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GWAS Meta-analysis Reveals 19 Loci Linked to Age-related Macular Degeneration Risk

NEW YORK (GenomeWeb News) – A meta-analysis of genome-wide association studies has uncovered seven new loci linked to increased risk of age-related macular degeneration, the AMD Gene Consortium reported in Nature Genetics yesterday. The international consortium includes researchers from the University of Michigan, Germany's Universität Regensburg, Boston University, and elsewhere.

The group also confirmed 12 loci previously linked to AMD risk. A number of the 19 total loci were found to be associated with genes involved in the immune complement system and the atherosclerotic signaling pathways.

"Combining data from multiple studies, this international effort provides insight into the molecular basis of AMD, which will help researchers search for causes of the disease and will inform future development of new diagnostic and treatment strategies," Paul Sieving, the director of the National Eye Institute, said in a statement. NEI partially funded the study.

The researchers first slogged through GWAS data from more than 7,600 patients with advanced AMD and from more than 50,000 controls, homing in on 32 putative loci linked to disease risk. Those variants were then genotyped in an additional set of more than 9,500 cases and 8,200 controls. From this, the researchers reported 19 AMD susceptibility loci, seven of which were novel. They further estimated that these loci account for between 10 percent and 30 percent of the variability of disease risk.

They also broke down their samples into subsets, based on age, ancestry, disease phenotype, and gender, to try tease out the sources of heterogeneity they observed between the studies. While they did not find any additional risk loci, they noted that the effect size of the loci varied between populations of Asian or European ancestry. The researchers speculated that those differences may be due to linkage disequilibrium differences or environmental or diagnostic factors.

In addition, the researchers determined that some of the 19 risk loci were associated with multiple alleles linked to AMD, finding signals near the CFH and C2-CFB genes as well as near the C3, CETP, LIPC, FRK-COL10A1, IER3-DDR1, and RAD51B genes. For four of these, the researchers added, the new, independently identified alleles are located quite close to the original signal. "This shows that each locus can harbor multiple susceptibility alleles, encouraging searches for rare variants that elucidate disease-related gene function in these regions," the consortium wrote.

About a quarter of the variants, the researchers added, affect protein sequences. For example, rs4698775 is in strong linkage disequilibrium with a variant that would damage the CCDC109B gene, which encodes a coiled-coil domain-containing protein that is thought to regulate gene expression.

Through RNA sequencing of post-mortem human retina, the group examined the transcription of 85 genes found within 100 kilobases of their index SNPs and found that two genes, CFH and VEGFA, were differentially expressed in young and elderly people.

Then, by performing a pathway analysis of genes located within 100 kilobases of the index SNPs, the researchers determined that many of the risk loci appear to affect the complement and atherosclerosis signaling systems.

"The identification of novel genes and pathways involved in disease enables the pursuit of a larger range of disease-specific targets for the development of new therapeutic interventions," the consortium wrote. "We expect that future therapies directed at earlier stages of the disease process will allow patients to retain visual function for longer periods, improving the quality of life for individuals with AMD."