Dataset Information

Bidirectional Expression of Metabolic, Structural, and Immune Pathways in Early Myopia and Hyperopia.

ABSTRACT: Myopia (short-sightedness) affects 1.45 billion people worldwide, many of whom will develop sight-threatening secondary disorders. Myopic eyes are characterized by excessive size while hyperopic (long-sighted) eyes are typically small. The biological and genetic mechanisms underpinning the retina's local control of these growth patterns remain unclear. In the present study, we used RNA sequencing to examine gene expression in the retina/RPE/choroid across 3 days of optically-induced myopia and hyperopia induction in chick. Data were analyzed for differential expression of single genes, and Gene Set Enrichment Analysis (GSEA) was used to identify gene sets correlated with ocular axial length and refraction across lens groups. Like previous studies, we found few single genes that were differentially-expressed in a sign-of-defocus dependent manner (only BMP2 at 1 day). Using GSEA, however, we are the first to show that more subtle shifts in structural, metabolic, and immune pathway expression are correlated with the eye size and refractive changes induced by lens defocus. Our findings link gene expression with the morphological characteristics of refractive error, and suggest that physiological stress arising from metabolic and inflammatory pathway activation could increase the vulnerability of myopic eyes to secondary pathologies.

SUBMITTER: Riddell N

PROVIDER: S-EPMC5003873 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Bidirectional Expression of Metabolic, Structural, and Immune Pathways in Early Myopia and Hyperopia.

Riddell Nina N Giummarra Loretta L Hall Nathan E NE Crewther Sheila G SG

Frontiers in neuroscience 20160830

Myopia (short-sightedness) affects 1.45 billion people worldwide, many of whom will develop sight-threatening secondary disorders. Myopic eyes are characterized by excessive size while hyperopic (long-sighted) eyes are typically small. The biological and genetic mechanisms underpinning the retina's local control of these growth patterns remain unclear. In the present study, we used RNA sequencing to examine gene expression in the retina/RPE/choroid across 3 days of optically-induced myopia and h ...[more]

PMID: 27625591

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Project description:ImportanceUncertainty currently exists about whether the same genetic variants are associated with susceptibility to low myopia (LM) and high myopia (HM) and to myopia and hyperopia. Addressing this question is fundamental to understanding the genetics of refractive error and has clinical relevance for genotype-based prediction of children at risk for HM and for identification of new therapeutic targets.ObjectiveTo assess whether a common set of genetic variants are associated with susceptibility to HM, LM, and hyperopia.Design, setting, and participantsThis genetic association study assessed unrelated UK Biobank participants 40 to 69 years of age of European and Asian ancestry. Participants 40 to 69 years of age living in the United Kingdom were recruited from January 1, 2006, to October 31, 2010. Of the total sample of 502 682 participants, 117 279 (23.3%) underwent an ophthalmic assessment. Data analysis was performed from December 12, 2019, to June 23, 2020.ExposuresFour refractive error groups were defined: HM, -6.00 diopters (D) or less; LM, -3.00 to -1.00 D; hyperopia, +2.00 D or greater; and emmetropia, 0.00 to +1.00 D. Four genome-wide association study (GWAS) analyses were performed in participants of European ancestry: (1) HM vs emmetropia, (2) LM vs emmetropia, (3) hyperopia vs emmetropia, and (4) LM vs hyperopia. Polygenic risk scores were generated from GWAS summary statistics, yielding 4 sets of polygenic risk scores. Performance was assessed in independent replication samples of European and Asian ancestry.Main outcomes and measuresOdds ratios (ORs) of polygenic risk scores in replication samples.ResultsA total of 51 841 unrelated individuals of European ancestry and 2165 unrelated individuals of Asian ancestry were assigned to a specific refractive error group and included in our analyses. Polygenic risk scores derived from all 4 GWAS analyses were predictive of all categories of refractive error in both European and Asian replication samples. For example, the polygenic risk score derived from the HM vs emmetropia GWAS was predictive in the European sample of HM vs emmetropia (OR, 1.58; 95% CI, 1.41-1.77; P = 1.54 × 10-15) as well as LM vs emmetropia (OR, 1.15; 95% CI, 1.07-1.23; P = 8.14 × 10-5), hyperopia vs emmetropia (OR, 0.83; 95% CI, 0.77-0.89; P = 4.18 × 10-7), and LM vs hyperopia (OR, 1.45; 95% CI, 1.33-1.59; P = 1.43 × 10-16).Conclusions and relevanceGenetic risk variants were shared across HM, LM, and hyperopia and across European and Asian samples. Individuals with HM inherited a higher number of variants from among the same set of myopia-predisposing alleles and not different risk alleles compared with individuals with LM. These findings suggest that treatment interventions targeting common genetic risk variants associated with refractive error could be effective against both LM and HM.

