Integrative Multiomics Identifies CD64⁺ Monocytes as Potential Contributors to Age-Related Macular Degeneration

Age-related macular degeneration (AMD) is a leading cause of irreversible vision loss in the elderly, characterized by chronic retinal inflammation and immune dysregulation. While myeloid cells have been increasingly implicated in AMD pathogenesis, the specific immune subsets responsible remain poorly defined. This study aimed to identify causal immune cell populations and elucidate their functional roles in AMD progression.

We employed an integrative multiomics strategy encompassing Mendelian randomization (MR) analysis using genome-wide association study summary statistics, single-cell RNA sequencing (scRNA-seq) analysis of retinal pigment epithelium (RPE)/choroid tissues from patients with AMD and healthy controls (GSE230348), and flow cytometric (FCM) validation in a sodium iodate-induced dry AMD mouse model.

MR analysis identified a significant causal association between CD64 expression on CD14⁻CD16⁻ monocytes and increased AMD risk (odds ratio, 1.179; P < 0.001). scRNA-seq profiling revealed a pronounced enrichment of CD14⁻CD16⁻ monocytes in AMD tissues, with FCGR1A (CD64) expression specifically localized within this subset. Pseudotime trajectory analysis demonstrated dynamic activation and differentiation states among monocyte populations in AMD. Ligand-receptor interaction modeling identified three major signaling pathways, MIF-CD74-CXCR4, IGF1-IGF1R, and SEMA3C-PLXND1, mediating interactions between CD14⁻CD16⁻ monocytes and RPE cells. FCM analysis of retinal single-cell suspensions in AMD mice confirmed a significantly higher proportion of CD64⁺ myeloid cells compared to controls.

This study identifies CD64⁺CD14⁻CD16⁻ monocytes as potential contributors to AMD and reveals their putative immunomodulatory crosstalk with RPE cells. These findings highlight CD64 as a promising biomarker and therapeutic target for mitigating myeloid-driven inflammation in AMD.