Genetic Variants Associated With Human Eye Size Are Distinct From Those Conferring Susceptibility to Myopia.
ABSTRACT: 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. 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. 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). 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.
Project description:Corneal astigmatism refers to refractive abnormalities and irregularities in the curvature of the cornea, and this interferes with light being accurately focused at a single point in the eye. This ametropic condition is highly prevalent, influences visual acuity, and is a highly heritable trait. There is currently a paucity of research in the genetic etiology of corneal astigmatism. Here we report the results from five genome-wide association studies of corneal astigmatism across three Asian populations, with an initial discovery set of 4,254 Chinese and Malay individuals consisting of 2,249 cases and 2,005 controls. Replication was obtained from three surveys comprising of 2,139 Indians, an additional 929 Chinese children, and an independent 397 Chinese family trios. Variants in PDGFRA on chromosome 4q12 (lead SNP: rs7677751, allelic odds ratio?=?1.26 (95% CI: 1.16-1.36), P(meta)?=?7.87×10(-9)) were identified to be significantly associated with corneal astigmatism, exhibiting consistent effect sizes across all five cohorts. This highlights the potential role of variants in PDGFRA in the genetic etiology of corneal astigmatism across diverse Asian populations.
Project description:Corneal curvature is a key determinant of the refractive power of the eye. Variants in two genes, FKBP12-rapamycin complex-associated protein 1 (FRAP1) on chromosome 1p36.2 and platelet-derived growth factor receptor alpha (PDGFRA) on chromosome 4q12, have shown genome-wide significant association with normal variation in corneal curvature in a study of subjects of Asian origin. Variants at the PDGFRA locus have also shown genome-wide significant association with corneal astigmatism. Whether these variants influence other ocular parameters such as axial length has yet to be reported. We performed a genome-wide association study for corneal curvature in white European subjects from a population-based birth cohort, with the aim of replicating and extending the above findings.White European children participating in the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort were examined at age about 15.5 years (95% confidence interval=15.45 to 15.48 years). Radius of corneal curvature and axial eye length were measured with an IOLmaster. DNA samples were genotyped with Illumina HumanHap550 arrays and untyped variants imputed using MACH, with CEU individuals from HapMap release 22, Phase II NCBI B36, Single Nucleotide Polymorphism database 126 as the reference panel. Association between corneal curvature and single nucleotide polymorphism (SNP) genotype was tested, genome-wide, using mach2qtl, with sex as a covariate (n=2023; 46.6% male).The variant exhibiting the strongest evidence for association with corneal curvature (rs6554163; p=2.8×10(-6)) was located in the same linkage disequilibrium block as the previously discovered PDGFRA variants. Meta-analysis of the current and prior findings enhanced the evidence for association (rs17084051, p=4.5×10(-14)). rs6554163 genotype predicted 1.0% of variation in corneal curvature. In addition, these PDGFRA variants were associated with axial eye length, predicting 0.6% of the normal trait variation (p=5.3×10(-4)). Each copy of the minor allele of variants at the locus also increased the risk of corneal astigmatism in this white European cohort (odds ratio [OR]=1.24, 95% confidence interval=1.07-1.45; p=0.006).As in Asians, variants at the PDGFRA locus influence corneal curvature (and corneal astigmatism). However, rather than affecting corneal curvature in isolation, this locus influences the size of the eye while maintaining its scaling.
Project description:PURPOSE:Stature at a particular age can be considered the cumulative result of growth during a number of preceding growth trajectory periods. We investigated whether height and weight growth trajectories from birth to age 10 years were related to refractive error at ages 11 and 15 years, and eye size at age 15 years. DESIGN:Prospective analysis in a birth cohort. PARTICIPANTS:Children participating in the Avon Longitudinal Study of Parents and Children (ALSPAC) U.K. birth cohort (minimum N = 2676). METHODS:Growth trajectories between birth and 10 years were modeled from a series of height and weight measurements (N = 6815). Refractive error was assessed by noncycloplegic autorefraction at ages 11 and 15 years (minimum N = 4737). Axial length (AXL) and radius of corneal curvature were measured with an IOLMaster (Carl Zeiss Meditec, Welwyn Garden City, U.K.) at age 15 years (minimum N = 2676). Growth trajectories and an allelic score for 180 genetic variants associated with adult height were tested for association with refractive error and eye size. MAIN OUTCOME MEASURES:Noncycloplegic autorefraction at ages 11 and 15 years, and AXL and corneal curvature at age 15 years. RESULTS:Height growth trajectory during the linear phase between 2.5 and 10 years was negatively associated with refractive error at 11 and 15 years (P<0.001), but explained <0.5% of intersubject variation. Height and weight growth trajectories, especially shortly after birth, were positively associated with AXL and corneal curvature (P<0.001), predicting 1% to 5% of trait variation. Height growth after 2.5 years was not associated with corneal curvature, whereas the association with AXL continued up to 10 years. The height allelic score was associated with corneal curvature (P = 0.03) but not with refractive error or AXL. CONCLUSIONS:Up to the age of 10 years, shared growth mechanisms contribute to scaling of eye and body size but minimally to the development of myopia. FINANCIAL DISCLOSURE(S):The author(s) have no proprietary or commercial interest in any materials discussed in this article.
