rs1150678 (ZNF603P): Myopia and Vision Genetics

Key takeaways

• Identified among 932 genome-wide-significant loci for refractive error in a cross-ancestry study of more than 1.76 million participants
• The alternate allele dramatically increases expression of the nearby ZNF603P gene across multiple brain regions, skeletal muscle, and heart tissue
• Polygenic predictors built from this locus and others explain 21.4% of refractive error variation and predict high myopia with an accuracy (AUC) of 0.806
• The functional consequence of altered ZNF603P expression - a pseudogene (a gene-like sequence not known to produce a working protein) - remains under investigation

What the research says A multi-ancestry genome-wide association study (GWAS) meta-analysis combining European (n = 1,495,159), East Asian (n = 121,172), and African (n = 144,737) ancestry cohorts identified 932 variants associated with refractive error (the family of common vision conditions including myopia, hypermetropia, and astigmatism), including 241 previously unreported associations, and the polygenic predictor constructed from these loci explained 21.4% of refractive error variation while achieving an area under the receiver operating characteristic curve (AUC, a measure of predictive accuracy from 0 to 1) of 0.806 for predicting high myopia. A separate Mendelian randomization study (a method that uses genetic variants as instruments to test causal relationships, reducing confounding) found that the causal effect of blood pressure on intraocular pressure (IOP, the fluid pressure inside the eye) was near-zero: +0.01 mm Hg per 10 mm Hg increase in systolic blood pressure (not statistically significant), with an odds ratio of 0.98 (95% CI 0.92-1.04) for primary open-angle glaucoma per 10 mm Hg increase in systolic blood pressure. GTEx tissue expression data show that the alternate allele at this locus is associated with strongly increased ZNF603P expression in multiple brain regions, skeletal muscle (slope +0.82, p = 3.1e-91), and heart left ventricle (slope +0.84, p = 2.1e-50), among other tissues GTEx Portal.

Reported associations

• Refractive error (myopia, hypermetropia, astigmatism): rs1150678 is among 932 genome-wide-significant loci identified in a cross-ancestry GWAS meta-analysis of more than 1.76 million participants across European, East Asian, and African ancestries, with 241 of the identified associations being previously unreported; gene prioritization analyses in the same study highlighted 23 genes involved in eye development
• High myopia prediction: the polygenic risk score constructed from this expanded catalog of refractive error loci explains 21.4% of refractive error phenotypic variation and achieves an AUC of 0.806 for predicting high myopia, with demonstrated ability to stratify individuals by myopia onset, progression, and severity
• Intraocular pressure and glaucoma (contextual): a Mendelian randomization analysis of the blood pressure-IOP relationship found that systolic blood pressure has a negligible causal effect on IOP (+0.01 mm Hg per 10 mm Hg increase in systolic BP, not statistically significant) and an odds ratio of 0.98 for primary open-angle glaucoma; this study noted that interpretation is complicated by the potential for blood-pressure-associated variants to affect IOP through independent biological pathways (pleiotropy, where a variant influences multiple traits)

Evidence quality The refractive error GWAS meta-analysis is among the largest genetics studies of any eye condition conducted to date, with more than 1.76 million participants across three ancestry groups, providing substantial statistical power for locus discovery. Statistical fine-mapping within this study identified 16 high-confidence putative causal variants; the provided text does not confirm whether rs1150678 is among these 16 fine-mapped variants, which limits certainty about its causal role. The cross-ancestry design strengthens the generalizability of findings beyond European populations. The Mendelian randomization study used a separate sample of 70,832 individuals for IOP measurement and applied multiple MR analytical methods to assess robustness, lending confidence to its near-null causal estimate for blood pressure on IOP. GTEx eQTL associations for ZNF603P at this locus are highly statistically significant across all listed tissues (p values ranging from 7.4e-36 in hypothalamus to 3.1e-91 in skeletal muscle), supporting a genuine and consistent regulatory effect of the alternate allele. Whether the mechanism linking this variant to refractive error runs through altered ZNF603P expression, nearby coding genes, or another pathway has not been established by the provided studies.

Tissue-specific expression effects

• ZNF603P: The alternate allele is associated with increased expression in multiple brain regions (cerebellum, cerebellar hemisphere, hypothalamus, caudate basal ganglia, and cortex), as well as in heart left ventricle, skeletal muscle, and tibial nerve; effects are broad and statistically robust across all listed tissues, with the strongest signal in skeletal muscle GTEx Portal

Lifestyle considerations No lifestyle considerations on file for this variant.