Functional characterization of Alzheimer's disease genetic variants in microglia.

TitleFunctional characterization of Alzheimer's disease genetic variants in microglia.
Publication TypeJournal Article
Year of Publication2023
AuthorsYang X, Wen J, Yang H, Jones IR, Zhu X, Liu W, Li B, Clelland CD, Luo W, Wong MYing, Ren X, Cui X, Song M, Liu H, Chen C, Eng N, Ravichandran M, Sun Y, Lee D, Van Buren E, Jiang M-Z, S Y Chan C, Ye CJimmie, Perera RM, Gan L, Li Y, Shen Y
JournalNat Genet
Volume55
Issue10
Pagination1735-1744
Date Published2023 Oct
ISSN1546-1718
KeywordsAlzheimer Disease, Cell Membrane, Genome-Wide Association Study, Humans, Microglia, Phenotype
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.

DOI10.1038/s41588-023-01506-8
Alternate JournalNat Genet
PubMed ID37735198
PubMed Central ID7028213
Grant ListR01AG057497 / / U.S. Department of Health and Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging /
RF1AG079557 / / U.S. Department of Health and Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging /
R56AG079271 / / U.S. Department of Health and Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging /
R01AG079271 / / U.S. Department of Health and Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging /
R01AG072758 / / U.S. Department of Health and Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging /
R01AG054214 / / U.S. Department of Health and Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging /
R01EY027789 / / U.S. Department of Health and Human Services | NIH | National Eye Institute (NEI) /
UM1HG009402 / / U.S. Department of Health and Human Services | NIH | National Human Genome Research Institute (NHGRI) /
U01HG011720 / / U.S. Department of Health and Human Services | NIH | National Human Genome Research Institute (NHGRI) /
P50HD103573 / / U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI) /
R01MH125236 / / U.S. Department of Health and Human Services | NIH | National Institute of Mental Health (NIMH) /
R01MH123724 / / U.S. Department of Health and Human Services | NIH | National Institute of Mental Health (NIMH) /