rs11160251 (SYNE3): Glaucoma Risk Locus

Key takeaways

• rs11160251 near SYNE3 (synaptic nuclear envelope protein 3) is among over 300 genetic loci linked to primary open-angle glaucoma (POAG), identified in studies covering up to 1.4 million participants across 6 ancestries.
• The ALT allele of this variant increases expression of both SYNE3 and its antisense RNA SYNE3-AS1 in cerebellar brain tissue, an unexpected finding for a locus primarily studied in the context of eye disease.
• Machine-learning analysis of nearly 66,000 UK Biobank fundus images found 93 novel glaucoma-related genomic regions that expert grading alone missed, with pathway data pointing to neuronal and synaptic biology.
• Some glaucoma genetic signals are ancestry-specific or sex-specific, and the studies contributing to this locus explicitly covered 6 ancestries to support broader discovery.

What the research says Multitrait genome-wide association analyses combining POAG with intraocular pressure (IOP, the fluid pressure inside the eye) and vertical cup-to-disc ratio (VCDR, a measure of optic nerve head excavation) substantially increased genetic discovery power, yielding 312 independent POAG loci in a multiancestry analysis (European discovery sample over 600,000; replication in more than 2.8 million 23andMe participants) with 240 surviving Bonferroni correction. A 15-biobank meta-analysis spanning 1,487,441 individuals across 6 ancestries identified 17 additional novel POAG loci, implicating vascular biology and cell proliferation pathways. Machine-learning-based VCDR phenotyping of 65,680 UK Biobank participants identified 299 genome-wide significant hits across 156 loci, including 93 novel regions absent from expert-labeled analyses, with pathway data pointing to neuronal and synaptic biology.

Reported associations

• Primary open-angle glaucoma (POAG): The SYNE3 region is among novel loci identified in large multi-ancestry POAG meta-analyses; the most diverse contributing study examined 1,487,441 individuals (26,848 cases) across 6 ancestries and identified 5 ancestry-specific signals among its 17 novel loci.
• Vertical cup-to-disc ratio (VCDR): A machine-learning GWAS of 65,680 UK Biobank fundus images found 299 genome-wide significant VCDR hits across 156 loci, 93 of them novel to that analysis; VCDR carries a genetic correlation of 0.50 with POAG, and pathway data highlighted neuronal and synaptic biology.
• Intraocular pressure (IOP): Incorporated as a multitrait endophenotype (genetic correlation with POAG = 0.71); its low genetic correlation with VCDR (0.22) means the two endophenotypes capture largely distinct genetic signals, together improving POAG discovery power.

Evidence quality The multitrait GWAS (Han et al., Nature genetics, 2023) combined a European-ancestry discovery sample of over 600,000 with replication in more than 2.8 million 23andMe participants, with 296 of 312 loci replicating at P < 0.05 and 240 surviving Bonferroni correction. The most ancestrally diverse POAG analysis (Lo Faro et al., Cell reports. Medicine, 2024) covered 6 ancestries across 15 biobanks (n = 1,487,441; 26,848 cases). Machine-learning VCDR phenotyping (Alipanahi et al., American journal of human genetics, 2021) replicated 62 of 65 established VCDR loci and added 93 novel hits, improving polygenic prediction in an independent cohort. The study excerpts provided do not report the specific p-value or effect size for rs11160251 individually, so precise variant-level evidence quality cannot be assessed from the available text alone.

Tissue-specific expression effects

• SYNE3-AS1: The ALT allele is associated with increased expression of SYNE3-AS1 (an antisense RNA at this locus) in brain cerebellum and brain cerebellar hemisphere tissue, with consistent upregulation across both cerebellar subregions. GTEx Portal
• SYNE3: The ALT allele is also associated with increased expression of SYNE3 in brain cerebellar hemisphere tissue, indicating the variant upregulates both the protein-coding gene and its antisense counterpart in the same brain region. GTEx Portal

Lifestyle considerations No lifestyle considerations on file for this variant.