Abstract
Purpose :
Early identification and treatment of keratoconus can prevent further visual loss or blindness. Although keratoconus is highly genetic, recent whole-genome association studies explain only about 12.5% of the disease variance in the population. The contribution of environmental factors to keratoconus is even less well understood. This work aims to use genomic-based tools to identify environmental exposures that causally affect keratoconus risk in the population.
Methods :
We used Mendelian Randomization (MR) models to assess the presence of causal relationships between environmental exposures and keratoconus. We selected instruments from GWAS summary statistics available from public datasets, such as the GWAS Catalog. Among published SNPs significantly associated with the respective phenotypes (exposures), we selected instrumental variables (IVs) that were fully independent (r2<0.1 and distance >1Mbp). Through MR, we compared IVs association with the exposures and keratoconus in individuals of European ancestry. Specifically, we used two-sample MR simple median, inverse-variance weighted and MR-Egger tests to evaluate the strength of the relationship and test for directional horizontal pleiotropy. We considered the results significant when all three models were at least nominally significant, their estimated confidence intervals overlapped, and the MR-Egger intercept test for pleiotropy was not significant (p>0.05)
Results :
Among other exposures, we identified that asthma (PIVW=9.11x10-14) and atopic disease (PIVW=7.57x10-09) we significant causes of keratoconus. For example, keratoconus risk was increased in the presence of hay fever or atopic dermatitis history (ORIVW=1.63, 95% CI 1.43-1.86]) and asthma (ORIVW=1.50, 95% CI 1.11-2.04]). In our dataset none of the IVs or other genetic variants reportedly associated with asthma or other atopic traits showed a significant association with keratoconus. Our MR tests also identified specific metabolic changes that significantly affected the risk of keratoconus.
Conclusions :
For the first time, our analyses offer statistical evidence supporting the involvement of specific environmental factors in keratoconus. The significant MR tests in absence of any significant overlapping genetic risk between atopic disease and keratoconus, suggests that atopy acts as an external environmental factor that accounts for a significant proportion of keratoconus risk.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.