[Show abstract][Hide abstract] ABSTRACT: To identify genetic variants associated with refractive astigmatism in the general population, meta-analyses of genome-wide association studies were performed for: White Europeans aged at least 25 years (20 cohorts, N = 31,968); Asian subjects aged at least 25 years (7 cohorts, N = 9,295); White Europeans aged < 25 years (4 cohorts, N = 5,640); and all independent individuals from the above three samples combined with a sample of Chinese subjects aged < 25 years (N = 45,931). Participants were classified as cases with refractive astigmatism if the average cylinder power in their two eyes was at least 1.00 diopter and as controls otherwise. Genome-wide association analysis was carried out for each cohort separately using logistic regression. Meta-analysis was conducted using a fixed effects model. In the older European group the most strongly associated marker was downstream of the neurexin-1 (NRXN1) gene (rs1401327, P = 3.92E-8). No other region reached genome-wide significance, and association signals were lower for the younger European group and Asian group. In the meta-analysis of all cohorts, no marker reached genome-wide significance: The most strongly associated regions were, NRXN1 (rs1401327, P = 2.93E-07), TOX (rs7823467, P = 3.47E-07) and LINC00340 (rs12212674, P = 1.49E-06). For 34 markers identified in prior GWAS for spherical equivalent refractive error, the beta coefficients for genotype versus spherical equivalent, and genotype versus refractive astigmatism, were highly correlated (r = -0.59, P = 2.10E-04). This work revealed no consistent or strong genetic signals for refractive astigmatism; however, the TOX gene region previously identified in GWAS for spherical equivalent refractive error was the second most strongly associated region. Analysis of additional markers provided evidence supporting widespread genetic co-susceptibility for spherical and astigmatic refractive errors.
[Show abstract][Hide abstract] ABSTRACT: Severe myopia (defined as spherical equivalent < −6.0 D) is a predominant problem in Asian countries, resulting in substantial
morbidity. We performed a meta-analysis of four genome-wide association studies (GWAS), all of East Asian descent totaling
1603 cases and 3427 controls. Two single nucleotide polymorphisms (SNPs) (rs13382811 from ZFHX1B [encoding for ZEB2] and rs6469937 from SNTB1) showed highly suggestive evidence of association with disease (P < 1 × 10−7) and were brought forward for replication analysis in a further 1241 severe myopia cases and 3559 controls from a further
three independent sample collections. Significant evidence of replication was observed, and both SNP markers surpassed the
formal threshold for genome-wide significance upon meta-analysis of both discovery and replication stages (P = 5.79 × 10−10, per-allele odds ratio (OR) = 1.26 for rs13382811 and P = 2.01 × 10−9, per-allele OR = 0.79 for rs6469937). The observation at SNTB1 is confirmatory of a very recent GWAS on severe myopia. Both genes were expressed in the human retina, sclera, as well as
the retinal pigmented epithelium. In an experimental mouse model for myopia, we observed significant alterations to gene and
protein expression in the retina and sclera of the unilateral induced myopic eyes for Zfhx1b and Sntb1. These new data advance our understanding of the molecular pathogenesis of severe myopia.
Full-text · Article · Nov 2013 · Human Molecular Genetics
[Show abstract][Hide abstract] ABSTRACT: Refractive error is a complex ocular trait governed by both genetic and environmental factors and possibly their interplay.
Thus far, data on the interaction between genetic variants and environmental risk factors for refractive errors are largely
lacking. By using findings from recent genome-wide association studies, we investigated whether the main environmental factor,
education, modifies the effect of 40 single nucleotide polymorphisms on refractive error among 8461 adults from five studies
including ethnic Chinese, Malay and Indian residents of Singapore. Three genetic loci SHISA6-DNAH9, GJD2 and ZMAT4-SFRP1 exhibited a strong association with myopic refractive error in individuals with higher secondary or university education
(SHISA6-DNAH9: rs2969180 A allele, β = −0.33 D, P = 3.6 × 10–6; GJD2: rs524952 A allele, β = −0.31 D, P = 1.68 × 10−5; ZMAT4-SFRP1: rs2137277 A allele, β = −0.47 D, P = 1.68 × 10−4), whereas the association at these loci was non-significant or of borderline significance in those with lower secondary education
or below (P for interaction: 3.82 × 10−3–4.78 × 10−4). The evidence for interaction was strengthened when combining the genetic effects of these three loci (P for interaction = 4.40 × 10−8), and significant interactions with education were also observed for axial length and myopia. Our study shows that low level
of education may attenuate the effect of risk alleles on myopia. These findings further underline the role of gene–environment
interactions in the pathophysiology of myopia.
Full-text · Article · Sep 2013 · Human Molecular Genetics
[Show abstract][Hide abstract] ABSTRACT: Refractive errors are common eye disorders of public health importance worldwide. Ocular axial length (AL) is the major determinant of refraction and thus of myopia and hyperopia. We conducted a meta-analysis of genome-wide association studies for AL, combining 12,531 Europeans and 8,216 Asians. We identified eight genome-wide significant loci for AL (RSPO1, C3orf26, LAMA2, GJD2, ZNRF3, CD55, MIP, and ALPPL2) and confirmed one previously reported AL locus (ZC3H11B). Of the nine loci, five (LAMA2, GJD2, CD55, ALPPL2, and ZC3H11B) were associated with refraction in 18 independent cohorts (n = 23,591). Differential gene expression was observed for these loci in minus-lens-induced myopia mouse experiments and human ocular tissues. Two of the AL genes, RSPO1 and ZNRF3, are involved in Wnt signaling, a pathway playing a major role in the regulation of eyeball size. This study provides evidence of shared genes between AL and refraction, but importantly also suggests that these traits may have unique pathways.
