Molecular and genetic landscapes of retina and brain microglia in neurodegenerative diseases

Abstract

Microglia-driven dysregulation has emerged as a significant underlying mechanism in many neurodegenerative diseases, such as age-related macular degeneration (AMD) and Alzheimer's disease (AD). Although both brain and retinal microglia originate from the yolk sac, it is uncertain whether they share molecular similarities or genetic and molecular foundations related to neurodegenerative diseases. In this study, we examine the transcriptomic and epigenetic profiles of retina and brain microglia through integrative analyses of single-nucleus RNA sequencing (snRNA-seq) and single-nucleus ATAC sequencing (snATAC-seq) from 97 independent human samples across 11 different studies. Our findings reveal that retina and brain microglia share similar expression and regulatory profiles compared with other cell types in the retina and brain. By integrating genome-wide association study (GWAS) data with gene expression profiles, we demonstrate that genetic variants associated with AMD and AD are linked to microglia-specific gene signatures. Furthermore, integrating regulatory annotations with GWAS data shows that susceptibility loci for both AMD and AD are notably enriched in the open chromatin regions of microglia from the brain and retina, emphasizing their relevance to these neurodegenerative conditions. Finally, a comparison with microglia annotations from other tissues highlights the specific enrichment of microglia in relation to neurodegenerative diseases. These findings contribute to the understanding of the role of microglia in AMD and AD pathogenesis and offer an opportunity to utilize resources from both retinal and brain microglia to deepen our understanding of their contributions to genetic variations in neurodegenerative diseases.