Project description:<h4>Purpose</h4>Studies of myopia in mice have been complicated by the difficulty in obtaining accurate measurements of small changes observed in the growing mouse eye in vivo and the lack of data on refractive eye development. The purpose of this study was to carry out an in vivo high-resolution analysis of mouse eye growth and refractive development.<h4>Methods</h4>High-resolution small animal magnetic resonance imaging and high-resolution infrared photorefraction were used to analyze refractive development in postnatal day (P)21 to P89 C57BL/6J mice.<h4>Results</h4>The growth of the mouse eye decelerated after P40. The eye maintained a slightly prolate shape during growth. The anterior chamber growth exhibited a similar pattern, whereas the corneal radius of curvature (CRC) increased linearly. The growth rate of the lens remained constant until P89. The lens "overgrew" the eye at P40, resulting in a decline in vitreous chamber depth. Mice showed myopic refractive errors at a younger age (-13.2 +/- 2.0 D; mean +/- SD, P21). The refractive errors stabilized around emmetropic values by P32 and remained emmetropic until P40. Mice became progressively hyperopic with age (+1.2 +/- 1.7 D, P67; +3.6 +/- 2.3 D, P89).<h4>Conclusions</h4>Development of ocular components in the mouse is similar to that of the tree shrew but different from that of higher primates and humans. Primary differences can be attributed to the age-related changes of the crystalline lens and CRC. In spite of these differences, mice appear to be able to achieve and maintain emmetropic refractive status at P32 to P40.
Project description:Introduction:Even though ocular refractive state is highly heritable and under strong genetic control, the identification of susceptibility genes remains a challenge. Several HGF (hepatocyte growth factor) gene variants have been associated with ocular refractive errors and corneal pathology. Purpose:Here, we assess the association of an HGF gene variant, previously reported as associated with hyperopia, and ocular biometric parameters in a multicenter Spanish cohort. Methods:An observational prospective multicenter cross-sectional study was designed, including a total of 403 unrelated subjects comprising 188 hyperopic children (5 to 17?years) and 2 control groups: 52 emmetropic adolescents (13 to 17?years) and 163 emmetropic young adults (18 to 28?years). Each individual underwent a comprehensive eye examination including cycloplegic refraction, and topographic and ocular biometric analysis. Genomic DNA was extracted from oral swabs. HGF single nucleotide polymorphism (SNP) rs12536657 was genotyped. Genotypic, allelic, and logistic regression analyses were performed comparing the different groups. A quantitative trait association test analyzing several biometric parameters was also performed using generalized estimating equations (GEEs) adjusting for age and gender. Results:No association between rs12536657 and hyperopia was found through gender-adjusted logistic regression comparing the hyperopic children with either of the two control groups. Significant associations between mean topographic corneal curvature and rs12536657 for G/A (slope?=?+0.32; CI 95%: 0.04-0.60; p=0.023) and A/A (slope?=?+0.76; CI 95%: 0.12-1.40; p=0.020) genotypes were observed with the age- and gender-adjusted univariate GEE model. Both flat and steep corneal topographic meridians were also significantly associated with rs12536657 for the G/A and A/A genotypes. No association was found between rs12536657 and any other topographic or biometric measurements. Conclusions:Our results support a possible role for HGF gene variant rs12536657 in corneal curvature in our population. To our knowledge, this is the first multicenter quantitative trait association study of HGF genotypes and ocular biometric parameters comprising a pediatric cohort.
Project description:Corneal curvature, a highly heritable trait, is a key clinical endophenotype for myopia - a major cause of visual impairment and blindness in the world. Here we present a trans-ethnic meta-analysis of corneal curvature GWAS in 44,042 individuals of Caucasian and Asian with replication in 88,218 UK Biobank data. We identified 47 loci (of which 26 are novel), with population-specific signals as well as shared signals across ethnicities. Some identified variants showed precise scaling in corneal curvature and eye elongation (i.e. axial length) to maintain eyes in emmetropia (i.e. HDAC11/FBLN2 rs2630445, RBP3 rs11204213); others exhibited association with myopia with little pleiotropic effects on eye elongation. Implicated genes are involved in extracellular matrix organization, developmental process for body and eye, connective tissue cartilage and glycosylation protein activities. Our study provides insights into population-specific novel genes for corneal curvature, and their pleiotropic effect in regulating eye size or conferring susceptibility to myopia.
