respectively (adjusted P < 0.05) (SI Appendix, Table S4).”
From Single-nucleus transcriptome analysis reveals dysregulation of angiogenic endothelial cells and neuroprotective glia in Alzheimer’s disease (2020) · cites this paper as [19]
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“We then intersected this gene list with 46 publicly available data sets for differentially regulated genes in neurodegenerative and behavioral disorders derived from microarray or RNA-seq analysis of intact tissue (39–53). Two-sided Fisher’s exact tests revealed significant enrichment or depletion of microglia signature genes in 28 of the 46 data sets (Table S3).”
From An environment-dependent transcriptional network specifies human microglia identity (2017) · cites this paper as [47]
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In the citing paper
“Downregulation of WASF1 expression in the AD brain has also been observed in publicly available datasets144,145.”
From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [144]
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“The first large transcriptomic study (involving 188 controls and 176 individuals with Alzheimer disease)147 connected genetic variation to expression changes by using expression quantitative trait locus analysis (eQTL analysis) in controls and Alzheimer disease, and further supported the pathway-level findings related to transcriptional regulation and energy metabolism in Alzheimer disease140,148.”
From Systems biology and gene networks in neurodevelopmental and neurodegenerative disorders (2015) · cites this paper as [147]
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“We also used the same pipeline to process the microarray dataset of AD temporal cortical samples from Webster et al. (GEO accession no. GSE15222) (19).”
From Single-nucleus transcriptome analysis reveals dysregulation of angiogenic endothelial cells and neuroprotective glia in Alzheimer’s disease (2020) · cites this paper as [19]
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Metadata
- Authors
- Webster, J. A., Gibbs, J. R., Clarke, J., Ray, M., Zhang, W., Holmans, P., Rohrer, K., Zhao, A., Marlowe, L., Kaleem, M., McCorquodale, D. S., Cuello, C., Leung, D., Bryden, L., Nath, P., Zismann, V. L., Joshipura, K., Huentelman, M. J., Hu-Lince, D., Coon, K. D., Craig, D. W., Pearson, J. V., Heward, C. B., Reiman, E. M., Stephan, D., Hardy, J., & Myers, A. J.
- Affiliations
- Translational Genomics Research Institute (US)
- National Institutes of Health (US)
- University of Miami (US)
- Washington University in St. Louis (US)
- Cardiff University (GB)
- Corresponding author
- Myers, Amanda J.
- ORCID
- Venue
- The American Journal of Human Genetics
- Publisher
- Elsevier BV
- Published
- 2009-04
- Volume
- 84
- Issue
- 4
- Pages
- 445-458
- ISSN
- 0002-9297 (ISSN-L)
- PMC
- PMC2667989
- OpenAlex
- W2101889545
- Cited by
- 304
- References
- 47
- Citations by year
- 2026: 8 · 2025: 9 · 2024: 17 · 2023: 18 · 2022: 8 · 2021: 19 · 2020: 15 · 2019: 18 · 2018: 19 · 2017: 15 · 2016: 14 · 2015: 18 · 2014: 24 · 2013: 25 · 2012: 41
- FWCI
- 17.01
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The American Journal of Human Genetics (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- National Institute on Aging (U01AG016976, P30AG019610)
- National Institute of Neurological Disorders and Stroke (R01NS059873)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Alzheimer's disease, late-onset Alzheimer's disease, brain transcriptome, gene expression, single nucleotide polymorphisms, genetic variants, endophenotypes, postmortem brain, genetic risk factors
- MeSH terms
- Aged, Alzheimer Disease, Brain, Female, Humans, Male, Transcription, Genetic, Case-Control Studies, Age of Onset, Oligonucleotide Array Sequence Analysis, Polymorphism, Single Nucleotide, Gene Expression Profiling, Transcription Initiation Site, Quantitative Trait Loci, Gene Regulatory Networks, Genome-Wide Association Study
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