TY - JOUR
T1 - Genetics of the human microglia regulome refines Alzheimer’s disease risk loci
AU - Kosoy, Roman
AU - Fullard, John F.
AU - Zeng, Biao
AU - Bendl, Jaroslav
AU - Dong, Pengfei
AU - Rahman, Samir
AU - Kleopoulos, Steven P.
AU - Shao, Zhiping
AU - Girdhar, Kiran
AU - Humphrey, Jack
AU - de Paiva Lopes, Katia
AU - Charney, Alexander W.
AU - Kopell, Brian H.
AU - Raj, Towfique
AU - Bennett, David
AU - Kellner, Christopher P.
AU - Haroutunian, Vahram
AU - Hoffman, Gabriel E.
AU - Roussos, Panos
N1 - Publisher Copyright:
© 2022, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.
PY - 2022/8
Y1 - 2022/8
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85135447024&partnerID=8YFLogxK
U2 - 10.1038/s41588-022-01149-1
DO - 10.1038/s41588-022-01149-1
M3 - Article
C2 - 35931864
AN - SCOPUS:85135447024
SN - 1061-4036
VL - 54
SP - 1145
EP - 1154
JO - Nature Genetics
JF - Nature Genetics
IS - 8
ER -