Cited by 304Alzheimer's disease research and treatmentsGenetic Associations and EpidemiologyDementia and Cognitive Impairment Research

Genetic Control of Human Brain Transcript Expression in Alzheimer Disease

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Webster, Jennifer A., Gibbs, J. Raphael, Clarke, Jennifer, Ray, Monika, Zhang, Weixiong, Holmans, Peter, Rohrer, Kristen, Zhao, Alice +19 more·2009·The American Journal of Human Genetics

Abstract

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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Crossref · 10.1016/j.ajhg.2009.03.011

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  • Intersection of the microglia signature gene list with 46 publicly available data sets for differentially regulated genes in neurodegenerative and behavioral disorders revealed significant enrichment or depletion of microglia signature genes in 28 of the 46 data sets.

    “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).”
  • Downregulation of WASF1 expression in the AD brain has also been observed in publicly available datasets.

    “Downregulation of WASF1 expression in the AD brain has also been observed in publicly available datasets144,145.”
  • The first large transcriptomic study (188 controls and 176 Alzheimer disease cases) connected genetic variation to expression changes using eQTL analysis and supported pathway-level findings related to transcriptional regulation and energy metabolism.

    “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.”
  • Among the DEGs identified in snRNA-seq, 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).

    “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).”
  • The same pipeline was used to process the microarray dataset of AD temporal cortical samples from Webster et al. (GEO GSE15222).

    “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).”

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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.
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)
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
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
  • Health Sciences › Medicine › Physiology › 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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