Abstract
Purpose :
We have previously applied methods in genomics, structural chemistry, ophthalmic epidemiology and clinical trials to demonstrate associations of L-DOPA, dopamine (DA) and monoaminergic receptors with advanced AMD. In this work we report findings on human retinal transcriptomes to extend our investigations.
Methods :
We used QC-validated and normalized RNA-seq data collected with Illumina HiSeq 2500 from a public-access NCBI GEO database (GSE115828) of retinal specimens in order to identify differential gene expression profiles in seven people with neovascular AMD (NV AMD), relative to twelve age-matched AMD-free peers. We conducted gene ontology and pathway analysis with Gene Set Enrichment Analysis (GSEA) software.
Results :
RNA levels of DBH-like monooxygenase protein 1 (MOXD1), an enzyme implicated in dopamine catabolism, were 3.3-fold higher in retinal specimens of people with NV AMD (P < 9.91E-5; FDR Q = 0.095) – these findings were concordant with a published work reporting a 2.8-fold increase in MOXD1 expression within macular specimens of people with NV AMD (PMID: 22364233). Gene Ontology Enrichment Analysis on the full set of 17910 transcripts yielded strongest relationships for down regulation of chemical synaptic transmission (GO: 0007268; FDR Q = 6.3E-13) in the NV AMD cohort – subsequent Pathway Enrichment Analysis showed significant NV AMD-associated retinal down regulation of 14 genes in the KEGG Dopamine Synapse Pathway (hsa04728; FDR Q = 1.4E-4) and 4 genes in the WikiPathways Nicotine Effect on Dopaminergic Neurons Pathway (WP1602; FDR = 0.048). Gene sets from the Reactome Dopamine Release Cycle (FDR Q = 0.14) and Gene Ontology Regulation of Dopamine Secretion (FDR Q = 0.17) also showed significantly lower experession values in people with NV AMD.
Conclusions :
Our findings strengthen inferences on AMD-associated alterations in function of monoaminergic signaling pathways.
This is a 2021 ARVO Annual Meeting abstract.