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

Nature Genetics volume 56, pages 605–614 (2024)Cite this article

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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.

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Fig. 1: Study design and summary of cell type-specific and subtype-specific cis-eQTL.
Fig. 2: Similarities and differences of cell type-specific eQTLs.
Fig. 3: Replication of eQTL using bulk cortical RNA and RNA from induced pluripotent stem cell lines.
Fig. 4: Chromatin states of cell type-level eQTLs.
Fig. 5: fQTLs between SNPs and cell subtype proportions.
Fig. 6: Overlap of the results from our eQTL and GWAS of selected neurodegenerative and neuropsychiatric diseases.

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Data availability

Raw sequence and processed data of single-nucleus RNA-seq are available at Synapse (https://www.synapse.org/#!Synapse:syn31512863). To preserve the anonymity of study participants, access to the datasets is restricted and requires a data use certificate (DUC) to be submitted. To submit a DUC, please see https://adknowledgeportal.synapse.org/Data%20Access. Cell (sub)type annotation and cell (sub)type-level eQTL summary statistics are available at Synapse (https://doi.org/10.7303/syn52335732). The cell type-level eQTLs of this study are also available from https://vmenon.shinyapps.io/rosmap_snrnaseq_eqtl/. The VCF files of the WGS are available at Synapse (https://www.synapse.org/#!Synapse:syn11724057). The reference human genome GRCh37 used for WGS variant calling is available from the European Molecular Biology Laboratory-European Bioinformatics Institute (https://ftp.1000genomes.ebi.ac.uk/vol1/ftp/technical/reference/human_g1k_v37.fasta.gz).

Code availability

All software used in the study is publicly available as described in the Methods and Reporting Summary. The custom code to prepare the pseudobulk gene expression and mapping cis-eQTL can be found at Zenodo (https://zenodo.org/records/10472216) and GitHub (https://github.com/masashi-CU/snuc-eQTL).

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Acknowledgements

We thank all the participants of the ROS/MAP study for their participation and generous donation of brains. This work was funded by NIH grant nos. U01AG061356 (P.L.D.J./D.A.B.), RF1AG057473 (P.L.D.J./D.A.B.) and U01AG046152 (P.L.D.J./D.A.B.) as part of the AMP-AD consortium, as well as NIH grant nos. R01AG066831 (V.M.), K25DK128563 (A.K.) and U01AG072572 (P.L.D.J./St George-Hyslop).

Author information

Author notes

  1. Orit Rozenblatt-Rosen, Devan Phillips & Aviv Regev

    Present address: Genentech, South San Francisco, CA, USA

  2. These authors contributed equally: Masashi Fujita, Zongmei Gao, Lu Zeng.

  3. These authors jointly supervised this work: Vilas Menon, Philip L. De Jager.

Authors and Affiliations

  1. Center for Translational and Computational Neuroimmunology, Department of Neurology, Columbia University Irving Medical Center, New York, NY, USA

    Masashi Fujita, Zongmei Gao, Lu Zeng, Charles C. White, Hans-Ulrich Klein, Vilas Menon & Philip L. De Jager

  2. Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Cristin McCabe, Orit Rozenblatt-Rosen, Devan Phillips, Liat Amir-Zilberstein & Aviv Regev

  3. Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, USA

    Bernard Ng, Julie A. Schneider, Yanling Wang & David A. Bennett

  4. Edmond & Lily Safra Center for Brain Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel

    Gilad Sahar Green & Naomi Habib

  5. Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Boston, MA, USA

    Hyo Lee, Richard V. Pearse II & Tracy Young-Pearse

  6. Harvard Medical School, Boston, MA, USA

    Hyo Lee, Richard V. Pearse II & Tracy Young-Pearse

  7. Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA

    Atlas Khan & Krzysztof Kiryluk

  8. Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, NY, USA

    Badri N. Vardarajan

  9. Department of Neurology, College of Physicians and Surgeons, Columbia University and the New York Presbyterian Hospital, New York, NY, USA

    Badri N. Vardarajan & Gao Wang

  10. The Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, NY, USA

    Badri N. Vardarajan

  11. Institute for Human Genetics, University of California, San Francisco, CA, USA

    Chun Jimmie Ye

  12. Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA

    Chun Jimmie Ye

  13. Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA

    Chun Jimmie Ye

  14. Chan Zuckerberg Biohub, San Francisco, CA, USA

    Chun Jimmie Ye

  15. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA

    Aviv Regev

  16. Department of Statistics, Centre for Molecular Medicine and Therapeutics, British Columbia Children’s Hospital, University of British Columbia, Vancouver, British Columbia, Canada

    Sara Mostafavi

  17. Paul G. Allen School of Computer Science and Engineering, University of Washington, Seattle, WA, USA

    Sara Mostafavi

Authors
  1. Masashi Fujita
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  2. Zongmei Gao
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  3. Lu Zeng
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  4. Cristin McCabe
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  6. Bernard Ng
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  27. Philip L. De Jager
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Contributions

V.M. and P.L.D.J. conceptualized the study. M.F., Z.G., L.Z., C.M., C.C.W., B.N., G.S.G., O.R.-R., D.P., L.A.-Z., H.L., R.V.P., A.K., B.N.V., K.K., C.J.Y., H.-U.K., G.W., A.R., N.H., J.A.S., Y.W., T.Y.-P., S.M., D.A.B., V.M. and P.L.D.J. carried out the investigation. D.A.B., V.M. and P.L.D.J. acquired the funding. V.M. and P.L.D.J. supervised the study. M.F., Z.G., L.Z. and P.L.D.J. wrote the original manuscript draft. M.F., C.C.W., B.N., G.S.G., K.K., C.J.Y., H.-U.K., T.Y.-P., D.A.B. and P.L.D.J. reviewed and edited the manuscript draft.

Corresponding author

Correspondence to Philip L. De Jager.

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Competing interests

A.R. is a cofounder and equity holder of Celsius Therapeutics, is an equity holder in Immunitas and was a scientific advisory board member of Thermo Fisher Scientific, Syros Pharmaceuticals, Neogene Therapeutics and Asimov until 31 July 2020. Since 1 August 2020, A.R. is an employee of Genentech with equity in Roche. O.R.-R. has been an employee of Genentech since 19 October 2020. She has given many lectures on the subject of single-cell genomics to a wide variety of audiences and, in some cases, received remuneration to cover time and costs. O.R.-R. and A.R. are coinventors on patent applications filed at the Broad Institute of MIT and Harvard related to single-cell genomics. Since 3 May 2021, D.P. is an employee of Genentech with equity in Roche. The other authors declare no competing interests.

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Fujita, M., Gao, Z., Zeng, L. et al. Cell subtype-specific effects of genetic variation in the Alzheimer’s disease brain. Nat Genet 56, 605–614 (2024). https://doi.org/10.1038/s41588-024-01685-y

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