Project description:Refractive error (RE) is a complex, multifactorial disorder characterized by a mismatch between the optical power of the eye and its axial length that causes object images to be focused off the retina. The two major subtypes of RE are myopia (nearsightedness) and hyperopia (farsightedness), which represent opposite ends of the distribution of the quantitative measure of spherical refraction. We performed a fixed effects meta-analysis of genome-wide association results of myopia and hyperopia from 9 studies of European-derived populations: AREDS, KORA, FES, OGP-Talana, MESA, RSI, RSII, RSIII and ERF. One genome-wide significant region was observed for myopia, corresponding to a previously identified myopia locus on 8q12 (p?=?1.25×10(-8)), which has been reported by Kiefer et al. as significantly associated with myopia age at onset and Verhoeven et al. as significantly associated to mean spherical-equivalent (MSE) refractive error. We observed two genome-wide significant associations with hyperopia. These regions overlapped with loci on 15q14 (minimum p value?=?9.11×10(-11)) and 8q12 (minimum p value 1.82×10(-11)) previously reported for MSE and myopia age at onset. We also used an intermarker linkage- disequilibrium-based method for calculating the effective number of tests in targeted regional replication analyses. We analyzed myopia (which represents the closest phenotype in our data to the one used by Kiefer et al.) and showed replication of 10 additional loci associated with myopia previously reported by Kiefer et al. This is the first replication of these loci using myopia as the trait under analysis. "Replication-level" association was also seen between hyperopia and 12 of Kiefer et al.'s published loci. For the loci that show evidence of association to both myopia and hyperopia, the estimated effect of the risk alleles were in opposite directions for the two traits. This suggests that these loci are important contributors to variation of refractive error across the distribution.

Project description:To compare early literacy of 4- and 5-year-old uncorrected hyperopic children with that of emmetropic children.Cross-sectional.Children attending preschool or kindergarten who had not previously worn refractive correction.Cycloplegic refraction was used to identify hyperopia (?3.0 to ?6.0 diopters [D] in most hyperopic meridian of at least 1 eye, astigmatism ?1.5 D, anisometropia ?1.0 D) or emmetropia (hyperopia ?1.0 D; astigmatism, anisometropia, and myopia <1.0 D). Threshold visual acuity (VA) and cover testing ruled out amblyopia or strabismus. Accommodative response, binocular near VA, and near stereoacuity were measured.Trained examiners administered the Test of Preschool Early Literacy (TOPEL), composed of Print Knowledge, Definitional Vocabulary, and Phonological Awareness subtests.A total of 492 children (244 hyperopes and 248 emmetropes) participated (mean age, 58 months; mean ± standard deviation of the most hyperopic meridian, +3.78±0.81 D in hyperopes and +0.51±0.48 D in emmetropes). After adjustment for age, race/ethnicity, and parent/caregiver's education, the mean difference between hyperopes and emmetropes was -4.3 (P = 0.01) for TOPEL overall, -2.4 (P = 0.007) for Print Knowledge, -1.6 (P = 0.07) for Definitional Vocabulary, and -0.3 (P = 0.39) for Phonological Awareness. Greater deficits in TOPEL scores were observed in hyperopic children with ?4.0 D than in emmetropes (-6.8, P = 0.01 for total score; -4.0, P = 0.003 for Print Knowledge). The largest deficits in TOPEL scores were observed in hyperopic children with binocular near VA of 20/40 or worse (-8.5, P = 0.002 for total score; -4.5, P = 0.001 for Print Knowledge; -3.1, P = 0.04 for Definitional Vocabulary) or near stereoacuity of 240 seconds of arc or worse (-8.6, P < 0.001 for total score; -5.3, P < 0.001 for Print Knowledge) compared with emmetropic children.Uncorrected hyperopia ?4.0 D or hyperopia ?3.0 to ?6.0 D associated with reduced binocular near VA (20/40 or worse) or reduced near stereoacuity (240 seconds of arc or worse) in 4- and 5-year-old children enrolled in preschool or kindergarten is associated with significantly worse performance on a test of early literacy.

Project description:The membrane-type frizzled-related protein (MFRP) gene is selectively expressed in the retinal pigment epithelium and ciliary body, and mutations of this gene cause nanophthalmos. The MFRP gene may not be essential for retinal function but has been hypothesized to play a role in ocular axial length regulation. The involvement of the MFRP gene in moderate to high hyperopic, isolated microphthalmic/anophthalmic, and high myopic patients was tested in two phases: a mutation screening/sequence variant discovery phase and a genetic association study phase.Eleven hyperopic, ten microphthalmic/anophthalmic, and seven non-syndromic high-grade myopic patients of varying ages and 11 control subjects participated in the mutation screening phase. Sixteen primer pairs were designed to amplify the 13 exons of the MFRP gene including intron/exon boundaries. Polymerase chain reactions were performed, and amplified products were sequenced using standard techniques. Normal and affected individual DNA sequences were compared alongside the known reference sequence (UCSC genome browser) for the MFRP gene. The genetic association study included 146 multiplex non-syndromic high-grade myopia families. Seventeen intragenic and flanking single nucleotide polymorphisms (SNPs) were chosen for the MFRP gene and genotyped in the large data set using the Taqman allelic discrimination assay. The family-based association Pedigree Disequilibrium Test (PDT) and GenoPDT were performed.The average spherical refractive error of the hyperopic patient cohort was +4.21 diopters (D; range +2.00 to +9.25 D) and of the myopic patient cohort was -12.36 D (range -8.25 to -14.50 D). A total of 16 SNPs were identified by direct sequencing. No significant association was determined between the 16 MFRP gene SNPs and the moderate to high hyperopia, microphthalmia/anophthalmia affection status, and high myopia. Family based association analysis did not reveal any association between the 17 SNPs genotyped in the larger family data set for any refractive error type.Sequence variants of the MFRP gene do not appear to be associated with either the less severe forms of hyperopia, extreme forms of limited eye growth and development, or high myopia. These results indicate that the MFRP gene may not play a role in regulating ocular axial length in these phenotypes.

