What Causes Glaucoma

Elevated Eye Pressure: The Main Driver of Glaucoma

Glaucoma often begins when aqueous humor (the eye’s clear fluid) builds up, raising intraocular pressure (IOP). Normally this fluid drains freely from the front of the eye through the trabecular meshwork and a secondary uveoscleral pathway. If these drainage channels become blocked or less efficient – due to age-related changes or other damage – fluid cannot exit fast enough and pressure rises (pmc.ncbi.nlm.nih.gov). This chronic pressure pushes on the optic nerve at the back of the eye. Over time, the nerve fibers (which carry vision to the brain) are compressed and die, leading to the classic “cupping” of glaucoma and blind spots. For example, mutations in the MYOC gene cause a misfolded protein in the trabecular meshwork that raises IOP (pmc.ncbi.nlm.nih.gov), directly illustrating how fluid outflow problems lead to glaucoma.

Normal-Tension Glaucoma: Beyond Pressure

Not all glaucoma patients have high eye pressure. In normal-tension glaucoma (NTG), IOP remains in the normal range, yet optic nerve damage still occurs. Research suggests reduced blood flow to the optic nerve plays a key role. Insufficient eye or brain blood supply (for instance from vascular disease, nocturnal low blood pressure or migraine) starves nerve fibers of oxygen (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). In support, studies show NTG patients often have signs of poor circulation or systemic blood pressure dips, making the optic nerve more vulnerable. Another theory is low cerebrospinal fluid (CSF) pressure around the optic nerve may increase the pressure difference across the nerve head, squeezing it even when eye pressure is “normal.” Indeed, NTG patients were found to have lower CSF pressure than healthy people (pmc.ncbi.nlm.nih.gov). In short, NTG likely involves a “bad blood flow/bad fluid environment” effect: optic nerve cells are inherently sensitive, and factors like low blood or CSF pressure, plus other insults, can injure them even without high IOP (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov).

Genetic Causes of Glaucoma

Family history is one of the strongest risks for glaucoma (pmc.ncbi.nlm.nih.gov). Specific gene mutations have been identified for different glaucoma types. For primary open-angle glaucoma (POAG), three genes stand out: MYOC, OPTN, and TBK1. MYOC (first discovered glaucoma gene) accounts for about 3–4% of typical open-angle cases with high IOP (pmc.ncbi.nlm.nih.gov). Mutant MYOC protein clogs the drainage meshwork, raising pressure (pmc.ncbi.nlm.nih.gov). The other genes, OPTN and TBK1, each cause roughly 1% of cases, usually in NTG (normal-pressure) patients (pmc.ncbi.nlm.nih.gov). These genes normally help cells clear waste and regulate survival, so when mutated they may impair cell housekeeping (autophagy) and trigger nerve-cell failure (pmc.ncbi.nlm.nih.gov).

For congenital glaucoma (seen in babies and young children), the CYP1B1 gene is a leading cause (pmc.ncbi.nlm.nih.gov). CYP1B1 is involved in eye development; recessive mutations disrupt the drainage system before birth, so pressure builds early (pmc.ncbi.nlm.nih.gov). Other genes tied to childhood glaucoma include FOXC1 and PITX2, which guide eye/front structure development – mutations in these (often in Axenfeld-Rieger syndrome) lead to abnormal angles and drainage block (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Rare TEK/ANGPT1 mutations (involved in forming fluid channels during development) also cause juvenile glaucoma (pmc.ncbi.nlm.nih.gov).

For angle-closure glaucoma, the genetics are more complex and less clear-cut. This form depends on eye shape (shallow front chamber) more than one gene. Some studies have found key variants affecting eye development or connective tissue (e.g. variants in MFRP, MMP9, HGF, NOS3, and HSPA1A/HSP70 have been linked with angle-closure in some populations) (pmc.ncbi.nlm.nih.gov). In practice, angle-closure often clusters in families due to inherited eye anatomy and race (see below).

Even when a specific gene isn’t found, having a parent or sibling with glaucoma vastly raises your own chance. For example, first-degree relatives of people with glaucoma had about a 22% lifetime risk, compared to 2–3% in people without a family history (pmc.ncbi.nlm.nih.gov). This shows how family factors (genes plus shared environment) are quantitatively strong risk factors.

Other Contributing Risk Factors

Age: Glaucoma risk climbs with age, especially after 40–50 years (pmc.ncbi.nlm.nih.gov).
Ethnicity: People of African descent face higher open-angle glaucoma rates, while East Asians and Inuit have much higher angle-closure risk (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). (For example, the incidence of angle-closure is disproportionately high in older Asian populations (pmc.ncbi.nlm.nih.gov).)
Refractive error: Long-sightedness (hyperopia) shortens the eye and hides the drainage angle (raising angle-closure risk), whereas severe nearsightedness (myopia) stretches the optic nerve fibers, increasing open-angle risk (pmc.ncbi.nlm.nih.gov).
Thin corneas: A thinner central cornea leads to underestimation of true IOP and seems associated with greater optic nerve vulnerability (pmc.ncbi.nlm.nih.gov).
Diabetes: People with diabetes may have slightly higher open-angle glaucoma risk – high blood sugar may sensitize nerve fibers to damage (pmc.ncbi.nlm.nih.gov). (Evidence is mixed, but some meta-analyses show higher glaucoma rates in diabetic patients.)
Chronic corticosteroid use: Steroid eye drops or systemic steroids often raise IOP, triggering secondary open-angle glaucoma (pmc.ncbi.nlm.nih.gov). Roughly one-third of individuals on steroids for uveitis or asthma can become steroid responders, with dangerous IOP spikes (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov).
Eye injury: Trauma can scar or tear the drainage angle (e.g. angle recession), leading to glaucoma months or years later (www.ncbi.nlm.nih.gov). Even blunt impact (from sports or accidents) carries a glaucoma risk, as precious outflow structures can be irreparably damaged (www.ncbi.nlm.nih.gov).
Inflammatory conditions: Chronic uveitis (inflammation of the iris or ciliary body) often causes raised IOP. Inflammatory cells and debris can clog the trabecular meshwork, and scarring can form sticky synechiae that seal off the angle (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Indeed, one review found about 20% of uveitis patients developed glaucoma (pmc.ncbi.nlm.nih.gov), and up to one-third of uveitic eyes gain pressure from steroid treatment (pmc.ncbi.nlm.nih.gov). Autoimmune diseases (sarcoidosis, juvenile arthritis, etc.) similarly increase glaucoma risk via chronic eye inflammation (pmc.ncbi.nlm.nih.gov).

