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Is a large eye size a risk factor for myopia? A Mendelian randomization study

Myopia (nearsightedness) is an increasingly common cause of irreversible visual impairment. The ocular structures with greatest impact on refractive error are corneal curvature and axial length. Emmetropic eyes range in size within and across species, yet possess a balance between corneal curvature and axial length that is under genetic control. This scaling goes awry in myopia: 1 mm axial elongation is associated with ~3 Dioptres (D) myopia. Evidence that eye size prior to onset is a risk factor for myopia is conflicting. We applied Mendelian randomisation to test for a causal effect of eye size on refractive error. Genetic variants associated with corneal curvature identified in emmetropic eyes (22,180 individuals) were used as instrumental variables and tested for association with refractive error (139,697 individuals). A genetic risk score for the variants was tested for association with corneal curvature and axial length in an independent sample (315 emmetropes). The genetic risk score explained 2.3% (P=0.007) and 2.7% (P=0.002) of the variance in corneal curvature and axial length, respectively, in the independent sample, confirming these variants are predictive of eye size in emmetropes. The estimated causal effect of eye size on refractive error was + 1.41 D (95% CI. 0.65 to 2.16) less myopic refractive error per mm flatter cornea (P<0.001), corresponding to +0.48 D (95% CI. 0.22 to 0.73) more hypermetropic refractive error for an eye with a 1mm longer axial length. These results do not support the hypothesis that a larger eye size is a risk factor for myopia. We conclude the genetic determinants of normal eye size are not shared with those influencing susceptibility to myopia.