The ocular tissue-specificity of differentially expressed age-related macular degeneration associated genes

Purpose Age-related macular degeneration (AMD) is a leading cause of blindness in the developed world. One of the most genetically well-characterized degenerative diseases, genome-wide association studies (GWAS) have identified 52 independent common or rare AMD risk associated variants. While transcriptome-wide association analyses (TWAS) and expression quantitative trait loci (eQTL) efforts have characterized the effects of these AMD-associated genes on mRNA expression in retinal tissue, we aimed to characterize the AMD-associated transcriptional profiles of functionally distinct ocular tissues including the macular and extramacular regions of the retina and the retinal-pigment epithelium (RPE)/choroid. Methods Using publicly available microarray data (NCBI GEO accession: GSE29801) comprised of retinal and RPE/choroidal tissue samples from 142 AMD patients and 151 healthy individuals (118 retina and 175 RPE/Choroid samples), tissue-specific differential gene expression analyses were conducted. Transcriptome analyses were focused on 878 genes surrounding known AMD-associated loci. Results Many genes which contain clinically significant or causal variants identified via GWAS or TWAS/eQTL studies were significantly differentially expressed and display transcriptional heterogeneity across different subtypes of ocular tissue and retinal geography in AMD-associated tissues. Conclusion These findings demonstrate the importance of spatial heterogeneity and tissue specificity in the mRNA expression of known AMD-associated genes. Genes known to harbor rare or causal AMD- associated variants are differentially expressed in functionally distinct ocular tissues of AMD patients, suggesting they might contribute to disease regardless of mutation status.