Project description:Refractive errors, myopia, and hyperopia are common visual disorders greatly affecting older individuals. Refraction is determined by genetic factors but only a small percentage of its variation has been explained. We performed a genetic association analysis with three ocular phenotypes: spherical equivalent (a continous measure of refraction), axial length, and corneal curvature in 1,871 European-Americans from the Beaver Dam Eye Study. Individuals were genotyped on the Illumina exome array and imputed to the Haplotype Reference Consortium reference panel. After increasing the number of analyzed variants in targeted protein-coding regions 10-fold via imputation, we confirmed associations for two previously known loci with corneal curvature (chr4q12, rs2114039; g.55092626T > C, ? = -0.03 (95% confidence interval [CI]): -0.06, -0.01, P value = 0.01) and spherical equivalent (chr15q14, rs634990; g.35006073T > C, ? = -0.27, 95% CI: -0.45, -0.09, P value = 3.79 × 10-3 ). Despite increased single nucleotide polymorphism (SNP) density, we did not detect any novel significant variants after correction for multiple comparisons. In summary, we confirmed two previous loci associated with corneal curvature and spherical equivalent in a European-American population highlighting the potential biological role of those regions in these traits.
Project description:<h4>Purpose</h4>Ocular biometry varies within groups of emmetropic, hyperopic or myopic children. The aim of this study was to quantify the effect of foetal and infant growth on ocular biometry in early childhood, to determine the most important period for this association, and to examine genetic overlap with height and birth weight.<h4>Methods</h4>5931 children (50.1% girls) from a population-based prospective birth cohort study underwent intra-uterine and infant growth measurements at second and third trimester, and from birth to 72 months. An ophthalmic examination including axial length (mm) and corneal radius of curvature (mm) was performed at 6 years of age. The associations between prenatal and postnatal growth variables and axial length and corneal radius of curvature were assessed with conditional linear regression analyses. Weighted genetic risk scores for birth weight and height were calculated and causality was tested with Mendelian randomisation.<h4>Results</h4>Weight and length from mid-pregnancy to 2 years of age were most important prognostic factors for axial length and corneal radius of curvature at age 4.9-9 years (mean 6.2 years S.D. 0.5). For height (Standard deviation score), the association with axial length and corneal radius of curvature was highest for the measurement at 12 months (? 0.171 p < 0.001 and 0.070 p < 0.001). The genetic height and birth weight risk scores were both significantly associated with ocular biometry.<h4>Conclusions</h4>Larger neonates had longer axial length and greater corneal radius of curvature. Growth during pregnancy and 2 years postnatally is the most important period underlying this association and may be partly genetically determined by genes associated with height.
Project description:PURPOSE: The purpose of this study was to determine if genetic variants in the hepatocyte growth factor receptor (MET) gene are associated with refractive error and ocular biometric measures in a Caucasian cohort. METHODS: A case-control association study using 818 Caucasian adults (37.2% male, 62.8% female; average age: 51.21+/-17.17 years) was undertaken. All individuals were genotyped for 16 tag single nucleotide polymorphisms (tSNPs) across the MET gene region. Myopia was defined as -0.5 DS or worse in both eyes and divided into high myopia (<or=-6.0 DS) and low/moderate myopia (-0.5 DS to -5.99 DS). Hypermetropia was defined as at least +1.0 DS in both eyes. Genotyping results were analyzed using PLINK, comparing cases (all myopia, high myopia, low/moderate myopia, and hypermetropia) to controls (emmetropia). Association tests were also performed using the quantitative traits of refraction, axial length, anterior chamber depth, and corneal curvature. RESULTS: No statistically significant genetic associations were detected for any of the 16 tSNPs with refractive error (myopia and hypermetropia) or ocular biometric measures. CONCLUSIONS: These data indicate there is likely no genetic association of the MET gene with myopia, axial length, anterior chamber depth, and corneal curvature in this cohort.
Project description:Spectral composition affects emmetropization in both humans and animal models. Because color vision interacts the effects of chromatic defocus, we developed a method to bypass the effects of longitudinal chromatic aberration by placing a spectral filter behind the optics of the eye, using genetic tools. Newborn C57BL/6J (B6) mice were reared in quasi-monochromatic red (410-510 nm) or blue (585-660 nm) light beginning before eye-opening. Refractive states and ocular dimensions were compared at 4, 6, 8, and 10 weeks with mice reared in normal white light. Cre recombinase-dependent Ai9 reporter mice were crossed with Chx10-Cre to obtain Chx10-Cre;Ai9 mice, expressing red fluorescent protein in retinal Cre-positive cells. Ai9 offsprings, with and without Cre, were reared under a normal visual environment. Refraction and axial components were measured as described above. Expression levels of M and S opsin were quantified by western blotting at 10 weeks. Compared with those reared in white light, B6 mice reared in red light developed relative hyperopia, principally characterized by flattening of corneal curvature. Emmetropization was not affected by blue light, possibly because the reduction in vitreous chamber depth compensated for the increase in corneal curvature. Compared with Cre-negative littermates, the refraction and axial dimensions of Chx10-Cre;Ai9 mice were not significantly different at the follow-up timepoints. M opsin levels were higher in Chx10-Cre;Ai9 mice at 10 weeks while S opsin levels were not different. Red light induced a hyperopic shift in mouse refractive development. Emmetropization was not impacted in mice with perturbed color vision caused by intrinsic red-fluorescent protein, suggesting that color vision may not be necessary in mouse emmetropization when other mechanisms are present.