A map of transcriptional heterogeneity and regulatory variation in human microglia
A map of transcriptional heterogeneity and regulatory variation in human microglia
Abstract Microglia, the tissue resident macrophages of the CNS, are implicated in a broad range of neurological pathologies, from acute brain injury to dementia. Here, we profiled gene expression variation in primary human microglia isolated from 141 patients undergoing neurosurgery. Using single cell and bulk RNA sequencing, we defined distinct cellular populations of acutely in vivo-activated microglia, and characterised a dramatic switch in microglial population composition in patients suffering from acute brain injury. We mapped expression quantitative trait loci (eQTLs) in human microglia and show that many disease-associated eQTLs in microglia replicate well in a human induced pluripotent stem cell (hIPSC) derived macrophage model system. Using ATAC-seq from 95 individuals in this hIPSC model we fine-map candidate causal variants at risk loci for Alzheimer’s disease, the most prevalent neurodegenerative condition in acute brain injury patients. Our study provides the first population-scale transcriptional map of a critically important cell for neurodegenerative disorders.
Knights Andrew、Santarius Thomas、Kumasaka Natsuhiko、Mannion Richard、Watts Colin、Soranzo Nicole、Stevens Beth、Hutchinson Peter J、Gaffney Daniel J、Timofeev Ivan、Hammond Timothy R.、Schwartzentruber Jeremy、Liu Jimmy、Murphy Natalia、McMurran Christopher E、Bulstrode Harry、Correia Jason、Budohoski Karol P、Kundu Kousik、Panousis Nikolaos、Trivedi Rikin、Fernandes Helen、Joannides Alexis、Young Adam MH、Garnett Matthew R、Guilfoyle Mathew R、Calvert Fiona、Kirollos Ramez、Morris Robert、Jalloh Ibrahim、Holland Katherine、Franklin Robin JM、Mair Richard、Segel Michael、Price Stephen J、Kirkpatrick Peter J
Wellcome Sanger Institute, Wellcome Genome Campus, HinxtonDivision of Neurosurgery, Department of Clinical Neurosciences, Cambridge University HospitalsWellcome Sanger Institute, Wellcome Genome Campus, HinxtonDivision of Neurosurgery, Department of Clinical Neurosciences, Cambridge University HospitalsDivision of Neurosurgery, Department of Clinical Neurosciences, Cambridge University Hospitals||Institute of Cancer and Genomic Sciences, College of Medical and Dental SciencesWellcome Sanger Institute, Wellcome Genome Campus, HinxtonFM Kirby Neurobiology Center, Boston Children?ˉs Hospital, Harvard University||Howard Hughes Medical Institute, Broad Institute of Harvard and MITDivision of Neurosurgery, Department of Clinical Neurosciences, Cambridge University HospitalsWellcome Sanger Institute, Wellcome Genome Campus, HinxtonDivision of Neurosurgery, Department of Clinical Neurosciences, Cambridge University HospitalsFM Kirby Neurobiology Center, Boston Children?ˉs Hospital, Harvard University||Howard Hughes Medical Institute, Broad Institute of Harvard and MITEMBL-EBI, Wellcome Genome CampusBiogenWellcome Trust MRC Stem Cell Institute, University of CambridgeWellcome Trust MRC Stem Cell Institute, University of CambridgeDivision of Neurosurgery, Department of Clinical Neurosciences, Cambridge University HospitalsDivision of Neurosurgery, Department of Clinical Neurosciences, Cambridge University HospitalsDivision of Neurosurgery, Department of Clinical Neurosciences, Cambridge University HospitalsWellcome Sanger Institute, Wellcome Genome Campus, HinxtonWellcome Sanger Institute, Wellcome Genome Campus, HinxtonDivision of Neurosurgery, Department of Clinical Neurosciences, Cambridge University HospitalsDivision of Neurosurgery, Department of Clinical Neurosciences, Cambridge University HospitalsDivision of Neurosurgery, Department of Clinical Neurosciences, Cambridge University HospitalsWellcome Trust MRC Stem Cell Institute, University of Cambridge||Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton||Division of Neurosurgery, Department of Clinical Neurosciences, Cambridge University HospitalsDivision of Neurosurgery, Department of Clinical Neurosciences, Cambridge University HospitalsDivision of Neurosurgery, Department of Clinical Neurosciences, Cambridge University HospitalsWellcome Sanger Institute, Wellcome Genome Campus, HinxtonDivision of Neurosurgery, Department of Clinical Neurosciences, Cambridge University HospitalsDivision of Neurosurgery, Department of Clinical Neurosciences, Cambridge University HospitalsDivision of Neurosurgery, Department of Clinical Neurosciences, Cambridge University HospitalsDivision of Neurosurgery, Department of Clinical Neurosciences, Cambridge University HospitalsWellcome Trust MRC Stem Cell Institute, University of CambridgeDivision of Neurosurgery, Department of Clinical Neurosciences, Cambridge University HospitalsWellcome Trust MRC Stem Cell Institute, University of CambridgeDivision of Neurosurgery, Department of Clinical Neurosciences, Cambridge University HospitalsDivision of Neurosurgery, Department of Clinical Neurosciences, Cambridge University Hospitals
神经病学、精神病学基础医学生物科学研究方法、生物科学研究技术
Knights Andrew,Santarius Thomas,Kumasaka Natsuhiko,Mannion Richard,Watts Colin,Soranzo Nicole,Stevens Beth,Hutchinson Peter J,Gaffney Daniel J,Timofeev Ivan,Hammond Timothy R.,Schwartzentruber Jeremy,Liu Jimmy,Murphy Natalia,McMurran Christopher E,Bulstrode Harry,Correia Jason,Budohoski Karol P,Kundu Kousik,Panousis Nikolaos,Trivedi Rikin,Fernandes Helen,Joannides Alexis,Young Adam MH,Garnett Matthew R,Guilfoyle Mathew R,Calvert Fiona,Kirollos Ramez,Morris Robert,Jalloh Ibrahim,Holland Katherine,Franklin Robin JM,Mair Richard,Segel Michael,Price Stephen J,Kirkpatrick Peter J.A map of transcriptional heterogeneity and regulatory variation in human microglia[EB/OL].(2025-03-28)[2025-04-24].https://www.biorxiv.org/content/10.1101/2019.12.20.874099.点此复制
评论