Cell subtype-specific effects of genetic variation in the Alzheimer’s disease brain

Masashi Fujita, Zongmei Gao, Lu Zeng, Cristin McCabe, Charles C. White, Bernard Ng, Gilad Sahar Green, Orit Rozenblatt-Rosen, Devan Phillips, Liat Amir-Zilberstein, Hyo Lee, Richard V. Pearse, Atlas Khan, Badri N. Vardarajan, Krzysztof Kiryluk, Chun Jimmie Ye, Hans Ulrich Klein, Gao Wang, Aviv Regev, Naomi HabibJulie A. Schneider, Yanling Wang, Tracy Young-Pearse, Sara Mostafavi, David A. Bennett, Vilas Menon, Philip L. De Jager*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

The relationship between genetic variation and gene expression in brain cell types and subtypes remains understudied. Here, we generated single-nucleus RNA sequencing data from the neocortex of 424 individuals of advanced age; we assessed the effect of genetic variants on RNA expression in cis (cis-expression quantitative trait loci) for seven cell types and 64 cell subtypes using 1.5 million transcriptomes. This effort identified 10,004 eGenes at the cell type level and 8,099 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’s disease pathology, after adjusting for APOEε4, providing mechanistic insights into both pathologies. Furthermore, only a TMEM106B variant affects the proportion of cell subtypes. Integration of these results with genome-wide association studies highlighted the targeted cell type and probable causal gene within Alzheimer’s disease, schizophrenia, educational attainment and Parkinson’s disease loci.

Original languageAmerican English
JournalNature Genetics
DOIs
StateAccepted/In press - 2024

Bibliographical note

Publisher Copyright:
© The Author(s), under exclusive licence to Springer Nature America, Inc. 2024.

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