Low-Pressure Glaucoma Risk and Your Genetics

Written by Scott Peeples, BS Biomedical Sciences · ExomeDNA Founder Reviewed by ExomeDNA Editorial Process Last reviewed: 2026-05-29

This page contains general information only. For personal health decisions, consult a qualified clinician.

Low-pressure glaucoma (also called normal-tension glaucoma) is a form of optic nerve disease in which vision-damaging nerve loss occurs despite intraocular pressure readings that fall within the normal range — a finding that has driven substantial genetic research into why some optic nerves are inherently more vulnerable. Heritability estimates for open-angle glaucoma broadly exceed 50%, and genome-wide studies have now identified over 127 associated loci.^[²] Below: how genetic variants contribute to optic nerve vulnerability independent of eye pressure, the key genes involved, and what current research suggests about monitoring and lifestyle factors.

What is low-pressure glaucoma?

Low-pressure glaucoma — formally classified under ICD-10 code H40.12 (low-tension glaucoma) and sometimes called normal-tension glaucoma (NTG) — is a subtype of open-angle glaucoma in which characteristic optic nerve cupping and visual field loss occur even though intraocular pressure (IOP) remains at or below the conventional threshold of 21 mmHg. It accounts for an estimated 30–40% of all open-angle glaucoma cases in Western populations, and a higher proportion among East Asian populations.

What distinguishes low-pressure glaucoma from other glaucoma subtypes is the pathophysiology. In the more common high-tension open-angle glaucoma, elevated IOP mechanically stresses the trabecular meshwork and the lamina cribrosa — the sieve-like connective tissue plate through which retinal ganglion cell (RGC) axons exit the eye. In low-pressure glaucoma, IOP is not elevated, yet the optic nerve still deteriorates. This distinction is clinically significant: standard IOP-lowering treatments help slow progression, but they do not fully prevent it, because the underlying nerve vulnerability extends beyond the pressure mechanism.

Several non-pressure mechanisms are thought to contribute. Inadequate blood flow to the optic nerve head — particularly during episodes of nocturnal hypotension — can deprive axons of oxygen and nutrients. A low cerebrospinal fluid (CSF) pressure relative to IOP creates a trans-lamina cribrosa pressure gradient that places mechanical stress on exiting axons. And intrinsic genetic factors affect how resilient retinal ganglion cells and their axons are to any of these stresses. It is this intrinsic vulnerability pathway that genetic testing illuminates.

The genetics behind low-pressure glaucoma

Genome-wide association studies (GWAS — studies that scan hundreds of thousands of genetic variants across the genome) have identified several loci where common variants are over-represented among people with glaucoma that occurs without elevated IOP. Six genes from these studies are reflected in the ExomeDNA low-pressure glaucoma score: TMCO1, ZFPM2, ABCA1, FLNB, GMDS, and TMEM263.

TMCO1 (transmembrane and coiled-coil domains protein 1) is one of the most consistently replicated genes across open-angle glaucoma GWAS signals.^[¹] TMCO1 encodes a calcium channel and regulatory protein in the endoplasmic reticulum that prevents calcium overload inside cells. It is expressed in the trabecular meshwork and ciliary epithelium — both tissues involved in aqueous humor production and drainage — and also in optic nerve head tissue. In low-pressure glaucoma specifically, TMCO1 variants may compromise calcium homeostasis in retinal ganglion cell axons, making those axons less able to survive metabolic or vascular stress at normal IOP.

ZFPM2 (zinc finger protein multitype 2, also known as FOG2) is a transcriptional co-regulator that works alongside GATA family transcription factors to control the development and long-term survival of retinal ganglion cells. GATA factors are expressed in RGCs and in the developing optic nerve, where they influence axon myelination and neuronal resilience. Variants near ZFPM2 have been associated with glaucoma risk, and the mechanism is thought to operate through reduced RGC survival capacity — meaning the optic nerve becomes susceptible to damage even at pressures that a typical eye would tolerate without harm.^[²]

ABCA1 encodes a cholesterol efflux transporter expressed in the trabecular meshwork and optic nerve head. Lipid and cholesterol homeostasis in the optic nerve head influences the composition of myelin sheaths around RGC axons and the structural integrity of the lamina cribrosa. Disrupted ABCA1 function may impair axonal lipid balance in a way that is more consequential in the low-pressure glaucoma context than in pressure-driven forms, where mechanical stress is the dominant insult.

FLNB (filamin B) is an actin-binding cytoskeletal cross-linker. In the trabecular meshwork, FLNB shapes the mechanical properties of trabecular cells and affects how the meshwork responds to pressure fluctuations and fluid flow. FLNB is also relevant to the structural biomechanics of the optic nerve head — the cytoskeletal properties of astrocytes and laminar cells in that tissue determine how well axons are protected from deformation.

GMDS encodes GDP-mannose 4,6-dehydratase, an enzyme in the N-glycosylation pathway. Protein glycosylation is required for the correct folding and function of many extracellular matrix proteins and cell-surface receptors in the trabecular meshwork and optic nerve head. Abnormal GMDS function may impair the structural organization of the extracellular matrix that supports and protects optic nerve axons.

TMEM263 (transmembrane protein 263) is a less-characterized membrane protein; current evidence places it at the association level without a fully resolved molecular mechanism.

127 independent genetic loci for open-angle glaucoma — including signals for low-pressure forms — were identified in a genome-wide meta-analysis across diverse ancestries, with consistent effect directions across populations.^[²]

What the research says

Research base: Moderate. The genetic architecture of low-pressure glaucoma has been substantially illuminated over the past decade, with large-scale GWAS providing reliable association signals. However, the precise functional mechanisms for several of the identified loci remain under active investigation, and effect sizes for individual common variants are modest.

Bailey et al. (2016) reported a GWAS of primary open-angle glaucoma identifying multiple susceptibility loci in a multi-ancestry analysis, with TMCO1 and several co-localized genes showing consistent signals across cohorts.^[¹] The study highlighted the genetic complexity of glaucoma and the existence of distinct biological pathways — including those not mediated through IOP — that contribute to optic nerve vulnerability.

Gharahkhani et al. (2021) conducted a genome-wide meta-analysis identifying 127 open-angle glaucoma loci, integrating GWAS data across ancestries to characterize the polygenic architecture of the disease.^[²] This work expanded understanding of the genetic contributors to glaucoma subtypes and confirmed that many loci operate through pathways involving optic nerve head biology, vascular regulation, and cell survival — mechanisms directly relevant to the low-pressure form of the disease.

127 genome-wide significant loci for open-angle glaucoma were mapped in the Gharahkhani et al. (2021) meta-analysis, representing the largest genetic study of this condition to date and encompassing signals relevant to both high- and low-pressure forms.^[²]

An important clinical nuance supported by genetic evidence: IOP-lowering treatment reduces progression even in people whose IOP is already in the normal range. The likely explanation is that lowering IOP from, say, 15 mmHg to 12 mmHg reduces mechanical stress on the lamina cribrosa, which benefits optic nerve axons regardless of the primary cause of their vulnerability. Genetics helps identify who is at heightened risk before damage accumulates — enabling earlier and more targeted monitoring.

How low-pressure glaucoma affects you

Glaucoma damage is irreversible — once retinal ganglion cells and their axons are lost, vision cannot be restored. Low-pressure glaucoma is particularly insidious because the absence of elevated eye pressure means it is less likely to trigger investigation unless other risk factors prompt comprehensive evaluation. Peripheral visual field loss typically begins before central vision is affected, and many people are unaware of early defects until the disease is moderately advanced.

The functional consequences follow the anatomy of retinal ganglion cell loss. Early damage typically produces arcuate scotomas — arc-shaped blind spots that follow the pattern of RGC axon bundles entering the optic nerve. As the disease advances, these scotomas can coalesce and encroach on central vision, though central vision loss is a late feature. For people in occupations requiring full visual field — driving, certain professions, sports — even moderate field loss can be functionally significant.

Family history is one of the strongest non-genetic risk factors, reflecting the high heritability of the condition. People with a first-degree relative with any form of glaucoma, especially normal-tension glaucoma, have meaningfully higher lifetime risk. Ethnicity also plays a role: normal-tension glaucoma represents a larger fraction of glaucoma cases among people of East Asian ancestry compared to European ancestry, a pattern that may partly reflect genetic architecture differences across populations.

Vascular and systemic factors interact with genetic susceptibility. Nocturnal hypotension — a drop in blood pressure during sleep, sometimes caused by over-aggressive antihypertensive medication — is associated with optic nerve damage in normal-tension glaucoma. Obstructive sleep apnea (OSA) produces repeated episodes of nocturnal hypoxia that may similarly stress optic nerve axons. Migraine with aura has also been associated with NTG risk, possibly through vascular dysregulation mechanisms.

Working with your low-pressure glaucoma result

A higher genetic score for this trait indicates that the genetic variants in your profile are collectively over-represented among people in whom glaucoma has occurred at normal IOP levels, relative to the population baseline. This does not indicate the presence or future development of glaucoma. The score is one input into a broader picture of eye health, family history, and clinical examination findings.

Steps that eye care professionals and research evidence support for people monitoring their optic nerve health:

1. Schedule comprehensive eye exams including optic nerve assessment. Standard refractive exams do not include optic nerve evaluation. A comprehensive dilated exam with optic nerve photography and optical coherence tomography (OCT) of the retinal nerve fiber layer provides a baseline and enables longitudinal tracking of any change.
2. Request automated visual field testing if monitoring. Humphrey visual field testing detects functional loss that structural imaging may not yet capture. For people with elevated risk or a family history of NTG, periodic visual field testing is part of standard glaucoma surveillance.
3. Discuss blood pressure management with your physician. If you take antihypertensive medications, discuss whether the timing of doses — particularly avoiding large nocturnal blood pressure dips — is appropriate. Systemic hypotension at night is associated with optic nerve damage in NTG.
4. Evaluate for obstructive sleep apnea. OSA is associated with normal-tension glaucoma through nocturnal hypoxia. Those with symptoms of OSA (snoring, unrefreshing sleep, daytime fatigue) may benefit from evaluation and treatment relevant to optic nerve health in addition to cardiovascular health.
5. Monitor IOP even when it is in the normal range. IOP fluctuation over time and across times of day can be informative. Even modest IOP lowering — within the normal range — has been shown to slow optic nerve progression in NTG, so establishing a personal IOP baseline matters.
6. Know your family history in detail. First-degree relatives of someone with normal-tension glaucoma should discuss proactive screening with their eye care provider, particularly from midlife onward.

