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

Autor: Lopes KP; Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Department of Genetics and Genomic Sciences & Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Snijders GJL; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Mental Illness Research, Education and Clinical Center, James J Peters VA Medical Center, New York, NY, USA., Humphrey J; Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Department of Genetics and Genomic Sciences & Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Allan A; Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Department of Genetics and Genomic Sciences & Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Sneeboer MAM; Department of Translational Neuroscience, University Medical Center Utrecht Brain Center, Utrecht University, Utrecht, the Netherlands., Navarro E; Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Department of Genetics and Genomic Sciences & Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Schilder BM; Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Department of Genetics and Genomic Sciences & Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Vialle RA; Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Department of Genetics and Genomic Sciences & Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Parks M; Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Department of Genetics and Genomic Sciences & Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Missall R; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA., van Zuiden W; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Gigase FAJ; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Mental Illness Research, Education and Clinical Center, James J Peters VA Medical Center, New York, NY, USA., Kübler R; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA., van Berlekom AB; Department of Translational Neuroscience, University Medical Center Utrecht Brain Center, Utrecht University, Utrecht, the Netherlands., Hicks EM; Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Department of Genetics and Genomic Sciences & Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Bӧttcher C; Department of Neuropsychiatry and Laboratory of Molecular Psychiatry, Charité-Universitätsmedizin Berlin, Berlin, Germany., Priller J; Department of Neuropsychiatry and Laboratory of Molecular Psychiatry, Charité-Universitätsmedizin Berlin, Berlin, Germany., Kahn RS; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Mental Illness Research, Education and Clinical Center, James J Peters VA Medical Center, New York, NY, USA., de Witte LD; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA. lotje.dewitte@mssm.edu.; Mental Illness Research, Education and Clinical Center, James J Peters VA Medical Center, New York, NY, USA. lotje.dewitte@mssm.edu., Raj T; Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. towfique.raj@mssm.edu.; Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA. towfique.raj@mssm.edu.; Department of Genetics and Genomic Sciences & Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. towfique.raj@mssm.edu.; Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. towfique.raj@mssm.edu.
Jazyk: angličtina
Zdroj: Nature genetics [Nat Genet] 2022 Jan; Vol. 54 (1), pp. 4-17. Date of Electronic Publication: 2022 Jan 06.
DOI: 10.1038/s41588-021-00976-y
Abstrakt: 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.)
Databáze: MEDLINE
Externí odkaz: