Childhood gene-environment interactions and age-dependent effects of genetic variants associated with refractive error and myopia: The CREAM Consortium

Abstract

Myopia, currently at epidemic levels in East Asia, is a leading cause of untreatable visual impairment. Genome-wide association studies (GWAS) in adults have identified 39 loci associated with refractive error and myopia. Here, the age-of-onset of association between genetic variants at these 39 loci and refractive error was investigated in 5200 children assessed longitudinally across ages 7-15 years, along with gene-environment interactions involving the major environmental risk-factors, nearwork and time outdoors. Specific variants could be categorized as showing evidence of: (a) early-onset effects remaining stable through childhood, (b) early-onset effects that progressed further with increasing age, or (c) onset later in childhood (N = 10, 5 and 11 variants, respectively). A genetic risk score (GRS) for all 39 variants explained 0.6% (P = 6.6E-08) and 2.3% (P = 6.9E-21) of the variance in refractive error at ages 7 and 15, respectively, supporting increased effects from these genetic variants at older ages. Replication in multi-ancestry samples (combined N = 5599) yielded evidence of childhood onset for 6 of 12 variants present in both Asians and Europeans. There was no indication that variant or GRS effects altered depending on time outdoors, however 5 variants showed nominal evidence of interactions with nearwork (top variant, rs7829127 in ZMAT4; P = 6.3E-04).

Figure 1. SNPs associated with early-onset and later-onset effects on refractive development during childhood.

Analyses were carried out using data from longitudinal eye examinations in 5,200 ALSPAC participants. Each panel shows how refractive error trajectory varied with SNP genotype, for 4 different SNPs: rs1881492, rs17648524, rs1656404 and rs2155413. The lines in each panel show the refractive error trajectories predicted by the best-fit linear mixed model (LMM) for participants carrying the number of risk alleles indicated (0, 1 or 2). The SNPs in panels (a,c) showed an association with refractive error at baseline, i.e. evidence of early onset in childhood. The SNPs in panels (b,c) showed an age-dependent interaction with refractive error over later childhood. The SNP in panel (d) did not show evidence of effects during childhood.

Figure 2. Association between a genetic risk score for 39 SNPs and refractive error trajectories in ALSPAC participants.

The genetic risk score was calculated as the sum of the number of risk alleles (0–2) carried by an individual at each of the 39 myopia-susceptibility SNPs. The coloured lines show the trajectories for children carrying the number of risk alleles indicated, as predicted by the best-fit linear mixed model.

Figure 3. Refractive error trajectories in ALSPAC participants for SNPs showing evidence of an interaction with nearwork or time outdoors.

Levels of nearwork activity and time spent outdoors were assessed at 8–9 years of age and classified as high or low (above or below the median level). Panels (a–d) show how refractive error trajectories varied depending on nearwork level and the number of risk alleles (0–2) carried for 4 different markers that showed SNP x nearwork x age-from-baseline (3-way) interactions. Panel (e) Refractive trajectories for the only marker to show a SNP x nearwork (2-way) interaction at baseline age. Panel (f ) Refractive trajectories for the only marker to show a SNP x time outdoors x age-from-baseline (3-way) interaction. The coloured lines show the trajectories predicted by the best-fit linear mixed model for children carrying the number of copies of the risk allele indicated in the legend.