Home > Genome-Wide Association Scan for Age-related Macular Degeneration Reveals New Susceptibility Loci and Points to Novel Pathways Involved in Disease Pathogenesis

Genome-Wide Association Scan for Age-related Macular Degeneration Reveals New Susceptibility Loci and Points to Novel Pathways Involved in Disease Pathogenesis


Age-related macular degeneration (AMD) is a progressive neurodegenerative disease of the macular region of the retina. It affects the aging population in developed countries, causing loss of central vision and accounts for 50 percent of blindness. In its early stages, it is characterized by the presence of deposits (drusen) which are initially small in size and number and progressively become larger and more numerous and are located between the retinal pigment epithelium (RPE) and the Bruchs membrane adjacent to the choroid. AMD may progress to geographic atrophy of the RPE and/or to neovascularization, and ultimately result in loss of photoreceptors.


NEI investigators in collaboration with more than twenty universities and research institutions in the U.S. and Europe completed the first genome-wide association scan (GWAS) for age-related macular degeneration (AMD). GWAS are designed to identify common variants implicated in common diseases, which are normally not covered by linkage studies. Known AMD susceptibility loci near complement factor H (CFH), age-related maculopathy susceptibility 2 (ARMS2), complement component2/complement factor B (C2/CFB), complement component 3 (C3), and complement factor I (CFI) were confirmed by this study. Other previously suggested susceptibility loci did not show significance with P<0.05. However, in some cases a trend was observed in the same direction as that of the published data. The three strongest signals were associated with loci in the synapsin III (SYN3)/tissue inhibitor of metalloproteinase 3 (TIMP3) region, the hepatic lipase (LIPC) and cholesteryl ester transfer protein (CETP) genes. The SYN3/TIMP3 susceptibility locus had been previously linked to AMD. It is a large intron in the SYN3 gene (involved in neurotransmission and synapse formation) that also contains the TIMP3 gene (involved in extracellular matrix degradation and implicated in early-onset maculopathy Sorby’s fundus dystrophy).

Two other strong signals were identified near the hepatic lipase (LIPC) and cholesteryl ester transfer protein (CETP) genes, loci also associated with high-density lipoprotein cholesterol HDL-c levels in the blood. Other HDL-c-associated alleles were examined and lipoprotein lipase (LPL) and ATP-binding cassette sub-family member 1 (ABCA1) genes showed evidence of strong association with AMD. All four alleles are associated with decreased blood HDL-c. However, alleles near CEPT and LPL appear to increase the risk of AMD, while alleles near LIPC and ABCA1 seem to decrease the risk of AMD. Thus, blood HDL-c may not be an appropriate marker for its impact on the risk of AMD. The susceptibility loci identified in this study point to two molecular pathways that could be considered as therapeutic targets in AMD: HDL-c metabolism and systemic transport and extracellular matrix degradation.

Public Impact Statement/Significance:

AMD is a raising public health concern because of the constant increase in the aging population. The identification of susceptibility variants associated with AMD may contribute to the prediction of individual risk of AMD. This, in association with the identification of molecular and cellular pathways involved in the pathogenesis of the disease can lead to better preventive and therapeutic interventions.

Publication Citation:

Chen W., et. al. Genetic variants near TIMP3 and high-density lipoprotein-associated loci influence susceptibility to age-related macular degeneration. Proc Natl Acad Sci U S A. 2010; 107(16):7401-6. Apr 12. [Epub ahead of print] PubMed

Last Reviewed: April 2010