Nine Loci for Ocular Axial Length Identified through Genome-wide Association Studies, Including Shared Loci with Refractive Error

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.

Refraction data survey: 2nd generation correlation of myopia

“…These well-known inherited traits are frequently observed among the N = 34 families (data not reported here). Thus, it is not surprising that refraction is also correlated, in many instances [23,24,25]. In terms of observed myopia progression rates after college, Bullimore et al [26], N = 104 report that 36 % of myopes continue to progress at a rate of -0.75 D per 5-year interval (-1.5 D per decade) after college, consistent with our myopia rate results from Fig.…”

Identification of myopia-associated WNT7B polymorphisms provides insights into the mechanism underlying the development of myopia

“…This strategy provided a dense, high-quality data set and enabled us to find a novel susceptibility gene for corneal curvature and axial length. The novel susceptibility gene, WNT7B, had stronger effects on axial length (b ¼ 0.13) than the established susceptibility gene, GJD2 (b ¼ 0.09 in the current study and b ¼ 0.06-0.07 in a previous report 12 ).…”

“…Of these components, axial length plays a major role in refraction; therefore, in clinical settings, the degree of myopia is predominantly determined by axial length [8][9][10] . A recent large-scale, genome-wide meta-analysis by the Consortium for Refractive Error and Myopia (CREAM) reported that 23 of 29 loci associated with refraction were also associated with axial length 11,12 . However, genes associated with axial length are not necessarily associated with refractive error 12 .…”

“…A recent large-scale, genome-wide meta-analysis by the Consortium for Refractive Error and Myopia (CREAM) reported that 23 of 29 loci associated with refraction were also associated with axial length 11,12 . However, genes associated with axial length are not necessarily associated with refractive error 12 . This can be explained on the basis of the compensatory effects of other ocular biometric components, such as corneal curvature that influence the effect of an increased axial length through a flatter cornea 6 .…”

The genetic mechanisms of primary angle closure glaucoma

“…Nine genome-wide significant loci for axial length were identified including RSPO1, C3orf26, LAMA2, GJD2, ZNRF3, CD55, MIP, and ALPPL2 and ZC3H11B. 87 Variation in gene expression was observed for these loci in a minus-lens-induced myopia mouse model and human ocular tissues. Furthermore, RSPO1 and ZNRF3 have been previously described to influence Wnt signaling, a pathway implicated in the regulation of eyeball size.…”