Genetic testing for myopia

Director of research at Cardiff University, Professor Jeremy Guggenheim, tells OT  about devising a genetic test for identifying children at risk of developing myopia

DNA Chain

How was the genetic test developed?

We began by meta-analysing results from three different genetic studies: a genome-wide association study (GWAS) for refractive error in 95,000 UK Biobank participants, a GWAS for age-of-onset of glasses in a further 287,000 UK Biobank participants, and a GWAS for educational attainment in 329,000 participants. This allowed us to quantify the degree of association with refractive error of a set of 1.1m genetic markers distributed across the human genome. The genetic test was developed by considering each of these 1.1m genetic markers as independent risk factors for refractive error.

What are the steps of the genetic test?

The test works by predicting the refractive error based purely on genetics. DNA extracted from a blood or saliva sample is analysed in order to identify a person’s ‘genotype’ at the 1.1m genetic markers mentioned above. From this information we predict their refractive error as the cumulative risk conferred by each of the 1.1m risk factors. We can also test the likelihood that an individual will develop high myopia by asking whether their predicted refractive error is at least -5.00D.

What were the main findings from the analysis of UK Biobank data?

To quantify how accurate the genetic test was in predicting refractive error, we calculated the correlation between the ‘true’ autorefraction-measured refractive error and the genetically-predicted refractive error of a sample of 1500 individuals. The correlation for the genetic test was approximately 0.33, ie far from perfect but still informative. By comparison, knowing if a child has zero, one or two parents with myopia is less predictive of refractive error, having a correlation of approximately 0.22. The ‘area under the ROC curve’ (AUC) for predicting high myopia was 0.73, which is midway between chance level (AUC = 0.50) and perfect prediction (AUC = 1.00).

How and when should it be used in practice?

Currently, the genetic test is not accurate enough to be used in clinical practice. In general, an AUC > 0.80 is recommended in order to have a sufficiently good balance between sensitivity and specificity. If we were to carry out genetic testing of 100 children, then the 10 children at highest genetic risk would be about six times more likely to develop high myopia by adulthood than the remaining 90 children. Although this six-fold increased risk is informative, it hides the fact that several of the 10 children at highest genetic risk will not in fact develop high myopia and also that a few of the 90 children at lower genetic risk will develop high myopia.

What potential impact could it have on managing myopia?

An accurate genetic test might be helpful in managing myopia by identifying children with the highest risk of developing high myopia. In theory, children genetically predisposed to high myopia may benefit from early and sustained treatment for reducing the incidence of myopia, eg greater time outdoors, or for slowing myopia progression with treatments such as atropine eyedrops or dual-focus lenses. However, we need more research to find out if such genetically predisposed children really do benefit from these types of treatment interventions.

What’s next for the research team?

Integrating data from further GWAS analyses and implementing new statistical methods will allow us to improve the accuracy of the genetic test. We aim to collaborate with researchers conducting clinical trials of myopia control interventions to find out whether our genetic test can predict children who will respond well or respond poorly to a specific intervention.

Image credit: Pixabay/Darwin Laganzon