Single-Cell Gene Expression and eQTL Analyses in the Human Retina, RPE, and Choroid in Macular Degeneration.

Area of Science:

• Ophthalmology
• Genetics
• Molecular Biology

Background:

• Age-related macular degeneration (AMD) is a leading cause of vision loss in older adults.
• AMD involves complex genetic and environmental factors affecting the retina, retinal pigment epithelium (RPE), and choroid.
• Understanding the molecular mechanisms linking genetic risk to AMD pathology is crucial.

Purpose of the Study:

• To investigate the impact of AMD-associated genetic variants on gene expression in ocular tissues.
• To identify expression quantitative trait loci (eQTLs) related to AMD risk.
• To explore age-related changes in ocular tissues relevant to AMD pathogenesis.

Main Methods:

• Single-nucleus RNA sequencing of retina, RPE, and choroid from individuals with varying AMD stages.
• Genotyping and imputation of 1.8 million single nucleotide polymorphisms (SNPs).
• Analysis of eQTLs for AMD-risk loci, including PILRB and ARMS2/HTRA1.

Main Results:

• The PILRB AMD-risk locus was associated with increased PILRB RNA levels in multiple cell types, including RPE and cones.
• The ARMS2/HTRA1 risk locus correlated with decreased HTRA1 RNA expression in the RPE.
• An age-related decline in complement inhibitors was observed in the choriocapillaris.

Conclusions:

• Specific AMD genetic risk loci directly influence gene expression patterns in key ocular tissues.
• These expression changes may contribute to the development and progression of AMD.
• Age-related changes in complement regulation in the choriocapillaris may increase susceptibility to AMD-related damage.