Functional characterization of Alzheimer’s disease genetic variants in microglia

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 pr...

Full description

Saved in:

Bibliographic Details
Published in:	Nature genetics Vol. 55; no. 10; pp. 1735 - 1744
Main Authors:	Yang, Xiaoyu, Wen, Jia, Yang, Han, Jones, Ian R., Zhu, Xiaodong, Liu, Weifang, Li, Bingkun, Clelland, Claire D., Luo, Wenjie, Wong, Man Ying, Ren, Xingjie, Cui, Xiekui, Song, Michael, Liu, Hongjiang, Chen, Cady, Eng, Nicolas, Ravichandran, Mirunalini, Sun, Yang, Lee, David, Van Buren, Eric, Jiang, Min-Zhi, Chan, Candace S. Y., Ye, Chun Jimmie, Perera, Rushika M., Gan, Li, Li, Yun, Shen, Yin
Format:	Journal Article
Language:	English
Published:	New York Nature Publishing Group US 01-10-2023 Nature Publishing Group
Subjects:	13/100 38/43 45/47 631/208/177 631/208/191 Agriculture Alzheimer Disease - genetics Alzheimer Disease - metabolism Alzheimer's disease Animal Genetics and Genomics Annotations Biomedical and Life Sciences Biomedicine Brain Cancer Research Cell Membrane - metabolism Cell surface Gene expression Gene Function Gene loci Genetic diversity Genetic variance Genome-wide association studies Genome-Wide Association Study Genomes Heritability Human Genetics Humans Interferon Microglia Microglia - metabolism Neurodegenerative diseases Pathogenesis Phenotype Phenotypes Physiological effects Regulatory sequences Signal transduction Stem cells
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	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. Genetic fine-mapping and CRISPRi screens identify functional variants and their target genes associated with Alzheimer’s disease in microglia. The variant rs7922621 modulates AD risk through control of TSPAN14 expression in this cell type.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Y.S. L.G. and Y.L. conceived the study. Y.S., L.G., and Y.L. supervised the study. X.Y., H.Y., I.R.J., X.Z., C.C., W.L., M.Y.W., X.R., X.C., M.S., M.R., and C.S.Y.C. performed experiments under the supervision of Y.S., L.G., and R.P. X.Y., J.W., W. L. B.L., H.L, C.C. N.E., E.V.B., I.R.J., and M.J. performed computational analysis under the supervision of Y.S. and Y.L. Y.S., and D.L. performed scRNA-seq with the supervision of C.J.Y. X.Y., Y.L., and Y.S. analyzed and interpreted the data. Y.S., Y.L., and X.Y. prepared the manuscript with input from all other authors. Author contributions
ISSN:	1061-4036 1546-1718
DOI:	10.1038/s41588-023-01506-8