rs524952 — GJD2

Intergenic variant near GJD2 affecting myopia risk and axial eye growth through retinal gap junction signaling

Strong Risk Factor

Details

Gene: GJD2
Chromosome: 15
Risk allele: T
Consequence: Regulatory
Inheritance: Additive
Clinical: Risk Factor
Evidence: Strong
Chip coverage: v3 v4 v5

Population Frequency

36%

48%

16%

Ancestry Frequencies

african

45%

latino

42%

european

40%

south_asian

38%

east_asian

35%

External

SNPedia ClinVar dbSNP

GJD2 and the Genetic Architecture of Myopia

The rs524952 variant sits in a regulatory region near the GJD2 gene on chromosome 15q14, one of the first and most consistently replicated genetic associations with myopia¹¹ one of the first and most consistently replicated genetic associations with myopia
discovered in genome-wide association studies since 2010. GJD2 encodes connexin 36 (Cx36), a gap junction protein that forms channels between neuronal cells in the retina, enabling the exchange of ions and small molecules critical for visual signal transmission²² retina, enabling the exchange of ions and small molecules critical for visual signal transmission
Gap junctions are essential for coordinating electrical activity in retinal circuits. While rs524952 itself lies outside the coding region of GJD2, it appears to influence gene expression levels, affecting how efficiently retinal neurons communicate during the critical period of eye development.

The Mechanism

Gap junctions formed by connexin 36 are particularly abundant in the inner retina, connecting amacrine cells, bipolar cells, and ganglion cells³³ inner retina, connecting amacrine cells, bipolar cells, and ganglion cells
These connexins enable synchronized electrical activity across retinal circuits. Animal studies have demonstrated that disruption of connexin 36 function leads to defects in the ON pathway of rod signaling, and mice with defective ON pathways develop myopia⁴⁴ defects in the ON pathway of rod signaling, and mice with defective ON pathways develop myopia
The ON pathway processes light increments and is critical for emmetropization—the process by which the eye grows to the correct length. The rs524952 T allele appears to alter GJD2 expression, potentially disrupting this finely tuned signaling system. In guinea pig myopia models, researchers found 31-38% decreased GJD2 mRNA and connexin 36 protein levels in myopic eyes compared to controls⁵⁵ 31-38% decreased GJD2 mRNA and connexin 36 protein levels in myopic eyes compared to controls
This suggests reduced gap junction function may permit excessive axial elongation.

The Evidence

The association between rs524952 and myopia has been replicated across multiple large studies and diverse populations. A 2013 meta-analysis of 45,758 individuals of European and Asian ancestry⁶⁶ 2013 meta-analysis of 45,758 individuals of European and Asian ancestry
Verhoeven et al., Human Genetics, 2013 found the T allele associated with more myopic refractive error (β = -0.158 diopters, P = 1.44 × 10⁻¹⁵). In Japanese populations, the T allele showed an odds ratio of 1.32 for high myopia⁷⁷ the T allele showed an odds ratio of 1.32 for high myopia
Hayashi et al., Investigative Ophthalmology & Visual Science, 2011. Importantly, this variant shows strong gene-environment interaction with education: in individuals with university education, each T allele conferred -0.31 diopters of myopia, while in those with lower education the effect was only -0.08 diopters⁸⁸ strong gene-environment interaction with education: in individuals with university education, each T allele conferred -0.31 diopters of myopia, while in those with lower education the effect was only -0.08 diopters
Fan et al., Human Molecular Genetics, 2014, suggesting that environmental factors like near work amplify the genetic risk.

Children carrying T alleles show progressive myopia development starting as early as age 6, with a clear dose-response pattern: those with two T alleles have the longest axial length, followed by one T allele, with AA individuals having the shortest eyes⁹⁹ progressive myopia development starting as early as age 6, with a clear dose-response pattern: those with two T alleles have the longest axial length, followed by one T allele, with AA individuals having the shortest eyes
Haarman et al., Investigative Ophthalmology & Visual Science, 2021. The GJD2 risk genotype appears to drive myopia primarily through enlarged vitreous depth, possibly compensated by subtle thinning of the cornea and lens¹⁰¹⁰ enlarged vitreous depth, possibly compensated by subtle thinning of the cornea and lens
Rotterdam Study phenotype analysis. A study of 1,057 Hong Kong children found rs524952 T allele carriers had significantly faster myopia progression over 3 years, with polygenic risk scores including this variant showing 2.26-fold increased risk of fast progression¹¹¹¹ study of 1,057 Hong Kong children found rs524952 T allele carriers had significantly faster myopia progression over 3 years, with polygenic risk scores including this variant showing 2.26-fold increased risk of fast progression
Chen et al., British Journal of Ophthalmology, 2021.

