Functional characterization of Alzheimer's disease genetic variants in microglia

Xiaoyu Yang; Jia Wen; Han Yang; Ian R Jones; Xiaodong Zhu; Weifang Liu; Bingkun Li; Claire D Clelland; Wenjie Luo; Man Ying Wong; Xingjie Ren; Xiekui Cui; Michael Song; Hongjiang Liu; Cady Chen; Nicolas Eng; Mirunalini Ravichandran; Yang Sun; David Lee; Eric Van Buren; Min-Zhi Jiang; Candace S Y Chan; Chun Jimmie Ye; Rushika M Perera; Li Gan; Yun Li; Yin Shen

doi:10.1038/s41588-023-01506-8

Functional characterization of Alzheimer's disease genetic variants in microglia

Nat Genet. 2023 Oct;55(10):1735-1744. doi: 10.1038/s41588-023-01506-8. Epub 2023 Sep 21.

Authors

Xiaoyu Yang¹, Jia Wen², Han Yang¹, Ian R Jones^{1

3}, Xiaodong Zhu⁴, Weifang Liu^{2

5}, Bingkun Li¹, Claire D Clelland^{6

7}, Wenjie Luo⁴, Man Ying Wong⁴, Xingjie Ren¹, Xiekui Cui¹, Michael Song^{1

3}, Hongjiang Liu¹, Cady Chen¹, Nicolas Eng¹, Mirunalini Ravichandran⁸, Yang Sun^{1

9}, David Lee^{1

9}, Eric Van Buren¹⁰, Min-Zhi Jiang², Candace S Y Chan¹¹, Chun Jimmie Ye^{1

9

12

13

14

15

16}, Rushika M Perera^{8

17

18}, Li Gan⁴, Yun Li^{19

20

21}, Yin Shen^{22

23

24}

Affiliations

¹ Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA.
² Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
³ Pharmaceutical Sciences and Pharmacogenomics Graduate Program, University of California, San Francisco, San Francisco, CA, USA.
⁴ Helen and Robert Appel Alzheimer's Disease Research Institute, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York City, NY, USA.
⁵ Department of Biostatistics, University of North Carolina, Chapel Hill, NC, USA.
⁶ Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
⁷ Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA.
⁸ Department of Anatomy, University of California, San Francisco, San Francisco, CA, USA.
⁹ Division of Rheumatology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
¹⁰ Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
¹¹ Tetrad Graduate Program, University of California, San Francisco, San Francisco, CA, USA.
¹² Rosalind Russell/Ephraim P. Engleman Rheumatology Research Center, University of California, San Francisco, San Francisco, CA, USA.
¹³ Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA.
¹⁴ Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA.
¹⁵ Chan Zuckerberg Biohub, San Francisco, CA, USA.
¹⁶ Bakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA, USA.
¹⁷ Department of Pathology, University of California, San Francisco, San Francisco, CA, USA.
¹⁸ Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
¹⁹ Department of Genetics, University of North Carolina, Chapel Hill, NC, USA. yun_li@med.unc.edu.
²⁰ Department of Biostatistics, University of North Carolina, Chapel Hill, NC, USA. yun_li@med.unc.edu.
²¹ Department of Computer Science, University of North Carolina, Chapel Hill, NC, USA. yun_li@med.unc.edu.
²² Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA. yin.shen@ucsf.edu.
²³ Department of Neurology, University of California, San Francisco, San Francisco, CA, USA. yin.shen@ucsf.edu.
²⁴ Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA. yin.shen@ucsf.edu.

Abstract

Candidate cis-regulatory elements (cCREs) in microglia demonstrate the most substantial enrichment for Alzheimer's disease (AD) heritability compared to other brain cell types. However, whether and how these genome-wide association studies (GWAS) variants contribute to AD remain elusive. Here we prioritize 308 previously unreported AD risk variants at 181 cCREs by integrating genetic information with microglia-specific 3D epigenome annotation. We further establish the link between functional variants and target genes by single-cell CRISPRi screening in microglia. In addition, we show that AD variants exhibit allelic imbalance on target gene expression. In particular, rs7922621 is the effective variant in controlling TSPAN14 expression among other nominated variants in the same cCRE and exerts multiple physiological effects including reduced cell surface ADAM10 and altered soluble TREM2 (sTREM2) shedding. Our work represents a systematic approach to prioritize and characterize AD-associated variants and provides a roadmap for advancing genetic association to experimentally validated cell-type-specific phenotypes and mechanisms.

MeSH terms

Alzheimer Disease* / genetics
Alzheimer Disease* / metabolism
Cell Membrane / metabolism
Genome-Wide Association Study
Humans
Microglia / metabolism
Phenotype

Abstract

MeSH terms

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