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Refractive errors, in particular myopia, are a leading cause of morbidity and disability worldwide. Genetic investigation can improve understanding of the molecular mechanisms that underlie abnormal eye development and impaired vision. We conducted a meta-analysis of genome-wide association studies (GWAS) that involved 542,934 European participants and identified 336 novel genetic loci associated with refractive error. Collectively, all associated genetic variants explain 18.4% of heritability and improve the accuracy of myopia prediction (area under the curve (AUC) = 0.75). Our results suggest that refractive error is genetically heterogeneous, driven by genes that participate in the development of every anatomical component of the eye. In addition, our analyses suggest that genetic factors controlling circadian rhythm and pigmentation are also involved in the development of myopia and refractive error. These results may enable the prediction of refractive error and the development of personalized myopia prevention strategies in the future. Meta-analysis of genome-wide association studies of 542,934 individuals identifies 336 novel loci associated with refractive error and implicates eye development, circadian rhythm and pigmentation pathways in controlling myopia.

Refractive errors, including myopia, are the most frequent eye disorders worldwide and an increasingly common cause of blindness. This genome-wide association meta-analysis in 160,420 participants and replication in 95,505 participants increased the number of established independent signals from 37 to 161 and showed high genetic correlation between Europeans and Asians (>0.78). Expression experiments and comprehensive in silico analyses identified retinal cell physiology and light processing as prominent mechanisms, and also identified functional contributions to refractive-error development in all cell types of the neurosensory retina, retinal pigment epithelium, vascular endothelium and extracellular matrix. Newly identified genes implicate novel mechanisms such as rod-and-cone bipolar synaptic neurotransmission, anterior-segment morphology and angiogenesis. Thirty-one loci resided in or near regions transcribing small RNAs, thus suggesting a role for post-transcriptional regulation. Our results support the notion that refractive errors are caused by a light-dependent retina-to-sclera signaling cascade and delineate potential pathobiological molecular drivers. Transancestral GWAS meta-analysis in 160,420 individuals identifies 139 loci associated with refractive error, including myopia. Newly identified genes implicate pathways involved in eye growth and light signaling cascades.

Caroline Klaver and colleagues report a meta-analysis for refractive error and myopia, including 37,382 individuals from 27 European studies and 8,376 individuals from 5 Asian studies, as part of the Consortium for Refractive Error and Myopia (CREAM). Refractive error is the most common eye disorder worldwide and is a prominent cause of blindness. Myopia affects over 30% of Western populations and up to 80% of Asians. The CREAM consortium conducted genome-wide meta-analyses, including 37,382 individuals from 27 studies of European ancestry and 8,376 from 5 Asian cohorts. We identified 16 new loci for refractive error in individuals of European ancestry, of which 8 were shared with Asians. Combined analysis identified 8 additional associated loci. The new loci include candidate genes with functions in neurotransmission ( GRIA4 ), ion transport ( KCNQ5 ), retinoic acid metabolism ( RDH5 ), extracellular matrix remodeling ( LAMA2 and BMP2 ) and eye development ( SIX6 and PRSS56 ). We also confirmed previously reported associations with GJD2 and RASGRF1 . Risk score analysis using associated SNPs showed a tenfold increased risk of myopia for individuals carrying the highest genetic load. Our results, based on a large meta-analysis across independent multiancestry studies, considerably advance understanding of the mechanisms involved in refractive error and myopia.

Myopia, or nearsightedness, is the most common eye disorder, resulting primarily from excess elongation of the eye. The etiology of myopia, although known to be complex, is poorly understood. Here we report the largest ever genome-wide association study (45,771 participants) on myopia in Europeans. We performed a survival analysis on age of myopia onset and identified 22 significant associations ([Formula: see text]), two of which are replications of earlier associations with refractive error. Ten of the 20 novel associations identified replicate in a separate cohort of 8,323 participants who reported if they had developed myopia before age 10. These 22 associations in total explain 2.9% of the variance in myopia age of onset and point toward a number of different mechanisms behind the development of myopia. One association is in the gene PRSS56, which has previously been linked to abnormally small eyes; one is in a gene that forms part of the extracellular matrix (LAMA2); two are in or near genes involved in the regeneration of 11-cis-retinal (RGR and RDH5); two are near genes known to be involved in the growth and guidance of retinal ganglion cells (ZIC2, SFRP1); and five are in or near genes involved in neuronal signaling or development. These novel findings point toward multiple genetic factors involved in the development of myopia and suggest that complex interactions between extracellular matrix remodeling, neuronal development, and visual signals from the retina may underlie the development of myopia in humans.

Myopia is the most common human eye disorder and it results from complex genetic and environmental causes. The rapidly increasing prevalence of myopia poses a major public health challenge. Here, the CREAM consortium performs a joint meta-analysis to test single-nucleotide polymorphism (SNP) main effects and SNP × education interaction effects on refractive error in 40,036 adults from 25 studies of European ancestry and 10,315 adults from 9 studies of Asian ancestry. In European ancestry individuals, we identify six novel loci ( FAM150B-ACP1 , LINC00340 , FBN1 , DIS3L-MAP2K1 , ARID2-SNAT1 and SLC14A2 ) associated with refractive error. In Asian populations, three genome-wide significant loci AREG , GABRR1 and PDE10A also exhibit strong interactions with education ( P <8.5 × 10 −5 ), whereas the interactions are less evident in Europeans. The discovery of these loci represents an important advance in understanding how gene and environment interactions contribute to the heterogeneity of myopia. This report by the Consortium for Refractive Error and Myopia uses gene-environment-wide interaction study (GEWIS) to identify genetic loci that affect environmental influence in myopia development, and identifies ethnic specific genetic loci that attribute to eye refractive errors.

Myopia represents a refractive anomaly characterized by impaired vision resulting from a misfocused image in front of the fovea. Although numerous genes linked to high myopia (HM) have been identified, the exact etiology and pathogenesis mechanisms of HM remain predominantly obscure. In a prior investigation, a mutation in the P4HA2 gene was identified in association with HM. To illuminate the potential mechanisms of action of P4HA2 in HM, we established a P4HA2‐knockout mouse line (P4ha2−/−) and a P4HA2‐knockout HEK293 cell line for this study. P4ha2−/− mice exhibited compromised visual acuity and altered light transmission pathways as evidenced by multiple biometric assessments. Furthermore, we observed a time‐dependent disruption in the arrangement of collagen fibrils in the sclera and cornea of the P4ha2−/− mice, attributed to diminished thermal stability due to decreased collagen hydroxylation. Our findings also revealed elevated fibronectin levels and reduced Collagen I expression in the sclera and cornea of the P4ha2−/− mice, as well as in P4HA2‐knockout HEK293 cells, suggesting an imbalance in extracellular matrix (ECM) components that could further perturb light transmission pathways, which induced HM‐associated refractive error. In summary, P4HA2 contributes significantly to the pathogenesis and progressive deterioration of refractive error by accelerating collagen degeneration via reduced collagen hydroxylation.

Nanophthalmos is a rare, potentially devastating eye condition characterized by small eyes with relatively normal anatomy, a high hyperopic refractive error, and frequent association with angle closure glaucoma and vision loss. The condition constitutes the extreme of hyperopia or farsightedness, a common refractive error that is associated with strabismus and amblyopia in children. NNO1 was the first mapped nanophthalmos locus. We used combined pooled exome sequencing and strong linkage data in the large family used to map this locus to identify a canonical splice site alteration upstream of the last exon of the gene encoding myelin regulatory factor (MYRF c.3376-1G>A), a membrane bound transcription factor that undergoes autoproteolytic cleavage for nuclear localization. This variant produced a stable RNA transcript, leading to a frameshift mutation p.Gly1126Valfs*31 in the C-terminus of the protein. In addition, we identified an early truncating MYRF frameshift mutation, c.769dupC (p.S264QfsX74), in a patient with extreme axial hyperopia and syndromic features. Myrf conditional knockout mice (CKO) developed depigmentation of the retinal pigment epithelium (RPE) and retinal degeneration supporting a role of this gene in retinal and RPE development. Furthermore, we demonstrated the reduced expression of Tmem98, another known nanophthalmos gene, in Myrf CKO mice, and the physical interaction of MYRF with TMEM98. Our study establishes MYRF as a nanophthalmos gene and uncovers a new pathway for eye growth and development.

AimsTo investigate the associations of genetic variants previously linked to axial length (AL) and spherical equivalent refraction (SE) in adults with refractive error and related endophenotypes in children, at baseline and 3-year follow-up.Methods15 candidate single-nucleotide polymorphisms (SNPs), selected from previous Genome-Wide Association Studies and meta-analyses, were genotyped in 2819 Chinese children, who had undergone baseline and 3-year follow-up cycloplegic refraction, ocular biometry and ocular health examinations. Linear regression analyses were conducted to assess the associations of the SNPs with baseline measurements and longitudinal changes in SE, spherical power (SPH), AL, corneal radius of curvature (CR) and AL/CR ratio.ResultsSNPs ZMAT4 rs7829127, ZMAT4 rs16890057, TOX rs7837791, GRIA4 rs11601239 and RDH5 rs3138142 were associated with SE (β=0.233, p=4.21×10−4; β=0.221, p=7.87×10−4; β=0.106, p=0.0076; β=0.084, p=0.041; β=0.14, p=0.013, respectively) and SPH (β=0.24, p=2.3×10−4; β=0.232, p=3.8×10−4; β=0.088, p=0.025; β=0.086, p=0.034; β=0.14, p=0.012, respectively). Among them, ZMAT4 rs7829127 and rs16890057, were also associated with AL (β=−0.128, p=5.6×10−4; β=−0.128, p=5.21×10−4) and AL/CR ratio (β=−0.014, p=0.0028; β=−0.014, p=0.0034), whereas TOX rs7837791 was associated with AL (β=−0.062, p=0.0058) and GRIA4 11 601 239 with AL/CR ratio (β=−0.0058, p=0.049). Additionally, CD55 rs1652333 and RDH5 rs3138142 were associated with 3-year longitudinal changes in AL (β=0.062, p=0.018; β=−0.079, p=0.029) and CR (β=0.014, p=0.027; β=−0.018, p=0.035).ConclusionAmong SNPs previously associated with AL and SE in adults, variants in ZMAT4, TOX and GRIA4 were associated with AL, SE, SPH, and/or AL/CR ratio, while variants in RDH5 and CD55 showed associations with AL and CR changes in children.

