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

Katia de Paiva Lopes; Gijsje J L Snijders; Jack Humphrey; Amanda Allan; Marjolein A M Sneeboer; Elisa Navarro; Brian M Schilder; Ricardo A Vialle; Madison Parks; Roy Missall; Welmoed van Zuiden; Frederieke A J Gigase; Raphael Kübler; Amber Berdenis van Berlekom; Emily M Hicks; Chotima Bӧttcher; Josef Priller; René S Kahn; Lot D de Witte; Towfique Raj

doi:10.1038/s41588-021-00976-y

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

Nat Genet. 2022 Jan;54(1):4-17. doi: 10.1038/s41588-021-00976-y. Epub 2022 Jan 6.

Authors

Katia de Paiva Lopes^#^{1

2

3

4}, Gijsje J L Snijders^#^{5

6}, Jack Humphrey^#^{1

2

3

4}, Amanda Allan^{1

2

3

4}, Marjolein A M Sneeboer⁷, Elisa Navarro^{1

2

3

4}, Brian M Schilder^{1

2

3

4}, Ricardo A Vialle^{1

2

3

4}, Madison Parks^{1

2

3

4}, Roy Missall⁵, Welmoed van Zuiden⁵, Frederieke A J Gigase^{5

6}, Raphael Kübler⁵, Amber Berdenis van Berlekom⁷, Emily M Hicks^{1

2

3

4}, Chotima Bӧttcher⁸, Josef Priller⁸, René S Kahn^{5

6}, Lot D de Witte^#^{9

10}, Towfique Raj^#^{11

12

13

14}

Affiliations

¹ Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
² Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
³ 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.
⁴ Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁵ Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁶ Mental Illness Research, Education and Clinical Center, James J Peters VA Medical Center, New York, NY, USA.
⁷ Department of Translational Neuroscience, University Medical Center Utrecht Brain Center, Utrecht University, Utrecht, the Netherlands.
⁸ Department of Neuropsychiatry and Laboratory of Molecular Psychiatry, Charité-Universitätsmedizin Berlin, Berlin, Germany.
⁹ Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA. [email protected].
¹⁰ Mental Illness Research, Education and Clinical Center, James J Peters VA Medical Center, New York, NY, USA. [email protected].
¹¹ Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. [email protected].
¹² Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA. [email protected].
¹³ 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. [email protected].
¹⁴ Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. [email protected].

^# Contributed equally.

Abstract

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.

Publication types

Meta-Analysis
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Aging / genetics
Aging / metabolism*
Alzheimer Disease / metabolism
Atlases as Topic
Brain / metabolism*
Datasets as Topic
Female
Gene Expression Profiling
Genetic Heterogeneity
Genetic Predisposition to Disease
Humans
Male
Microglia / metabolism*
Parkinson Disease / metabolism
Quantitative Trait Loci
RNA Splicing
Transcriptome

Abstract

Publication types

MeSH terms

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