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

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 microglia samples isolated at autopsy from multiple brain regions of 100 human subjects. 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 microglia 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 microglia transcriptome and propose candidate functional variants in neurological and psychiatric disorders.

An Alzheimer’s disease pathway uncovered by functional omics: the risk gene CELF1 regulates KLC1 splice variant E expression, which drives Aβ pathology

“…Green: The CELF1 locus was associated with AD in genome-wide association studies (Ref. [3][4][5][6]. Red: Transcriptomic studies using CELF1 knockdown revealed strong regulation of KLC1 by CELF1; cross-linking and immunoprecipitation sequencing identified KLC1 RNA as a binding partner of the CELF1 protein and revealed its binding site.…”

“…As a result, there has been precipitous increase in the number of associated loci and genes identified whose function in disease is unknown 1 . Many researchers have suggested that the innovative use of functional omics will be crucial to interpret GWAS results and reveal molecular pathways in complex diseases in the post-GWAS era, but concrete strategies are still being explored 1,2,3,4 .…”

“…As a result, there has been precipitous increase in the number of associated loci and genes identified whose function in disease is unknown 1 . Many researchers have suggested that the innovative use of functional omics will be crucial to interpret GWAS results and reveal molecular pathways in complex diseases in the post-GWAS era, but concrete strategies are still being explored 1,2,3,4 . In Alzheimer's disease (AD), there is a sharp disparity between the criticality of the disease, including the large number of patients and the burden of care, and the availability of treatments.…”

Microglial Piezo1 senses Aβ fibrils stiffness to restrict Alzheimer’s disease

“…The preponderance of human genetics evidence has shed light on a number of common and rare genetic loci closely associated with AD risk. Notably, many of these risk loci are associated with genes that have been reported as microglia specific or highly expressed in microglia relative to other cell types in the central nervous system (CNS) (Lopes et al, 2022; Verheijen and Sleegers, 2018). This broad trend implicates microglia, as the predominant immune cells residing in the brain parenchymal have emerged as crucial players in the pathogenesis of AD.…”

Iminosugar Amino Acid idoBR1 Reduces Inflammatory Responses in Microglia

“…In neuroinflammation, microglia become activated, undergo a change in morphology, and release various cytotoxic mediators. Microglia are thought to be important factors in brain aging and pathologies, including Alzheimer’s and Parkinson’s [ 8 , 9 ]. They are known to release pro-inflammatory cytokines, such as TNF α , when activated, as well as potentially neurotoxic substances, such as nitric oxide.…”