Project description:PurposeTo investigate the prevalence of myopia in Chinese primary school students and their ocular biometrics including axial length (AL), corneal radius of curvature (CRC) and spherical equivalent refraction (SER). To analyze their association with potential myopia risk factors, such as body mass index (BMI), cram school, time of outdoor activity and electronic screen use.MethodsIn this cross-sectional study of 4500 primary school students from 5 schools, participants underwent refraction using non-cycloplegic autorefractor and visual acuity testing. A follow-up study in the same schools was conducted in 2022. Myopia was defined as SER ≤ -0.50 diopter (D) and uncorrected visual acuity (UCVA) < 0.00 logMAR (6/6). Logistic regression models were used to determine factors associated with myopia.ResultsAfter excluding 389 participants, the overall prevalence of myopia was 33.6%. The prevalence of high myopia was 0.6%. The prevalence of myopia in girls was significantly higher than that in boys (37.6% vs. 30.0%, p < 0.001). The height, weight and BMI were significantly associated with AL (r = 0.471, r = 0.440, r = 0.276, p < 0.001, respectively). AL/CRC ratio was more highly correlated with SER than AL alone. Regression analysis showed that AL/CRC and hyperopia reserve were associated with myopia onset in the subsequent year (F = 201.557, p < 0.001; F = 68.934, p < 0.001). The cut point of hyperopia reserve for myopia in the subsequent year for grade 1 students was + 0.31D. Age (p < 0.001), parental myopia (p = 0.001) and lack of outdoor activity between classes (p = 0.049) were independently associated with higher prevalence rates of myopia.ConclusionThe prevalence of myopia among Chinese schoolchildren is alarming high. Consistent with previous cross-sectional data, AL/CRC and hyperopia reserve could function as myopia detection indicators. The hyperopia reserve among children aged between 6 ~ 7 years was low. Healthcare providers need to raise parents' awareness of the importance of regular eye examination and proper optical correction.

Project description:To test the hypothesis that genes known to cause clinical syndromes featuring myopia also harbor polymorphisms contributing to nonsyndromic refractive errors.Clinical phenotypes and syndromes that have refractive errors as a recognized feature were identified using the Online Mendelian Inheritance in Man (OMIM) database. One hundred fifty-four unique causative genes were identified, of which 119 were specifically linked with myopia and 114 represented syndromic myopia (i.e., myopia and at least one other clinical feature). Myopia was the only refractive error listed for 98 genes and hyperopia and the only refractive error noted for 28 genes, with the remaining 28 genes linked to phenotypes with multiple forms of refractive error. Pathway analysis was carried out to find biological processes overrepresented within these sets of genes. Genetic variants located within 50 kb of the 119 myopia-related genes were evaluated for involvement in refractive error by analysis of summary statistics from genome-wide association studies (GWAS) conducted by the CREAM Consortium and 23andMe, using both single-marker and gene-based tests.Pathway analysis identified several biological processes already implicated in refractive error development through prior GWAS analyses and animal studies, including extracellular matrix remodeling, focal adhesion, and axon guidance, supporting the research hypothesis. Novel pathways also implicated in myopia development included mannosylation, glycosylation, lens development, gliogenesis, and Schwann cell differentiation. Hyperopia was found to be linked to a different pattern of biological processes, mostly related to organogenesis. Comparison with GWAS findings further confirmed that syndromic myopia genes were enriched for genetic variants that influence refractive errors in the general population. Gene-based analyses implicated 21 novel candidate myopia genes (ADAMTS18, ADAMTS2, ADAMTSL4, AGK, ALDH18A1, ASXL1, COL4A1, COL9A2, ERBB3, FBN1, GJA1, GNPTG, IFIH1, KIF11, LTBP2, OCA2, POLR3B, POMT1, PTPN11, TFAP2A, ZNF469).Common genetic variants within or nearby genes that cause syndromic myopia are enriched for variants that cause nonsyndromic, common myopia. Analysis of syndromic forms of refractive errors can provide new insights into the etiology of myopia and additional potential targets for therapeutic interventions.

Dataset Information

Bidirectional Expression of Metabolic, Structural, and Immune Pathways in Early Myopia and Hyperopia.

Publications

Bidirectional Expression of Metabolic, Structural, and Immune Pathways in Early Myopia and Hyperopia.

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