A genome-wide analysis of 340 318 participants identifies four novel loci associated with the age of first spectacle wear

Abstract

Refractive errors, particularly myopia, are the most common eye conditions, often leading to serious visual impairment. The age of onset is correlated with the severity of refractive error in adulthood observed in epidemiological and genetic studies and can be used as a proxy in refractive error genetic studies. To further elucidate genetic factors that influence refractive error, we analysed self-reported age of refractive error correction data from the UK Biobank European and perform genome-wide time-to-event analyses on the age of first spectacle wear (AFSW). Genome-wide proportional hazards ratio analyses were conducted in 340 318 European subjects. We subsequently assessed the similarities and differences in the genetic architectures of refractive error correction from different causes. All-cause AFSW was genetically strongly correlated (rg = -0.68) with spherical equivalent (the measured strength of spectacle lens required to correct the refractive error) and was used as a proxy for refractive error. Time-to-event analyses found genome-wide significant associations at 44 independent genomic loci, many of which (GJD2, LAMA2, etc.) were previously associated with refractive error. We also identified six novel regions associated with AFSW, the most significant of which was on chromosome 17q (P = 3.06 × 10-09 for rs55882072), replicating in an independent dataset. We found that genes associated with AFSW were significantly enriched for expression in central nervous system tissues and were involved in neurogenesis. This work demonstrates the merits of time-to-event study design in the genetic investigation of refractive error and contributes additional knowledge on its genetic risk factors in the general population.

Figure 1

Manhattan plot displaying 44 genome-significant associations with the AFSW in UK Biobank cohort (N = 340 318). The plot shows log10 transformed P-values for each marker plotted against the chromosomal location. The red dashed line indicates the genome-wide significance threshold (P-value <5 × 10⁻⁰⁸). Regions are named with symbols of the transcript-coding genes nearest to the most strongly associated variant in the region.

Figure 2

Scatterplot displaying the correlation between the AFSW hazards ratios and spherical equivalent beta coefficients. Hazard ratios shown here as (ln (HR)) represent the multiplicative change in the rate of first spectacle wear per copy of the myopia risk allele calculated in the full sample of 340 318 UK Biobank participants, which was taken as reference. The results are shown for the most strongly associated SNPs in their respective loci. The purple labels depict names of some of the gene loci exhibiting stronger effects over the AFSW, SNPs in blue are associated with spherical equivalent but not AFSW and SNPs in turquoise are associated with AFSW but not spherical equivalent.