Gene-environment interactions shape myopia development

Purpose Refractive development is highly heritable, yet also known to be regulated by visual experience during childhood. Recent genome-wide association studies for refractive error have identified very few variants, which together explain only a small fraction of the population attributable risk. Gene-environment interactions represent an attractive explanation for the paradoxical evidence supporting both genetic and environmental determination of refractive error, but to date their influence in complex disorders such as myopia is almost entirely unknown. Methods We carried out a selective breeding experiment in chicks monocularly deprived of sharp vision for 4 days, starting when they were 4 days old. Chicks in the extremes of the myopia susceptibility frequency distribution were retained for breeding. Heritability was estimated using variance components analysis with the SOLAR package. Results After 2 rounds of selection, chicks bred for low susceptibility developed less than half the treatment-induced myopia of those bred for high susceptibility ("Low line" = -6.88 ± 3.35 D; "High line" = 15.27 ± 3.47 D; mean ± SD; N = 392; P ~10e-80). Susceptibility to induced myopia was highly heritable (heritability = 0.53; N = 891; p ~10e-122). Furthermore, the Low line developed only half the myopia of the High line in response to a second type of environmentally-induced myopia, minus lens wear. The genetic variants that determined myopia susceptibility were found to be distinct from those controlling natural variations in eye size. Conclusion This work reveals that genetic variants determine susceptibility to myopia triggered by cues from the visual environment, implicating a potentially major role for gene-environment interactions in human myopia development.