This study investigated the differential gene expression of BMPs in chick retinal pigment epithelium (RPE) during recovery from short term exposure to optical defocus and form-deprivation (FD) treatments. 14-day old White-Leghorn chicks wore either monocular +10 or -10 D lenses, or diffusers for 2 or 48 h, after which eyes were allowed unobstructed vision for up to 96 h. Over this recovery period, refractive errors and choroidal thickness (ChT) were tracked using retinoscopy and high-frequency A-scan ultrasonography. Real-time PCR was used to examine the expression of BMP2, 4, and 7 genes in RPE samples collected 0, 15 min, 2, 24, 48, and 96 h after the termination of treatments. Expression levels in treated eyes and their contralateral control eyes were compared. After the termination of the lens and diffuser treatments, eyes gradually recovered from induced shifts in refractive error. With all three treatments, ChT changes reached statistical significance after 48 h of treatment, be it thinning with the -10 D lens and diffuser treatments (-0.06 ± 0.03mm, p < 0.05; -0.11 ± 0.04 mm, p < 0.05, resp.), or thickening with the +10 D lens (0.31 ± 0.04 mm, p < 0.001). BMP2 gene expression was rapidly upregulated in eyes wearing the +10 D lens, being statistical significance after 2 h, as well as 48 h of treatment. With the 2 h treatment, the latter gene expression pattern persisted for 15 min into the recovery period, before decreasing to the same level as that of contralateral control eyes, with a short-lived rebound, i.e., upregulation, 24 h into the recovery period. With the longer, 48 h treatment, BMP2 gene expression decreased more gradually, from 739 ± 121% at the end of the treatment period, to 72 ± 14% after 48 h of recovery. Two and 48 h of both -10 D and FD treatments resulted in BMP2 gene expression downregulation, with the time taken for gene expression levels to fully recover varying with the duration of initial treatments. In both cases, BMP2 gene expression downregulation persisted for 15 min into the recovery period, but reversed to upregulation by 2 h. Similar gene expression patterns were also observed for BMP4, although the changes were smaller. The observed changes in BMP gene expression in chick RPE imply dynamic, albeit complex regulation, with the duration of exposure and recovery being critical variables for all three types of visual manipulations. This study provides further evidence for a role of the RPE as an important signal relay linking the retina to the choroid and sclera in eye growth regulation.

Purpose The aim of this study is to investigate the distribution of spherical equivalent and axial length in the general population and to analyze the influence of education on spherical equivalent with a focus on ocular biometric parameters. Methods The Gutenberg Health Study is a population-based cohort study in Mainz, Germany. Participants underwent comprehensive ophthalmologic examinations as part of the 5-year follow-up examination in 2012–2017 including genotyping. The spherical equivalent and axial length distributions were modeled with gaussian mixture models. Regression analysis (on person-individual level) was performed to analyze associations between biometric parameters and educational factors. Mendelian randomization analysis explored the causal effect between spherical equivalent, axial length, and education. Additionally, effect mediation analysis examined the link between spherical equivalent and education. Results A total of 8532 study participants were included (median age: 57 years, 49% female). The distribution of spherical equivalent and axial length follows a bi-Gaussian function, partially explained by the length of education (i.e., < 11 years education vs. 11–20 years). Mendelian randomization indicated an effect of education on refractive error using a genetic risk score of education as an instrument variable (− 0.35 diopters per SD increase in the instrument, 95% CI, − 0.64–0.05, p  = 0.02) and an effect of education on axial length (0.63 mm per SD increase in the instrument, 95% CI, 0.22–1.04, p  = 0.003). Spherical equivalent, axial length and anterior chamber depth were associated with length of education in regression analyses. Mediation analysis revealed that the association between spherical equivalent and education is mainly driven (70%) by alteration in axial length. Conclusions The distribution of axial length and spherical equivalent is represented by subgroups of the population (bi-Gaussian). This distribution can be partially explained by length of education. The impact of education on spherical equivalent is mainly driven by alteration in axial length.