Genetics of age-related macular degeneration: current concepts, future directions

Abstract

Age-related macular degeneration (AMD) is a progressive degenerative disease which leads to blindness, affecting the quality of life of millions of Americans. More than 1.75 million individuals in the United States are affected by the advanced form of AMD. The etiological pathway of AMD is not yet fully understood, but there is a clear genetic influence on disease risk. To date, the 1q32 (CFH) and 10q26 (PLEKHA1/ARMS2/HTRA1) loci are the most strongly associated with disease; however, the variation in these genomic regions alone is unable to predict disease development with high accuracy. Therefore, current genetic studies are aimed at identifying new genes associated with AMD and their modifiers, with the goal of discovering diagnostic or prognostic biomarkers. Moreover, these studies provide the foundation for further investigation into the pathophysiology of AMD by utilizing a systems-biology-based approach to elucidate underlying mechanistic pathways.

FIGURE 1

Chromosomal location of AMD-associated genes. The schematic represents the location of AMD associated genes on the 22 autosomal chromosomes. The following genes are listed on either side of the cartoon, thereby depicting their location on the p or q arm: Hemicentin 1 (HMCN1), ATP-binding Cassette Transporter, subfamily A, member 4 (ABCA4), Coagulation Factor XIII, B Polypeptide (F13B), Complement Factor H Related Genes (CFHR1-5), Complement Factor H (CFH), Chemokine (C-X3-C Motif) Receptor 1 (CX3CR1), Complement Factor I (CFI), Toll-like Receptor 3 (TLR3), Vascular Endothelial Growth Factor A (VEGFA), Elongation of Very Long Chain Fatty Acids (ELOVL4), Complement Component 2 (C2)/Complement Factor B (CFB), Manganese Superoxide Dismutase 2 (SOD-2), Paraoxonase 1 (PON1), Very Low Density Lipoprotein Receptor (VLDLR), Toll-like Receptor 4 (TLR4), Excision Repair Cross-complementation Group 6 (ERCC6), Pleckstrin Homology Domain Containing, Family A (Phosphoinositide Binding Specific) Member 1 (PLEKHA1)/Age-Related Maculopathy Susceptibility 2 (ARMS2, formerly LOC387715)/HTRA Serine Peptidase 1 (HTRA1), Low Density Lipoprotein Receptor Related Protein 6 (LRP6), Fibulin 5 (FBLN5), RAR-related orphan receptor alpha (RORA), Angiotensin I Converting Enzyme (ACE), Complement Component 3 (C3), Apolipoprotein (APOE), Cystatin C (CST3), TIMP Metallopeptidase Inhibitor 3 (TIMP3), Synapsin III (SYN3). Next to each gene name is a symbol listed in the legend representing the function/cellular process most commonly associated with the gene product.