Cell-subtype specific effects of genetic variation in the aging and Alzheimer cortex
Open accessAbstract
The relationship between genetic variation and gene expression in individual brain cell types and subtypes has remained elusive. Here, we generated single-nucleus RNA sequencing data from the dorsolateral prefrontal cortex of 424 individuals of advanced age; analyzing 1.5 million nuclear transcriptomes, we assessed the effect of genetic variants on RNA expression in cis ( cis -eQTL) for 7 cell types and 81 cell subtypes. This effort identified 10,004 eGenes at the cell type level and 8,138 eGenes at the cell subtype level. Many eGenes are only detected within cell subtypes. A new variant influences APOE expression only in microglia and is associated with greater cerebral amyloid angiopathy but not Alzheimer pathology, accounting for the effect of APOEε4 , providing mechanistic insights into both pathologies. While eQTLs are readily detected, only a TMEM106B variant robustly affects the proportion of cell subtypes. Integration of these results with GWAS highlighted the targeted cell type and likely causal gene within susceptibility loci for Alzheimer’s, Parkinson’s, schizophrenia, and educational attainment.
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The pseudobulk snRNAseq data analyzed were generated from DLPFC (BA9) brain tissue from 131 AD and 162 NCI ROSMAP participants.
“These data were generated from brain tissue (DLPFC, BA9) from 131 AD and 162 NCI ROSMAP participants.”
From INPP5D regulates inflammasome activation in human microglia (2023) · cites this paper as [37]
The Description of the dataset and Study participants sections say the single-nucleus RNA-seq data came from DLPFC tissue donated by ROSMAP participants, and the Pseudobulk expression quantification section describes how pseudobulk data were generated. The paper reports 424 participants retained for genetic analysis, but our copy does not substantiate the stated breakdown of 131 AD and 162 NCI participants or specify BA9. (LLM, conf=0.87)
Experimental — accuracy not yet measuredRNA levels of INPP5D are elevated in Alzheimer's disease brain.
“confirm previous findings that RNA levels of INPP5D are elevated in AD brain21.”
From INPP5D regulates inflammasome activation in human microglia (2023) · cites this paper as [37]
The Results passage on AD-associated microglial genes discusses FNIP2 and RAPGEF2, and the Discussion addresses APOE expression; neither reports elevated INPP5D RNA in AD brain. Searches for INPP5D and for higher RNA expression in AD cases found no passage addressing that claim in our copy (page numbers unavailable). (LLM, conf=0.72)
Experimental — accuracy not yet measuredPseudobulk snRNAseq comparison of AD microglia with LP-NCI microglia yielded 260 DEGs at q < 0.05.
“This analysis yielded 260 DEGs (q < 0.05; Fig. 7j, Supplementary Data 19).”
From INPP5D regulates inflammasome activation in human microglia (2023) · cites this paper as [37]
The Pseudobulk expression quantification section describes how expression was measured, but does not report this AD-versus-LP-NCI microglia comparison or its results. Searches for “260,” “LP-NCI,” and “Figure 7j” found no passage supporting the DEG count or q-value in our copy. (LLM, conf=0.72)
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- Authors
- Fujita, M., Gao, Z., Zeng, L., McCabe, C., White, C. C., Ng, B., Green, G. S., Rozenblatt-Rosen, O., Phillips, D., Amir-Zilberstein, L., Lee, H., Pearse, R. V., Khan, A., Vardarajan, B. N., Kiryluk, K., Ye, C. J., Klein, H.-U., Wang, G., Regev, A., Habib, N., Schneider, J. A., Wang, Y., Young-Pearse, T., Mostafavi, S., Bennett, D. A., Menon, V., & De Jager, P. L.
- Affiliations
- Columbia University Irving Medical Center (US)
- Rush University Medical Center (US)
- Hebrew University of Jerusalem (IL)
- Broad Institute (US)
- Brigham and Women's Hospital (US)
- Columbia University (US)
- NewYork–Presbyterian Hospital (US)
- University of California, San Francisco (US)
- University of British Columbia (CA)
- ORCID
- Fujita, Masashi
- Gao, Zongmei
- Zeng, Lu
- White, Charles C.
- Ng, Bernard
- Green, Gilad Sahar
- Phillips, Devan
- Lee, Hyo
- Pearse, Richard V.
- Khan, Atlas
- Vardarajan, Badri N.
- Kiryluk, Krzysztof
- Ye, Chun Jimmie
- Klein, Hans-Ulrich
- Wang, Gao
- Regev, Aviv
- Habib, Naomi
- Schneider, Julie A.
- Wang, Yanling
- Mostafavi, Sara
- Bennett, David A.
- Menon, Vilas
- De Jager, Philip L.
- Venue
- bioRxiv (Cold Spring Harbor Laboratory)
- Publisher
- openRxiv
- Published
- 2022-11-08
- OpenAlex
- W4308572272
- Cited by
- 36
- References
- 11
- Citations by year
- 2025: 10 · 2024: 15 · 2023: 11
- Type
- posted content
- Language
- en
- Open access
- green
- doi.org
- Locations
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- Funders
- National Institutes of Health
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- cis-eQTL, cell type-specific gene expression, cell subtypes, single-nucleus RNA sequencing, dorsolateral prefrontal cortex, brain aging, Alzheimer's disease, apolipoprotein E, cerebral amyloid angiopathy, microglia, TMEM106B, genetic variants, eGenes, Parkinson's disease, schizophrenia, educational attainment
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