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Refractive Error GWAS Leads To More Than 300 New Loci

NEW YORK – A team from the UK, US, Netherlands, and elsewhere tracked down hundreds of new genetic loci linked to myopia or other refractive errors of the eye with a genome-wide association study involving more than half a million individuals.

"Our results suggest that refractive error is genetically heterogeneous, driven by genes that participate in the development of every anatomical component of the eye," co-first and corresponding author Pirro Hysi, an ophthalmology, genetic epidemiology,  researcher affiliated with King's College London and the University College London, and his colleagues wrote.

Using array-based genotypes for participants from several ongoing studies or from 23andMe customers consented for research, the researchers found and validated some 336 new loci associated with refractive errors — eye problems that affect focus by shifting incoming light ray convergence relative to the eye's retina.

As they reported in Nature Genetics on Monday, the newly-identified loci — together with those implicated in refractive errors in the past — appeared to explain some 18 percent of the heritability of these conditions in individuals of European ancestry.

By digging into the genes and pathways impacted by the refractive error-associated variants, the team saw signs that these conditions may stem from changes related to central nervous system or circadian rhythm-related processes, for example, or from changes that affect eye development, eye structures, or the intraocular pressure within the eye.

"Our results cast light on potential mechanisms that contribute to refractive error in the general population and have identified the genetic factors that explain a considerable proportion of the heritability and phenotypic variability of refractive error," the authors wrote.

They noted that the work "allows us to substantially improve our ability to make predictions of myopia risk and generate novel hypothesis on how multiple aspects of virtual processing affect emmetropization [eye processes that minimize refractive errors], which may pave the way to personalized risk management and treatment of refractive error in the population in the future."

For their GWAS, the researchers started by bringing together genotyping data, self-reported myopia information, insights on participants' use of prescription glasses, or myopia diagnostic data, when available, for UK Biobank participants, individuals enrolled in the Genetic Epidemiology Research on Adult Health and Aging, and individuals participating in the 23andMe research cohort.

After incorporating information for 34,079 participants in the Consortium for Refractive Error and Myopia for the validation stage of the study, the team was able to tap into data for 542,934 individuals with European ancestry. Of those, nearly 508,900 individuals included in a meta-analysis searching for refractive error culprits, which highlighted more than 66,000 SNPs in 449 suspicious parts of the genome and 336 new loci.

Of those, 904 SNPs appeared to have independent ties to the eye condition, prompting a series of gene set enrichment, pathway, and functional analyses, predictive modeling, and other follow-up work to explore the processes contributing to refractive error pathogenesis. 

"The findings implicate almost all anatomical components of the eye," the authors reported, "which, along with the [central nervous system], participate in the development of refractive error."