Genome-Wide Association of Genetic Variants With Refraction, Axial Length, and Corneal Curvature: A Longitudinal Study of Chinese Schoolchildren

Abstract

Background: Myopia is a common eye disorder that is approaching epidemic proportions worldwide. A genome-wide association study identified AREG (rs12511037), GABRR1 (rs13215566), and PDE10A (rs12206610) as being associated with refractive error in Asian populations. The present study investigated the associations between these three genetic variants and the occurrence and development of myopia, spherical equivalent refraction (SER), axial length (AL), and corneal curvature (CC) in a cohort of southeastern Chinese schoolchildren. Methods: We examined and followed 550 children in grade 1 enrolled in the Wenzhou Epidemiology of Refractive Error (WERE) project. During the 4-year follow-up, noncycloplegic refraction was evaluated twice each year, and the AL and CC were measured once every year. Age, sex, and the amounts of time spent on near work and outdoors were documented with a questionnaire. Sanger DNA sequencing was used to genotype single nucleotide polymorphisms (SNPs). SNPtest software was used to identify potential genetic variants associated with myopia, SER, AL, and CC. Ten thousand permutations were used to correct for multiple testing. Results: In total, 469 children, including 249 (53.1%) boys and 220 (46.9%) girls, were included in analyses. The mean age of all the children was 6.33 ± 0.48 years. After adjusting for age, sex, time spent on near work and time spent outdoors, neither the genotypes nor the allele frequencies of the three SNPs were significantly associated with myopic shift, incident myopia or the change in SER. After adjusting for age, sex, near-work time and outdoor time with 10,000 permutations, the genotype AREG (rs12511037) was associated with an increase in AL (P-values for the dominant, recessive, additive and general models were 0.0032, 0.0275, 0.0045, and 0.0099, respectively); the genotype PDE10A (rs12206610) was associated with a change in CC in the additive (P = 0.0096), dominant (P = 0.0096), and heterozygous models (P = 0.0096).

AREG is involved in scleral remodeling in form‐deprivation myopia via the ERK1/2‐MMP‐2 pathway

“…These results agreed with those in experimental myopia because the mRNA and protein expression of scleral AREG was increased with a prolonged covering time and decreased after the coverings were removed 13 . A genome‐wide association study found that the AREG SNP (rs12511037) was associated with increased AL, indicating that AREG is etiologically relevant for ocular traits 28 . Jonas et al found that the intraocular amount of EGF is higher in highly myopic eyes than in non‐highly myopic eyes, indicating a close association between the EGF family and myopia 29 .…”

“…13 A genome-wide association study found that the AREG SNP (rs12511037) was associated with increased AL, indicating that AREG is etiologically relevant for ocular traits. 28 Jonas et al found that the intraocular amount of EGF is higher in highly myopic eyes than in non-highly myopic eyes, indicating a close association between the EGF family and myopia. 29 In conclusion, measuring AREG in tears could serve as an important surrogate marker to probe myopia mechanisms.…”

Association of Myopia and Genetic Variants of TGFB2-AS1 and TGFBR1 in the TGF-β Signaling Pathway: A Longitudinal Study in Chinese School-Aged Children

“…Another study showed a 10.72 D shift toward myopia for every 1 unit of an increase in the AL/CRC ratio in Chinese schoolchildren aged 6–12 years ( He et al, 2015 ). Several genes were shown to be associated with AL and AL/CRC; however, previous studies did not report associations between TGFBR1 and AL or AL/CRC ( Cheng et al, 2013 ; Miyake et al, 2015 ; Li et al, 2020 ; Lin et al, 2020 ; Tang et al, 2020 ). Therefore, the present 3.5-year cohort study demonstrated that the TGFBR1 polymorphism was significantly associated with an increase in AL and AL/CRC.…”

Shedding light on myopia by studying complete congenital stationary night blindness

“…Several studies identified an association between GABRR1 and myopia (Supplementary Table S6 and Figure 8). A genome-wide association study identified GABRR1 as one of the genes associated with refractive error in Asian populations (Fan et al, 2016;Lin et al, 2020). TPMPA ((1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid)), a GABA-C antagonist has been shown to inhibit synaptic transmission in rat spinal cord (Rozzo et al, 1999), modulate sleep-waking behavior in rats (Arnaud et al, 2001), enhance memory in chicks (Gibbs and Johnston, 2005) and most importantly, inhibit myopia development in chicks and guinea pigs (Chebib et al, 2009;Cheng et al, 2014;Stone et al, 2003), indicating possible roles for GABA-C receptors in memory, circadian rhythms, and myopia (Cheng et al, 2011).…”