Research conducted by the International AMD Genomics Consortium (IAMDGC) has recently reported an almost doubling in the number of genetic risk loci associated with age-related macular degeneration (AMD). In a significant publication in the journal Nature Genetics, the research group has reported on an analysis of >12 million gene variants, “including 163,714 directly genotyped, mostly rare, protein-altering variants”. The study, which included 16,144 patients and 17,832 controls, resulted in the identification of 52 independently associated common and rare variants (P < 5X10^−8) covering 34 distinct loci. In addition, the consortium claims to have identified the first genetic association specific to wet AMD, a locus close to the matrix metalloproteinase gene, MMP9, (difference P value = 4.1X 10^−10).
The authors of the genomic study suggest that the results support an hypothesis that rare coding variants may pinpoint causal genes within known genetic loci. However, the research additionally indicates that reproducing and applying such an approach for the detection of new loci will likely require extremely large sample sizes. As a result, the researchers claim that a recent estimate suggesting 25,000 patients would be required (for sequencing) to identify rare variants for disease risk may be considerably optimistic. As the effect sizes for AMD risk alleles appear to be larger than for many other complex traits reported in the literature, future studies may require a large number of participants in order to secure robust and clinically relevant information.
Members of the IAMDGC, which comprise 26 centres worldwide, claim to have jointly assembled the largest collection of AMD case and control DNA in the world, an estimated ~50,000 sample dataset genotyped on the Illumina HumanCoreExome chip. According to the researchers, such a dataset enables the construction of a more comprehensive picture between association studies of common variants and sequencing studies of rare variants. In addition to the new loci reported, the consortium also uncovered two unexpected rare variant findings: one, a putative splicing variant in the SLC16A8 gene, which encodes a lactate transporter expressed in the RPE (which may increase the risk of AMD) and secondly, an >30-fold excess of rare TIMP3 mutations among suspect cases of macular degeneration within the population tested. Finally, the researchers conclude their study highlighting, for the first time, the identity of a variant, close to the MMP9 gene, thought to be specific to choroidal neovascularisation. From a clinical management perspective, the authors comment that if the majority of disease-associated variants impact on the risk of both wet and dry AMD, then individuals at high risk of choroidal neovascularization may also be at high risk of geographic atrophy. Consequently, therapies that target CNV alone, but not geographic atrophy, may only provide short-term relief while such patients remain at high risk of developing the dry form of the disease.