Practical Implications

For individuals carrying one or two T alleles, the primary concern is increased susceptibility to myopia, particularly when combined with high educational demands or intensive near work. Myopia itself is more than a simple inconvenience requiring glasses—it increases lifetime risk of sight-threatening complications including myopic macular degeneration, retinal detachment, glaucoma, and cataracts¹²¹² sight-threatening complications including myopic macular degeneration, retinal detachment, glaucoma, and cataracts
particularly concerning in high myopia (worse than -6 diopters). The gene-environment interaction suggests that lifestyle modifications during childhood may be particularly effective for genetic risk carriers.

For children with TT or AT genotypes, consider more frequent eye exams starting around age 6 to catch myopia early when interventions are most effective. Emerging evidence suggests that outdoor time may protect against myopia progression¹³¹³ outdoor time may protect against myopia progression
The protective effect may work through dopamine signaling pathways that also interact with gap junction function. Aim for at least 2 hours of outdoor time daily, especially during school-age years when the eye is actively growing. Myopia control interventions like specialized contact lenses (MiSight) or low-dose atropine eye drops can slow progression¹⁴¹⁴ specialized contact lenses (MiSight) or low-dose atropine eye drops can slow progression
though genetic variants may influence treatment response.

Interactions

rs524952 interacts with other myopia-associated variants to compound risk. Studies have examined interactions with rs7744813 (KCNQ5), rs13382811 (ZFHX1B), and rs634990 (another GJD2 variant in high linkage disequilibrium with rs524952). When rs524952 is combined with KCNQ5 and ZFHX1B variants, the combined polygenic risk score significantly predicts both myopia onset and progression rate in children, suggesting these variants work through partially overlapping pathways affecting eye growth regulation. The GJD2-RBFOX1-LAMA2 interaction specifically relates to how education levels modify genetic risk—all three loci show stronger myopia associations in highly educated individuals, possibly because extended near work creates an environment where reduced retinal signaling capacity becomes limiting.

Genotype Interpretations

What each possible genotype means for this variant:

AA “Standard Risk” Normal

Lower genetic susceptibility to myopia development

You carry two copies of the A allele at rs524952, which is associated with lower odds of developing myopia compared to T allele carriers. This is the ancestral allele and is relatively common across populations—about 36% of Europeans and 33% of East Asians share this genotype. While this genotype provides some genetic protection, it does not eliminate myopia risk entirely, as environmental factors like education level, near work, and time spent outdoors still play major roles. Studies show that even among AA individuals, university-level education is associated with some increase in myopic refractive error, though substantially less than in T allele carriers.

AT “Moderate Risk” Intermediate Caution

Moderately increased susceptibility to myopia with one risk allele

The heterozygous state appears to result in intermediate GJD2 expression levels, potentially reducing the efficiency of retinal gap junction signaling without completely disrupting it. Studies in children show that AT genotypes have about 50% increased odds of fast myopia progression compared to AA genotypes when exposed to high educational demands or intensive near work. The gene-environment interaction is particularly strong at this locus—your genetic predisposition becomes more relevant when combined with modern lifestyle factors.

TT “Higher Risk” High Risk Warning

Significantly increased susceptibility to myopia with two risk alleles

The TT genotype likely results in reduced GJD2 expression and lower connexin 36 levels in the retina, disrupting the gap junction-mediated signaling that normally regulates eye growth in response to visual input. Animal models suggest this may particularly affect the retinal ON pathway that processes light increments, leading to impaired emmetropization—the feedback mechanism that normally fine-tunes eye growth. In humans, the effect is strongly modulated by environment: the genetic risk is amplified by intensive near work, indoor environments, and high educational demands, while outdoor time and reduced near work appear partially protective. Polygenic risk scores that include rs524952 alongside other myopia variants show that TT carriers with additional risk alleles have 2-3 fold increased odds of fast myopia progression.