Nat Genet. 2022 Jan;54(1):4-17. doi: 10.1038/s41588-021-00976-y. Epub 2022 Jan 06.

Genetic analysis of the human microglial transcriptome across brain regions, aging and disease pathologies.

Nature genetics

Katia de Paiva Lopes, Gijsje J L Snijders, Jack Humphrey, Amanda Allan, Marjolein A M Sneeboer, Elisa Navarro, Brian M Schilder, Ricardo A Vialle, Madison Parks, Roy Missall, Welmoed van Zuiden, Frederieke A J Gigase, Raphael Kübler, Amber Berdenis van Berlekom, Emily M Hicks, Chotima Bӧttcher, Josef Priller, René S Kahn, Lot D de Witte, Towfique Raj

PMID: 34992268 DOI: 10.1038/s41588-021-00976-y

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 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.

© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.

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Publication Types

• Journal Article

Grant support

• U01-AG068880/U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)
• R01 AG054005/AG/NIA NIH HHS/United States
• R56 AG055824/AG/NIA NIH HHS/United States
• RF1-AG065926/U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)
• R01-AG054005/U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)
• R21 AG063130/AG/NIA NIH HHS/United States
• R01 NS116006/NS/NINDS NIH HHS/United States
• U01 AG068880/AG/NIA NIH HHS/United States
• RF1 AG065926/AG/NIA NIH HHS/United States
• R56-AG055824/U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)
• R21-AG063130/U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)