NEW YORK (GenomeWeb) – A new genome-wide association study meta-analysis has dramatically expanded the repertoire of genetic variants implicated in myopia, a nearsightedness-causing eye disease characterized by focusing incongruities between different parts of the eye that lead to refractive errors.
As they reported in Nature Genetics yesterday, members of an international research team considered genotyping data from 160,420 individuals of European or Asian ancestry who had been profiled in 37 prior studies. After the discovery and validation stages of the study, the researchers fixed on 161 suspicious loci — up from 37 myopia-related loci identified in the past — for a series of follow-up expression and functional analyses.
"Our list of plausible genes and pathways provides a plethora of data for future studies focusing on gene-environment interaction and on translation of GWAS findings into starting points for therapy," corresponding and co-senior author Caroline Klaver, an ophthalmology and epidemiology researcher affiliated with the Erasmus Medical Center and Radboud University, and her colleagues wrote.
Although environmental and lifestyle contributors have been implicated in myopia, the team explained, there is evidence that genetic factors are involved as well. With that in mind, they set out to search for potential genetic factors in individuals from European populations and from a population in East Asia where near-sightedness is particularly common.
"The myopia boom is particularly prominent in urban East Asia, where up to 95 percent of 20-year-olds in cities such as Seoul and Singapore have this refractive error," the authors wrote, noting that the "prevalence of myopia is also rising throughout Western Europe and the United States."
The researchers considered roughly 11 million SNPs genotyped on a range of platforms from the prior studies done by investigators with the Consortium for Refractive Error and Myopia (CREAM), 23andMe, and other teams. For their first analysis, the team included 44,192 individuals of European ancestry and 11,935 Asian individuals from CREAM cohorts, searching for variants associated with myopia diagnosis and age of onset. A second analysis included 104,293 European and Asian 23andMe customers enrolled for research, followed by a meta-analysis on both CREAM and 23andMe data.
In the process, the researchers tracked down nearly 8,000 variants with genome-wide significant ties to myopia, spanning 104 new loci and 37 loci previously implicated in the eye condition. They attempted to verify associations at these loci — and 21 more candidate sites from their conditional analysis — using data for another 95,505 individuals, successfully replicating 138 proposed associations.
A dozen more loci showed more tenuous ties to myopia, the team reported, while 22 loci came out of subsequent gene-based analyses. Along with efforts to come up with a polygenic risk score for the eye condition, the group incorporated annotation, fine mapping, expression, in silico analysis, and other clues to characterize the genes and pathways involved in it.
At least some of the variants identified overlapped with those contributing to other physical traits such as height and weight. The researchers also uncovered myopia-associated variants in genes involved in everything from dopaminergic signaling to angiogenesis, anterior-segment morphology, post-transcriptional regulation, and light-dependent pathways.
"Our genetic observations add credence to the current notion that refractive errors are caused by a retina-to-sclera signaling cascade that induces scleral remodeling in response to light stimuli," the authors wrote, noting that the new research "provides a large number of new molecular candidates for this cascade and clearly implicates a wide range of neuronal cell types in the retina, the [retinal pigment epithelium], the vascular endothelium, and components of the extracellular matrix."