Full-text · Article · Aug 2013 · The American Journal of Human Genetics
[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] ABSTRACT: Purpose:
To examine the extent to which the two major determinants of refractive error, corneal curvature and axial length, are scaled relative to one another by shared genetic variants, along with their relationship to the genetic scaling of height.
Corneal curvature, axial length, and height were measured in unrelated 14- to 17-year-old white European participants of the Avon Longitudinal Study of Parents and Children (ALSPAC; n = 1915) and in unrelated 40- to 80-year-old participants of the Singapore Chinese Eye Study (SCES; n = 1642). Univariate and bivariate heritability analyses were performed with methods that avoid confounding by common family environment, using information solely from genome-wide high-density genotypes.
IN ALSPAC SUBJECTS, AXIAL LENGTH, CORNEAL CURVATURE, AND HEIGHT HAD SIMILAR LOWER-BOUND HERITABILITY ESTIMATES: axial length, h(2) = 0.46 (SE = 0.16, P = 0.002); corneal curvature, h(2) = 0.42 (SE = 0.16, P = 0.004); height, h(2) = 0.48 (SE = 0.17, P = 0.002). The corresponding estimates in the SCES were 0.79 (SE = 0.18, P < 0.001), 0.35 (SE = 0.20, P = 0.036), and 0.31 (SE = 0.20, P = 0.061), respectively. The genetic correlation between corneal curvature and axial length was 0.69 (SE = 0.17, P = 0.019) for ALSPAC participants and 0.64 (SE = 0.22, P = 0.003) for SCES participants. In the subset of 1478 emmetropic ALSPAC individuals, the genetic correlation was 0.85 (SE = 0.12, P = 0.008).
These results imply that coordinated scaling of ocular component dimensions is largely achieved by hundreds to thousands of common genetic variants, each with a small pleiotropic effect. Furthermore, genome-wide association studies (GWAS) for either axial length or corneal curvature are likely to identify variants controlling overall eye size when using discovery cohorts dominated by emmetropes, but trait-specific variants in discovery cohorts dominated by ametropes.
No preview · Article · Feb 2013 · Investigative ophthalmology & visual science
[Show abstract][Hide abstract] ABSTRACT: Myopia is a complex genetic disorder and a common cause of visual impairment among working age adults. Genome-wide association studies have identified susceptibility loci on chromosomes 15q14 and 15q25 in Caucasian populations of European ancestry. Here, we present a confirmation and meta-analysis study in which we assessed whether these two loci are also associated with myopia in other populations. The study population comprised 31 cohorts from the Consortium of Refractive Error and Myopia (CREAM) representing 4 different continents with 55,177 individuals; 42,845 Caucasians and 12,332 Asians. We performed a meta-analysis of 14 single nucleotide polymorphisms (SNPs) on 15q14 and 5 SNPs on 15q25 using linear regression analysis with spherical equivalent as a quantitative outcome, adjusted for age and sex. We calculated the odds ratio (OR) of myopia versus hyperopia for carriers of the top-SNP alleles using a fixed effects meta-analysis. At locus 15q14, all SNPs were significantly replicated, with the lowest P value 3.87 × 10−12 for SNP rs634990 in Caucasians, and 9.65 × 10−4 for rs8032019 in Asians. The overall meta-analysis provided P value 9.20 × 10−23 for the top SNP rs634990. The risk of myopia versus hyperopia was OR 1.88 (95 % CI 1.64, 2.16, P < 0.001) for homozygous carriers of the risk allele at the top SNP rs634990, and OR 1.33 (95 % CI 1.19, 1.49, P < 0.001) for heterozygous carriers. SNPs at locus 15q25 did not replicate significantly (P value 5.81 × 10−2 for top SNP rs939661). We conclude that common variants at chromosome 15q14 influence susceptibility for myopia in Caucasian and Asian populations world-wide.
Electronic supplementary material
The online version of this article (doi:10.1007/s00439-012-1176-0) contains supplementary material, which is available to authorized users.
[Show abstract][Hide abstract] ABSTRACT: As one of the leading causes of visual impairment and blindness, myopia poses a significant public health burden in Asia. The primary determinant of myopia is an elongated ocular axial length (AL). Here we report a meta-analysis of three genome-wide association studies on AL conducted in 1,860 Chinese adults, 929 Chinese children, and 2,155 Malay adults. We identified a genetic locus on chromosome 1q41 harboring the zinc-finger 11B pseudogene ZC3H11B showing genome-wide significant association with AL variation (rs4373767, β = -0.16 mm per minor allele, P(meta) =2.69 × 10(-10)). The minor C allele of rs4373767 was also observed to significantly associate with decreased susceptibility to high myopia (per-allele odds ratio (OR) =0.75, 95% CI: 0.68-0.84, P(meta) =4.38 × 10(-7)) in 1,118 highly myopic cases and 5,433 controls. ZC3H11B and two neighboring genes SLC30A10 and LYPLAL1 were expressed in the human neural retina, retinal pigment epithelium, and sclera. In an experimental myopia mouse model, we observed significant alterations to gene and protein expression in the retina and sclera of the unilateral induced myopic eyes for the murine genes ZC3H11A, SLC30A10, and LYPLAL1. This supports the likely role of genetic variants at chromosome 1q41 in influencing AL variation and high myopia.
[Show abstract][Hide abstract] ABSTRACT: 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.