rs12299724 (C12orf75/CASC18): Corneal Resistance Factor

Key takeaways

• rs12299724 is one of 135 loci associated with corneal resistance factor (CRF) in a genome-wide study of more than 76,000 UK Biobank participants.
• CRF measures the cornea's mechanical response to applied pressure, relevant to glaucoma pressure assessment and diseases such as keratoconus.
• 91% of fine-mapped causal variants at CRF loci are non-coding, suggesting they act through gene regulation rather than direct protein changes.
• CRF shares approximately 70% (SE = 5%) of its genetic architecture with central corneal thickness, reflecting shared biology in the corneal stroma.
• The alternate allele at this locus is associated with reduced expression of C12orf75/CASC18 in testis tissue.

What the research says A genome-wide association study (GWAS) in 76,029 UK Biobank participants identified 135 loci reaching genome-wide significance (p < 5 x 10^-8) for CRF, an empirical measure of the cornea's biomechanical response to applied pressure. Fine-mapping across these loci identified 55 highly likely causal variants, 91% of which are non-coding, and variants associated with CRF were significantly enriched in open chromatin regions of a corneal stroma-derived keratocyte cell line, with enrichment exceeding 5-fold for fine-mapped candidates. CRF and central corneal thickness (CCT) share approximately 70% (SE = 5%) of their genetic architecture, and 13 of the 135 loci overlap with previously reported keratoconus risk variants, reinforcing the biological link between corneal biomechanics and corneal disease.

Reported associations

• Corneal resistance factor (CRF): rs12299724, located near C12orf75 and CASC18 (chromosome 12), is among 135 genome-wide-significant CRF loci identified in 76,029 UK Biobank participants; a locus-specific effect size for this variant is not reported in the available study text.
• Genetic overlap with central corneal thickness: CRF loci as a class share approximately 70% (SE = 5%) of their genetic architecture with CCT, reflecting shared corneal stromal biology.
• Corneal disease overlap: 13 of the 135 CRF loci harbor known keratoconus risk variants; whether this locus is among those 13 is not stated in the available text.

Evidence quality The association was identified in a single GWAS of 76,029 white-British UK Biobank participants, with a genome-wide significance threshold of p < 5 x 10^-8. The test-statistic inflation factor (lambda_gc = 1.147) was attributed primarily to polygenicity rather than bias, consistent with an LDScore intercept of 1.057 (SE = 0.007). No locus-specific p-value or effect size for rs12299724 is reported in the available text. The study was conducted in a single ancestry group (white British), limiting generalizability to non-European populations, and replication in independent cohorts is not described.

Tissue-specific expression effects

• C12orf75/CASC18 (ENSG00000309761): The alternate allele is associated with reduced expression in testis tissue. GTEx Portal

Lifestyle considerations No lifestyle considerations on file for this variant.