Novel Loci Implicated in Risk of Age-Related Macular Degeneration

A group of researchers investigated the genetic interactions between the nuclear and mitochondrial genome and discovered there are previously unrecognized associations related to the risk of age-related macular degeneration (AMD).

The researchers, led by Patrice J Persad, of the University of Miami, performed joint tests of nuclear single nucleotide polymorphisms (nSNPs) and mitochondrial single nucleotide polymorphisms (mtSNPs), finding associations at novel loci that were not apparent when only main effects were considered.

AMD is complex, and both genetic and nongenetic factors affect the risk of developing the disease. Currently, there are 34 genetic loci containing 52 SNPs known to be associated with advanced AMD risk, but there are additional genetic risks as well. Several previous studies have shown that some mtSNPs are also associated with AMD risk.

“A natural follow-up to these studies was to examine whether mitochondrial variation influenced risk of AMD by itself, or through interactions with other nuclear-encoded risk factors associated with AMD,” the researchers noted.

In order to investigate how gene-gene interactions might impact AMD risk, the researchers used a dataset consisting of 33976 participants to conduct a genome-wide interaction study (GWIS). They evaluated the joint effects with 4 mtSNPs, A4917G, T5004C, G12771A, and C16069T, based on prior studies.

“Results from mtSNP A4917G-nSNP and mtSNP G12771A-nSNP interaction analyses revealed, respectively two novel loci TRPM1 and ABHD2/RLBP1 on chromosome 15,” according to the authors.

William K Scott (pictured), PhD, of the University of Miami Miller School of Medicine, and author of the paper, told MD Magazine that the findings were not a big surprise. “The genome-wide association study is a discovery approach, where we make no assumptions about the location or nature of the genes associated with disease.”

Both of the loci discovered to have associations with AMD risk “have functional connections to the visual system.” TRPM1 mutations cause autosomal recessive congenital night blindness and RLBP1 variants are associated with Newfoundland rod-cone dystrophy. “The 2 loci contain plausible candidate genes for AMD, based on their biological functions and prior association with other disorders of the visual system,” according to the authors.

“In the near term, the discovery of two new genes influencing risk of AMD could help improve risk prediction models that consider both genetic and clinical factors,” Scott said. “In the longer term, if follow-up studies demonstrate the biological mechanism by which these genes influence risk of AMD, the discoveries could influence development of therapeutic approaches.”

There are, however, some reasons to exercise caution in interpreting the results of the current study. For example, the authors noted that the “statistical interactions” do not necessarily indicate physical interactions, such as protein on protein, or in biological systems. Additionally, the patterns of interaction could be due to genetic heterogeneity.

“Two next steps include attempting to replicate the association in additional data sets or populations, and conducting laboratory studies to identify potential biological mechanisms by which these genes influence the development of AMD,” Scott said.

The full study can be found in the journal Investigative Ophthalmology & Visual Science.