Genetic analysis of the human microglial transcriptome across brain regions, aging and disease pathologies
Lopes, Katia de Paiva; Snijders, Gijsje J L; Humphrey, Jack; Allan, Amanda; Sneeboer, Marjolein A M; Navarro, Elisa; Schilder, Brian M; Vialle, Ricardo A; Parks, Madison; Missall, Roy; van Zuiden, Welmoed; Gigase, Frederieke A J; Kübler, Raphael; van Berlekom, Amber Berdenis; Hicks, Emily M; Bӧttcher, Chotima; Priller, Josef; Kahn, René S; de Witte, Lot D; Raj, Towfique
(2022) Nature Genetics, volume 54, issue 1, pp. 4 - 17
(Article)
Abstract
Microglia have emerged as important players in brain aging and pathology. To understand how genetic risk for neurological and psychiatric disorders is related to microglial function, large transcriptome studies are essential. Here we describe the transcriptome analysis of 255 primary human microglial samples isolated at autopsy from multiple brain regions
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of 100 individuals. We performed systematic analyses to investigate various aspects of microglial heterogeneities, including brain region and aging. We mapped expression and splicing quantitative trait loci and showed that many neurological disease susceptibility loci are mediated through gene expression or splicing in microglia. Fine-mapping of these loci nominated candidate causal variants that are within microglia-specific enhancers, finding associations with microglial expression of USP6NL for Alzheimer's disease and P2RY12 for Parkinson's disease. We have built the most comprehensive catalog to date of genetic effects on the microglial transcriptome and propose candidate functional variants in neurological and psychiatric disorders.
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Keywords: Genetics, Journal Article
ISSN: 1061-4036
Publisher: Nature Publishing Group
Note: Funding Information: We thank members of the Raj and de Witte labs for their feedback on the manuscript. We thank the teams of the NBB and Mount Sinai Neuropathology Brain Bank and Research CoRE for their services. We thank the study participants for their generous gifts of brain donation. Microglia were isolated through the efforts of a large team and we thank M. Litjens, R. D. van Dijk, A. Fernández-Andreu, P. R. Ormel, H. C. van Mierlo, Y. He, S. Gumbs, M. E van Strien, S. Burm, V. Donega and E. M. Hol for all their contributions to this effort. We thank M. Chao for his assistance with genotyping quality control. This work was supported in part through the computational and data resources and staff expertise provided by Scientific Computing at the Icahn School of Medicine at Mount Sinai. The research reported in this paper was supported by the Office of Research Infrastructure of the National Institutes of Health (NIH) under award no. S10OD026880. T.R. is supported by grants from the NIH (nos. NIA R21-AG063130, NIA R01-AG054005, NIA U01-AG068880, NIA RF1-AG065926, NIA R56-AG055824 and NINDS R01-NS116006). G.S. was supported through ZonMw and the foundation ‘De Drie Lichten’ in the Netherlands. E.N. was supported by a Ramon Areces fellowship. The funders had no role in study design, data collection and analysis, decision to publish or manuscript preparation. Publisher Copyright: © 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.
(Peer reviewed)