Functional Characterization of Alzheimer's Disease Genetic Variants in Microglia

Overview

Journal Nat Genet

Specialty Genetics

Date 2023 Sep 21

PMID 37735198

Authors

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

Affiliations

Soon will be listed here.

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.

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References

Nott A, Holtman I, Coufal N, Schlachetzki J, Yu M, Hu R . Brain cell type-specific enhancer-promoter interactome maps and diseaserisk association. Science. 2019; 366(6469):1134-1139. PMC: 7028213. DOI: 10.1126/science.aay0793. View

Neuner S, Tcw J, Goate A . Genetic architecture of Alzheimer's disease. Neurobiol Dis. 2020; 143:104976. PMC: 7409822. DOI: 10.1016/j.nbd.2020.104976. View

Song M, Yang X, Ren X, Maliskova L, Li B, Jones I . Mapping cis-regulatory chromatin contacts in neural cells links neuropsychiatric disorder risk variants to target genes. Nat Genet. 2019; 51(8):1252-1262. PMC: 6677164. DOI: 10.1038/s41588-019-0472-1. View

Song M, Pebworth M, Yang X, Abnousi A, Fan C, Wen J . Cell-type-specific 3D epigenomes in the developing human cortex. Nature. 2020; 587(7835):644-649. PMC: 7704572. DOI: 10.1038/s41586-020-2825-4. View

Martin P, McGovern A, Orozco G, Duffus K, Yarwood A, Schoenfelder S . Capture Hi-C reveals novel candidate genes and complex long-range interactions with related autoimmune risk loci. Nat Commun. 2015; 6:10069. PMC: 4674669. DOI: 10.1038/ncomms10069. View

Martin J, Xu Z, Reiner A, Mohlke K, Sullivan P, Ren B . HUGIn: Hi-C Unifying Genomic Interrogator. Bioinformatics. 2017; 33(23):3793-3795. PMC: 5860315. DOI: 10.1093/bioinformatics/btx359. View

Ousman S, Kubes P . Immune surveillance in the central nervous system. Nat Neurosci. 2012; 15(8):1096-101. PMC: 7097282. DOI: 10.1038/nn.3161. View

Gjoneska E, Pfenning A, Mathys H, Quon G, Kundaje A, Tsai L . Conserved epigenomic signals in mice and humans reveal immune basis of Alzheimer's disease. Nature. 2015; 518(7539):365-9. PMC: 4530583. DOI: 10.1038/nature14252. View

Schwartzentruber J, Cooper S, Liu J, Barrio-Hernandez I, Bello E, Kumasaka N . Genome-wide meta-analysis, fine-mapping and integrative prioritization implicate new Alzheimer's disease risk genes. Nat Genet. 2021; 53(3):392-402. PMC: 7610386. DOI: 10.1038/s41588-020-00776-w. View

10.

Bellenguez C, Kucukali F, Jansen I, Kleineidam L, Moreno-Grau S, Amin N . New insights into the genetic etiology of Alzheimer's disease and related dementias. Nat Genet. 2022; 54(4):412-436. PMC: 9005347. DOI: 10.1038/s41588-022-01024-z. View

11.

Gosselin D, Skola D, Coufal N, Holtman I, Schlachetzki J, Sajti E . An environment-dependent transcriptional network specifies human microglia identity. Science. 2017; 356(6344). PMC: 5858585. DOI: 10.1126/science.aal3222. View

12.

Abud E, Ramirez R, Martinez E, Healy L, Nguyen C, Newman S . iPSC-Derived Human Microglia-like Cells to Study Neurological Diseases. Neuron. 2017; 94(2):278-293.e9. PMC: 5482419. DOI: 10.1016/j.neuron.2017.03.042. View

13.

Heinz S, Texari L, Hayes M, Urbanowski M, Chang M, Givarkes N . Transcription Elongation Can Affect Genome 3D Structure. Cell. 2018; 174(6):1522-1536.e22. PMC: 6130916. DOI: 10.1016/j.cell.2018.07.047. View

14.

Carlin A, Vizcarra E, Branche E, Viramontes K, Suarez-Amaran L, Ley K . Deconvolution of pro- and antiviral genomic responses in Zika virus-infected and bystander macrophages. Proc Natl Acad Sci U S A. 2018; 115(39):E9172-E9181. PMC: 6166801. DOI: 10.1073/pnas.1807690115. View

15.

Levine K, Leonard H, Blauwendraat C, Iwaki H, Johnson N, Bandres-Ciga S . Virus exposure and neurodegenerative disease risk across national biobanks. Neuron. 2023; 111(7):1086-1093.e2. PMC: 10079561. DOI: 10.1016/j.neuron.2022.12.029. View

16.

Sayed F, Kodama L, Fan L, Carling G, Udeochu J, Le D . AD-linked R47H- mutation induces disease-enhancing microglial states via AKT hyperactivation. Sci Transl Med. 2021; 13(622):eabe3947. PMC: 9345574. DOI: 10.1126/scitranslmed.abe3947. View

17.

Olah M, Menon V, Habib N, Taga M, Ma Y, Yung C . Single cell RNA sequencing of human microglia uncovers a subset associated with Alzheimer's disease. Nat Commun. 2020; 11(1):6129. PMC: 7704703. DOI: 10.1038/s41467-020-19737-2. View

18.

Mathys H, Adaikkan C, Gao F, Young J, Manet E, Hemberg M . Temporal Tracking of Microglia Activation in Neurodegeneration at Single-Cell Resolution. Cell Rep. 2017; 21(2):366-380. PMC: 5642107. DOI: 10.1016/j.celrep.2017.09.039. View

19.

Dolan M, Therrien M, Jereb S, Kamath T, Gazestani V, Atkeson T . Exposure of iPSC-derived human microglia to brain substrates enables the generation and manipulation of diverse transcriptional states in vitro. Nat Immunol. 2023; 24(8):1382-1390. PMC: 10382323. DOI: 10.1038/s41590-023-01558-2. View

20.

Bottcher C, Schlickeiser S, Sneeboer M, Kunkel D, Knop A, Paza E . Human microglia regional heterogeneity and phenotypes determined by multiplexed single-cell mass cytometry. Nat Neurosci. 2018; 22(1):78-90. DOI: 10.1038/s41593-018-0290-2. View