Genome-wide association study for refractive astigmatism reveals genetic co-determination with spherical equivalent refractive error: the CREAM consortium

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.Electronic supplementary materialThe online version of this article (doi:10.1007/s00439-014-1500-y) contains supplementary material, which is available to authorized users.

Genome-wide association studies for corneal and refractive astigmatism in UK Biobank demonstrate a shared role for myopia susceptibility loci

“…Astigmatism has often been analysed as a dichotomous trait in genetic studies; however, the choice of the threshold used to define case/control status has varied from study to study (Fan et al 2011; Vitale et al 2008; Li et al 2015; Hammond et al 2001; Dirani et al 2010; Quek et al 2004; He et al 2004; Huynh et al 2007; Shah et al 2018). In an attempt to determine an optimal trait definition for detecting commonly occurring genetic markers with additive effects on astigmatism, we calculated SNP-heritability estimates with GCTA for corneal astigmatism and refractive astigmatism (and, for comparison, spherical equivalent) classified either as continuous or dichotomous traits, and using a grid of case thresholds for the latter (namely, 0.50, 0.75, 1.00, 1.25 and 1.50 D of astigmatism; or − 0.50, − 0.75, − 1.00, − 1.25 and − 1.50 D of spherical equivalent).…”

“…Genome-wide association studies (GWAS) for refractive astigmatism and corneal astigmatism have identified a single locus for each; in the promoter of PDGFRA (4q12) for corneal astigmatism (Fan et al 2011; Guggenheim et al 2013; Shah et al 2018) and near NRXN1 (2p16.3) for refractive astigmatism (Li et al 2015). Additional loci demonstrating suggestive association ( P  < 1 × 10 −5 ) for refractive astigmatism have been identified near the genes VAX2, TOX and LINC00340 (Li et al 2015; Lopes et al 2013).…”

“…Genome-wide association studies (GWAS) for refractive astigmatism and corneal astigmatism have identified a single locus for each; in the promoter of PDGFRA (4q12) for corneal astigmatism (Fan et al 2011; Guggenheim et al 2013; Shah et al 2018) and near NRXN1 (2p16.3) for refractive astigmatism (Li et al 2015). Additional loci demonstrating suggestive association ( P  < 1 × 10 −5 ) for refractive astigmatism have been identified near the genes VAX2, TOX and LINC00340 (Li et al 2015; Lopes et al 2013). In contrast, more than a hundred markers have shown genome-wide significant association ( P  < 5 × 10 −8 ) for the highly heritable refractive traits spherical equivalent and myopia in GWAS studies (Kiefer et al 2013; Pickrell et al 2016; Verhoeven et al 2013; Tedja et al 2018).…”

“…risk alleles with a minor allele frequency (MAF) < 1%, which are typically excluded from GWAS analyses, and fourthly, the causal markers may have extremely small effect sizes, thus rendering previous studies underpowered to detect associated markers because of their insufficient sample size. The largest study published to date was a GWAS meta-analysis for refractive astigmatism performed by Li et al (2015), which had a sample of 45,931 individuals, including 36,636 individuals of European ancestry and 9295 individuals of Asian ancestry.…”

The Influence of Light Exposure and Seasonal Changes on Short-Term and Longer-Term Changes in Axial Length of the Human Eye

“…A variety of different genes have been reported to be associated with myopia (Kiefer et al, 2013;Li et al, 2015a). Sibling risk ratio is high in myopia with the risk increasing with the severity of myopia (Guggenheim et al, 2000).…”