rs10957177 (NASPP1/CLVS1): Optic Disc Morphology
Key takeaways
- rs10957177 was identified as a genome-wide significant locus for optic disc shape in studies covering up to 95,000 people
- The variant is linked to vertical cup-to-disc ratio (VCDR), a key measurement used in glaucoma evaluation
- A companion study tied this locus to vertical optic disc diameter, with effects replicating in independent cohorts
- The alternate allele increases activity of a nearby gene in cerebellar brain tissue
- Both studies focused on Europeans, so findings may not apply equally to all populations
Key takeaways
- rs10957177 was identified as a genome-wide significant locus for optic disc shape in studies covering up to 95,000 people
- The variant is linked to vertical cup-to-disc ratio (VCDR), a key measurement used in glaucoma evaluation
- A companion study tied this locus to vertical optic disc diameter, with effects replicating in independent cohorts
- The alternate allele increases activity of a nearby gene in cerebellar brain tissue
- Both studies focused on Europeans, so findings may not apply equally to all populations
What the research says
A genome-wide association study (GWAS) using machine-learning-based predictions of vertical cup-to-disc ratio (VCDR, the relative size of the optic cup within the disc, a marker used in glaucoma diagnosis) identified rs10957177 among 299 genome-wide significant loci across 156 regions in 65,680 Europeans from the UK Biobank PMID 33909986. A separate GWAS of vertical optic disc diameter in 95,549 individuals identified this locus among 81 significant regions, noting overlap at multiple loci with VCDR, intraocular pressure, glaucoma, and myopia PMID 32246756. Gene expression quantitative trait locus (eQTL) data, which measure how a genetic variant affects nearby gene activity, indicate that the alternate allele at rs10957177 increases expression of ENSG00000254802 specifically in cerebellar brain tissue GTEx Portal.
Reported associations
- Vertical cup-to-disc ratio (VCDR): Identified as a genome-wide significant locus (p <= 5 x 10^-8) in an ML-assisted GWAS of 65,680 UK Biobank Europeans; VCDR is a diagnostic parameter for optic nerve head morphology used in glaucoma assessment PMID 33909986
- Vertical optic disc diameter: Identified among 81 genome-wide significant loci in a discovery sample of 67,040 UK Biobank participants; effect size estimates showed high concordance (r=0.90) with two replication cohorts (IGGC, n=22,504; EPIC-Norfolk, n=6,005), with 44 of 66 novel loci replicating at p < 0.05 and 19 surviving Bonferroni correction PMID 32246756
- Glaucoma and related ophthalmic traits (pleiotropic overlap): The optic disc diameter GWAS reported that some identified loci showed overlap with VCDR, intraocular pressure, glaucoma susceptibility, and myopia; the specific contribution of rs10957177 to each of these traits individually is not detailed in the available study excerpts PMID 32246756
Evidence quality
Both associations were detected at the standard genome-wide significance threshold (p <= 5 x 10^-8). The VCDR study validated its ML-based approach by replicating 62 of 65 previously known loci and identified 93 novel loci in 65,680 UK Biobank Europeans; pathway analyses at novel hits implicated neuronal and synaptic biology PMID 33909986. The optic disc diameter study used expert measurements across 95,549 individuals in a multi-cohort design; human ocular tissue gene expression analyses showed that most identified genes are enriched in optic nerve head tissue PMID 32246756. Both studies enrolled primarily European-ancestry participants, which limits generalizability. Specific per-variant effect sizes (odds ratios or beta coefficients) for rs10957177 are not reported in the available excerpts. No conflict between the two studies was identified; they measure related but distinct optic nerve head features.
Tissue-specific expression effects
- ENSG00000254802: Increased expression in brain cerebellar hemisphere (p=1.3e-11) and brain cerebellum (p=8.7e-8) in carriers of the alternate allele; this eQTL pattern indicates the variant influences activity of this nearby gene in cerebellar tissue, acting as a cis-regulatory signal (meaning it acts on a gene in the same chromosomal region rather than at a distant site) GTEx Portal
Lifestyle considerations
No lifestyle considerations on file for this variant.
Frequently asked questions
What is rs10957177 linked to?
rs10957177 is linked to vertical cup-to-disc ratio and vertical optic disc diameter, both measurements of optic nerve head shape used in glaucoma evaluation.
What are the NASPP1 and CLVS1 genes?
NASPP1 and CLVS1 are genes flanking rs10957177. Gene expression data from GTEx show that the alternate allele increases activity of a nearby gene specifically in cerebellar brain tissue.
Is rs10957177 associated with glaucoma?
The variant is primarily associated with glaucoma-related structural measurements rather than a glaucoma diagnosis directly. A large GWAS noted pleiotropic overlap at optic disc loci with glaucoma susceptibility, but the specific contribution of rs10957177 to glaucoma risk is not stated in the research.
How large were the genetic studies that found this variant?
One GWAS analyzed 65,680 UK Biobank Europeans, while a second combined 95,549 individuals across multiple cohorts including UK Biobank, the International Glaucoma Genetic Consortium, and EPIC-Norfolk.
What is vertical cup-to-disc ratio and why does it matter for glaucoma?
The vertical cup-to-disc ratio (VCDR) measures how large the central depression of the optic disc is relative to the full disc. It is a standard quantitative marker in optic nerve head assessment, with abnormal values associated with glaucoma screening and diagnosis.