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. 2021 Oct 4;62(13):24.
doi: 10.1167/iovs.62.13.24.

Genetic Variants Associated With Human Eye Size Are Distinct From Those Conferring Susceptibility to Myopia

Denis Plotnikov  1   2 , Jiangtian Cui  1 , Rosie Clark  1 , Juho Wedenoja  3   4 , Olavi Pärssinen  5 , J Willem L Tideman  6   7 , Jost B Jonas  8   9   10 , Yaxing Wang  9 , Igor Rudan  11 , Terri L Young  12 , David A Mackey  13 , Louise Terry  1 , Cathy Williams  14 , Jeremy A Guggenheim  1 ; UK Biobank Eye and Vision Consortium and the CREAM Consortium
Affiliations

Genetic Variants Associated With Human Eye Size Are Distinct From Those Conferring Susceptibility to Myopia

Denis Plotnikov et al. Invest Ophthalmol Vis Sci. .

Abstract

Purpose: Emmetropization requires coordinated scaling of the major ocular components, corneal curvature and axial length. This coordination is achieved in part through a shared set of genetic variants that regulate eye size. Poorly coordinated scaling of corneal curvature and axial length results in refractive error. We tested the hypothesis that genetic variants regulating eye size in emmetropic eyes are distinct from those conferring susceptibility to refractive error.

Methods: A genome-wide association study (GWAS) for corneal curvature in 22,180 adult emmetropic individuals was performed as a proxy for a GWAS for eye size. A polygenic score created using lead GWAS variants was tested for association with corneal curvature and axial length in an independent sample: 437 classified as emmetropic and 637 as ametropic. The genetic correlation between eye size and refractive error was calculated using linkage disequilibrium score regression for approximately 1 million genetic variants.

Results: The GWAS for corneal curvature in emmetropes identified 32 independent genetic variants (P < 5.0e-08). A polygenic score created using these 32 genetic markers explained 3.5% (P < 0.001) and 2.0% (P = 0.001) of the variance in corneal curvature and axial length, respectively, in the independent sample of emmetropic individuals but was not predictive of these traits in ametropic individuals. The genetic correlation between eye size and refractive error was close to zero (rg = 0.00; SE = 0.06; P = 0.95).

Conclusions: These results support the hypothesis that genetic variants regulating eye size in emmetropic eyes do not overlap with those conferring susceptibility to myopia. This suggests that distinct biological pathways regulate normal eye growth and myopia development.

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Conflict of interest statement

Disclosure: D. Plotnikov, None; J. Cui, None; R. Clark, None; J. Wedenoja, None; O. Pärssinen, None; J.W.L. Tideman, None; J.B. Jonas, None; Y. Wang, None; I. Rudan, None; T.L. Young, None; D.A. Mackey, None; L. Terry, None; C. Williams, None; J.A. Guggenheim, None

Figures

Figure 1.
Figure 1.
Relationships among corneal curvature, axial length, and refractive error in an emmetropes sample and an ametropes sample from the ALSPAC study (15 years old). Data are from the emmetropic eyes of 437 individuals in the emmetropes sample and the ametropic eyes of 637 individuals in the ametropes sample (the criteria for defining eyes and participants as emmetropic and ametropic are shown in Table 2). Curves were fitted using LOESS smoothing.
Figure 2.
Figure 2.
Genetic correlations can be used to draw causal inferences about the shared genetic contribution to pairs of traits. (A) Single pathway involved in both well-coordinated eye growth and myopic eye growth. (B) Two separate pathways, one that mediates well-coordinated eye growth and the other that mediates myopic eye growth. Genetic correlation analysis can distinguish whether the pathways mediating well-coordinated eye growth and myopic eye growth are overlapping or separate.
Figure 3.
Figure 3.
Pairwise genetic correlations among eye size, refractive error, corneal curvature, and height. Error bars represent standard errors.
See this image and copyright information in PMC

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