TY - JOUR
T1 - Transcriptional landscape of human microglia implicates age, sex, and APOE-related immunometabolic pathway perturbations
AU - Patel, Tulsi
AU - Carnwath, Troy P.
AU - Wang, Xue
AU - Allen, Mariet
AU - Lincoln, Sarah J.
AU - Lewis-Tuffin, Laura J
AU - Quicksall, Zachary S.
AU - Lin, Shu
AU - Tutor-New, Frederick Q.
AU - Ho, Charlotte C.G.
AU - Min, Yuhao
AU - Malphrus, Kimberly G.
AU - Nguyen, Thuy T.
AU - Martin, Elizabeth
AU - Garcia, Cesar A.
AU - Alkharboosh, Rawan M.
AU - Grewal, Sanjeet
AU - Chaichana, Kaisorn
AU - Wharen, Jr, Robert E
AU - Guerrero-Cazares, Hugo
AU - Quinones-Hinojosa, Alfredo
AU - Ertekin-Taner, Nilüfer
N1 - Funding Information:
This study was supported by NIH funding U01 AG046193, RF1 AG051504, and R01 AG051504 to NET.
Funding Information:
The authors thank the patients and their families for their participation, without whom these studies would not have been possible. We thank our colleagues in the neurosurgery team Christopher Louie, Karim ReFaey, and Ivan Segura Duran. We thank our colleagues at the Mayo Clinic Genome Analysis Core (GAC) for their collaboration, particular gratitude to Bruce Eckloff and Julie Lau. We also acknowledge the AMP‐AD RNAseq reprocessing team, in particular Dr. Kirsten Dang, Dr. Thanneer Perumal and Dr. Ben Logsdon at Sage Bionetworks. This study is a cross‐consortia project using RNAseq data generated through grants U01AG046152, U01AG046170, and U01AG046139. The results published here are in whole or in part based on data obtained from the AD Knowledge Portal ( https://adknowledgeportal.synapse.org/ ). Study data were provided by the following sources: The Mayo Clinic Alzheimer’s Disease Genetic Studies, led by Dr. Nilüfer Ertekin‐Taner and Dr. Steven G. Younkin, Mayo Clinic, Jacksonville, FL using samples from the Mayo Clinic Study of Aging, the Mayo Clinic Alzheimer’s Disease Research Center, and the Mayo Clinic Brain Bank. Data collection was supported through funding by NIA grants P50 AG016574, R01 AG032990, U01 AG046139, R01 AG018023, U01 AG006576, U01 AG006786, R01 AG025711, R01 AG017216, R01 AG003949, NINDS grant R01 NS080820, CurePSP Foundation, and support from Mayo Foundation. Study data includes samples collected through the Sun Health Research Institute Brain and Body Donation Program of Sun City, Arizona. The Brain and Body Donation Program is supported by the National Institute of Neurological Disorders and Stroke (U24 NS072026 National Brain and Tissue Resource for Parkinson’s Disease and Related Disorders), the National Institute on Aging (P30 AG19610 Arizona Alzheimer’s Disease Core Center), the Arizona Department of Health Services (contract 211002, Arizona Alzheimer’s Research Center), the Arizona Biomedical Research Commission (contracts 4001, 0011, 05‐901, and 1001 to the Arizona Parkinson's Disease Consortium) and the Michael J. Fox Foundation for Parkinson’s Research. : The results published here are in whole or in part based on data obtained from the AD Knowledge Portal ( https://adknowledgeportal.synapse.org ). Study data were provided by the Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago. Data collection was supported through funding by NIA grants P30AG10161 (ROS), R01AG15819 (ROSMAP; genomics and RNAseq), R01AG17917 (MAP), R01AG30146, R01AG36042 (5hC methylation, ATACseq), RC2AG036547 (H3K9Ac), R01AG36836 (RNAseq), R01AG48015 (monocyte RNAseq) RF1AG57473 (single nucleus RNAseq), U01AG32984 (genomic and whole exome sequencing), U01AG46152 (ROSMAP AMP‐AD, targeted proteomics), U01AG46161(TMT proteomics), U01AG61356 (whole genome sequencing, targeted proteomics, ROSMAP AMP‐AD), the Illinois Department of Public Health (ROSMAP), and the Translational Genomics Research Institute (genomic). Additional phenotypic data can be requested at www.radc.rush.edu . The results published here are in whole or in part based on data obtained from the AD Knowledge Portal ( https://adknowledgeportal.synapse.org/ ). These data were generated from postmortem brain tissue collected through the Mount Sinai VA Medical Center Brain Bank and were provided by Dr. Eric Schadt from Mount Sinai School of Medicine. AMP‐AD RNASeq datasets: For the Mayo RNAseq study: For the ROSMAP study For the MSBB study:
Publisher Copyright:
© 2022 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.
PY - 2022
Y1 - 2022
N2 - Microglia have fundamental roles in health and disease; however, effects of age, sex, and genetic factors on human microglia have not been fully explored. We applied bulk and single-cell approaches to comprehensively characterize human microglia transcriptomes and their associations with age, sex, and APOE. We identified a novel microglial signature, characterized its expression in bulk tissue and single-cell microglia transcriptomes. We discovered microglial co-expression network modules associated with age, sex, and APOE-ε4 that are enriched for lipid and carbohydrate metabolism genes. Integrated analyses of modules with single-cell transcriptomes revealed significant overlap between age-associated module genes and both pro-inflammatory and disease-associated microglial clusters. These modules and clusters harbor known neurodegenerative disease genes including APOE, PLCG2, and BIN1. Meta-analyses with published bulk and single-cell microglial datasets further supported our findings. Thus, these data represent a well-characterized human microglial transcriptome resource and highlight age, sex, and APOE-related microglial immunometabolism perturbations with potential relevance in neurodegeneration.
AB - Microglia have fundamental roles in health and disease; however, effects of age, sex, and genetic factors on human microglia have not been fully explored. We applied bulk and single-cell approaches to comprehensively characterize human microglia transcriptomes and their associations with age, sex, and APOE. We identified a novel microglial signature, characterized its expression in bulk tissue and single-cell microglia transcriptomes. We discovered microglial co-expression network modules associated with age, sex, and APOE-ε4 that are enriched for lipid and carbohydrate metabolism genes. Integrated analyses of modules with single-cell transcriptomes revealed significant overlap between age-associated module genes and both pro-inflammatory and disease-associated microglial clusters. These modules and clusters harbor known neurodegenerative disease genes including APOE, PLCG2, and BIN1. Meta-analyses with published bulk and single-cell microglial datasets further supported our findings. Thus, these data represent a well-characterized human microglial transcriptome resource and highlight age, sex, and APOE-related microglial immunometabolism perturbations with potential relevance in neurodegeneration.
KW - APOE
KW - lipid metabolism
KW - microglia
KW - neurodegeneration
KW - single cell
KW - transcriptomics
UR - http://www.scopus.com/inward/record.url?scp=85127537913&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85127537913&partnerID=8YFLogxK
U2 - 10.1111/acel.13606
DO - 10.1111/acel.13606
M3 - Article
AN - SCOPUS:85127537913
JO - Aging Cell
JF - Aging Cell
SN - 1474-9718
ER -