Genetics of the human microglia regulome refines Alzheimer’s disease risk loci

Microglia are brain myeloid cells that play a critical role in neuroimmunity and the etiology of Alzheimer’s disease (AD), yet our understanding of how the genetic regulatory landscape controls microglial function and contributes to AD is limited. Here, we performed transcriptome and chromatin acces...

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Veröffentlicht in:Nature genetics 2022-08, Vol.54 (8), p.1145-1154
Hauptverfasser: Kosoy, Roman, Fullard, John F., Zeng, Biao, Bendl, Jaroslav, Dong, Pengfei, Rahman, Samir, Kleopoulos, Steven P., Shao, Zhiping, Girdhar, Kiran, Humphrey, Jack, de Paiva Lopes, Katia, Charney, Alexander W., Kopell, Brian H., Raj, Towfique, Bennett, David, Kellner, Christopher P., Haroutunian, Vahram, Hoffman, Gabriel E., Roussos, Panos
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Sprache:eng
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Zusammenfassung:Microglia are brain myeloid cells that play a critical role in neuroimmunity and the etiology of Alzheimer’s disease (AD), yet our understanding of how the genetic regulatory landscape controls microglial function and contributes to AD is limited. Here, we performed transcriptome and chromatin accessibility profiling in primary human microglia from 150 donors to identify genetically driven variation and cell-specific enhancer–promoter (E-P) interactions. Integrative fine-mapping analysis identified putative regulatory mechanisms for 21 AD risk loci, of which 18 were refined to a single gene, including 3 new candidate risk genes ( KCNN4 , FIBP and LRRC25 ). Transcription factor regulatory networks captured AD risk variation and identified SPI1 as a key putative regulator of microglia expression and AD risk. This comprehensive resource capturing variation in the human microglia regulome provides insights into the etiology of neurodegenerative disease. Transcriptomic and epigenomic profiling of human microglia identifies putative gene regulatory mechanisms for 21 Alzheimer’s disease (AD) risk loci. SPI1 /PU.1 is nominated as a key regulator of microglia gene expression and AD risk.
ISSN:1061-4036
1546-1718
1546-1718
DOI:10.1038/s41588-022-01149-1