Related traits and genes

Low-pressure glaucoma shares genetic architecture with other forms of open-angle glaucoma but is mechanistically distinct from angle-closure glaucoma and from ocular hypertension without optic nerve damage. Understanding the overlap and differences helps contextualize this result.

TMCO1 is implicated across multiple glaucoma subtypes, reflecting its broad role in calcium homeostasis in ocular tissues. People interested in understanding the broader open-angle glaucoma genetic picture may find the open-angle glaucoma risk trait page informative for the IOP-elevation pathway. The angle-closure glaucoma risk page covers the structurally distinct form driven by anatomical angle blockage — a different mechanism from either open-angle form.

Retinal ganglion cell health connects this trait to broader retinal and optic nerve biology. The age-related macular degeneration risk page covers a related retinal condition with overlapping lifestyle risk factors, and the myopia (nearsightedness) genetics page is relevant because high myopia is an established risk factor for open-angle glaucoma, including the normal-tension form.

For the vascular mechanism, the blood pressure genetics and sleep apnea risk pages cover traits whose interplay with optic nerve health is directly relevant to normal-tension glaucoma management.

Frequently asked questions

Why does glaucoma happen when eye pressure is normal? In low-pressure glaucoma, the optic nerve is more vulnerable than typical to whatever level of pressure it experiences, to vascular insufficiency, or to a pressure gradient across the back of the eye driven by cerebrospinal fluid dynamics. Genetic factors — including variants near ZFPM2, TMCO1, and ABCA1 — appear to reduce the inherent resilience of retinal ganglion cells and their axons, making them more susceptible to damage without requiring elevated IOP as the triggering mechanism.

Does a higher score on this trait mean I should see an eye doctor immediately? A higher polygenic score reflects a pattern of variants over-represented in people who have developed this condition — it is not a clinical finding on its own. It is reasonable context to share with your eye care provider, particularly for individuals with a family history of glaucoma or other risk factors, so they can decide whether proactive baseline optic nerve imaging is appropriate.

Can lifestyle changes reduce glaucoma risk if I have a higher genetic score? Genetics sets a background level of vulnerability, but several modifiable factors influence how that vulnerability manifests. Avoiding nocturnal blood pressure drops, treating obstructive sleep apnea, and maintaining regular comprehensive eye exams all represent evidence-supported approaches to protecting optic nerve health. IOP-lowering eye drops can be used preventively in people identified as high risk, even when IOP is normal.

Is low-pressure glaucoma inherited? Glaucoma broadly has high heritability — twin and family studies consistently place it above 50%. Low-pressure glaucoma specifically shows familial clustering, and first-degree relatives of someone with normal-tension glaucoma have an elevated lifetime risk of developing some form of glaucoma. Genetic testing identifies polygenic background risk, while rare high-impact variants in specific genes can confer stronger familial forms.

What is the difference between this result and the open-angle glaucoma result? The open-angle glaucoma result reflects genetic variants associated with the high-IOP-driven pathway, primarily through trabecular meshwork obstruction reducing aqueous humor outflow. The low-pressure glaucoma result focuses on variants associated with optic nerve damage occurring without IOP elevation — a distinct biological pathway emphasizing optic nerve vulnerability, vascular factors, and RGC survival rather than pressure dynamics. Some genes appear in both, but the weightings and mechanisms differ.

How accurate is the genetic score for this trait? Common variant polygenic scores for low-pressure glaucoma capture a meaningful portion of genetic background risk — research supports their association at the population level — but individual scores have substantial uncertainty. Most people who develop this condition do not carry a markedly elevated polygenic score, and most people with elevated scores will not develop it. The score is best understood as a probabilistic signal, not a deterministic prediction.

References

1. Bailey JN, et al. Genome-wide association analysis identifies TXNRD2, ATXN2 and FOXC1 as susceptibility loci for primary open-angle glaucoma. Nature Genetics. 2016. PMID: 26752265.
2. Gharahkhani P, et al. Genome-wide meta-analysis identifies 127 open-angle glaucoma loci with consistent effect across ancestries. Nature Communications. 2021. PMID: 33627673.

Data sources:

• GWAS Catalog (NHGRI-EBI, accessed 2026-05-29)
• Open Targets Platform (CC0 1.0, accessed 2026-05-29)
• ClinVar (NCBI, accessed 2026-05-29) — entries at 2-star review status or above
• ClinGen Gene-Disease Validity (CC0 1.0, accessed 2026-05-29)

ExomeDNA genetic results are for wellness and educational purposes only. Consult a clinician for personalized health guidance.