A map of transcriptional heterogeneity and regulatory variation in human microglia

• Published in: Nature genetics Vol. 53; no. 6; pp. 861 - 868
• Main Authors: Young, Adam M. H., Kumasaka, Natsuhiko, Calvert, Fiona, Hammond, Timothy R., Knights, Andrew, Panousis, Nikolaos, Park, Jun Sung, Schwartzentruber, Jeremy, Liu, Jimmy, Kundu, Kousik, Segel, Michael, Murphy, Natalia A., McMurran, Christopher E., Bulstrode, Harry, Correia, Jason, Budohoski, Karol P., Joannides, Alexis, Guilfoyle, Mathew R., Trivedi, Rikin, Kirollos, Ramez, Morris, Robert, Garnett, Matthew R., Timofeev, Ivan, Jalloh, Ibrahim, Holland, Katherine, Mannion, Richard, Mair, Richard, Watts, Colin, Price, Stephen J., Kirkpatrick, Peter J., Santarius, Thomas, Mountjoy, Edward, Ghoussaini, Maya, Soranzo, Nicole, Bayraktar, Omer A., Stevens, Beth, Hutchinson, Peter J., Franklin, Robin J. M., Gaffney, Daniel J.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.06.2021; Nature Publishing Group
• Subjects: 631/208/200; 631/208/205; 692/699/375/365; Age; Agriculture; Alzheimer Disease - genetics; Alzheimer's disease; Analysis; Animal Genetics and Genomics; Biomedical and Life Sciences; Biomedicine; Blood; Blood-brain barrier; Brain cancer; Cancer Research; Central nervous system; Gene expression; Gene Expression Regulation; Gene Function; Gene mapping; Gene sequencing; Genetic diversity; Genetic regulation; Genetic transcription; Genetic variance; Hemorrhage; Heterogeneity; Homeostasis; Human Genetics; Humans; Hydrocephalus; Immune system; Macrophages; Microglia; Microglia - metabolism; Models, Genetic; Neurodegenerative diseases; Neurosurgery; Pathology; Patients; Pluripotency; Population; Population studies; Quantitative trait loci; Quantitative Trait Loci - genetics; Sequence Analysis, RNA; Single-Cell Analysis; Stem cells; Transcription; Transcription, Genetic; Trauma; Traumatic brain injury; United Kingdom
• ISSN: 1061-4036; 1546-1718; 1546-1718
• DOI: 10.1038/s41588-021-00875-2

Microglia, the tissue-resident macrophages of the central nervous system (CNS), play critical roles in immune defense, development and homeostasis. However, isolating microglia from humans in large numbers is challenging. Here, we profiled gene expression variation in primary human microglia isolated from 141 patients undergoing neurosurgery. Using single-cell and bulk RNA sequencing, we identify how age, sex and clinical pathology influence microglia gene expression and which genetic variants have microglia-specific functions using expression quantitative trait loci (eQTL) mapping. We follow up one of our findings using a human induced pluripotent stem cell-based macrophage model to fine-map a candidate causal variant for Alzheimer’s disease at the BIN1 locus. Our study provides a population-scale transcriptional map of a critically important cell for human CNS development and disease. A population-scale map of gene expression in primary human microglia provides a systematic exploration of microglia diversity and how age, sex, pathology, cortical anatomy and common germline genetic variation influence the microglia transcriptome.