Combining these risk factors helps doctors identify high-risk patients. For instance, an older person with a strong family glaucoma history, high blood pressure issues, and a thin cornea would be monitored very closely, even if current IOP seems borderline.

Brain and Body Links: Glaucoma as Neurodegeneration

New research suggests glaucoma is not just “high pressure,” but a complex neurodegenerative disease. Key findings include:

Oxidative stress: The retina and drainage tissues show evidence of reactive oxygen damage in glaucoma patients (pmc.ncbi.nlm.nih.gov). Excess free radicals (ROS) can injure retinal ganglion cells and even stiffen the trabecular meshwork (pmc.ncbi.nlm.nih.gov), adding to outflow resistance. Low antioxidant nutrients in the diet have been linked to higher glaucoma risk in population studies (pmc.ncbi.nlm.nih.gov).
Mitochondrial dysfunction: Nerve cells in the optic nerve are high-energy, so mitochondrial health is critical. Glaucoma patients’ RGCs often have damage-associated mitochondrial signals that trigger inflammation and cell death (pmc.ncbi.nlm.nih.gov). For example, defective mitophagy (cellular recycling of old mitochondria) due to OPTN or TBK1 mutations can directly damage RGCs (pmc.ncbi.nlm.nih.gov).
Neuroinflammation: Support cells in the retina (glia) become chronically activated in glaucoma, releasing cytokines and damaging agents that kill neurons (pmc.ncbi.nlm.nih.gov). Microglial and astrocyte activation is now seen as an early step in nerve damage rather than a by-product. In essence, a low-level autoimmune-like process may worsen optic nerve injury (pmc.ncbi.nlm.nih.gov).
Gut-Eye Immune Axis: Even distant systems may play a role. A 2024 study found that glaucoma patients have distinct gut microbiome changes that can prime the immune system to attack eye nerves (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Gut-derived T-cells may cross-react with retinal antigens (so-called “gut-retina axis”), suggesting gut health and immunity influence glaucoma development (pmc.ncbi.nlm.nih.gov).

In sum, scientists now view glaucoma as akin to diseases like Alzheimer’s – involving metabolic, immune and aging-related factors – not just a plumbing problem of the eye (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov).

Glaucoma Subtypes: Different Triggers for Different Eyes

Primary Open-Angle Glaucoma (POAG): The most common form. It has an open drainage angle however the trabecular meshwork works poorly. Causes include inherited TM problems (e.g. MYOC gene) and risk factors above. Black and Hispanic people and older adults are especially affected. POAG usually develops slowly with mild initial symptoms (pmc.ncbi.nlm.nih.gov).
Primary Angle-Closure Glaucoma (PACG): Here the iris is pushed or pulled against the drainage angle, suddenly blocking outflow. This can cause acute high-pressure attacks (eye pain, halos, vomiting) or chronic damage. Predisposing factors are anatomical: hyperopic (farsighted) eyes with short front-to-back length, thick lenses, or shallow anterior chambers. East Asian and Inuit populations have much higher PACG rates (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Genes affecting eye size and development (e.g. MFRP, COL11A1, CYP1B1 variants in nanophthalmos) have been implicated (pmc.ncbi.nlm.nih.gov), reflecting the inherited nature of eye shape.
Normal-Tension Glaucoma: Often considered a subset of POAG, except IOP is consistently in the normal range. As noted, NTG likely stems from non-pressure causes: blood flow problems, autoimmunity or CSF pressure issues (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Patients are frequently older, may have vascular illnesses or migraines, and their optic nerves may appear especially susceptible even under average pressures.
Secondary Glaucoma: This is when another eye condition causes glaucoma. Common examples include uveitic glaucoma (from inflammation) (pmc.ncbi.nlm.nih.gov), steroid-induced glaucoma (pmc.ncbi.nlm.nih.gov), and trauma-induced glaucoma (www.ncbi.nlm.nih.gov). Each secondary subtype follows the trigger’s mechanism: e.g. angle-recession glaucoma after injury, neovascular glaucoma following diabetes (new vessels blocking angle), etc. Knowing the cause (inflammation, steroids, injury) is key to treatment.
Congenital and Juvenile Glaucoma: These appear in infants or young children. They come from developmental defects of the drainage angle. Genetics is a major factor: CYP1B1 mutations cause many cases of true congenital glaucoma, and the disease is often autosomal-recessive (pmc.ncbi.nlm.nih.gov). Syndrome cases (Axenfeld-Rieger, aniridia) from FOXC1 or PITX2 mutations also lead to early glaucoma (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). A family history of childhood glaucoma can sharply raise risk for newborns, so siblings of affected children are screened very early.

Conclusion

Glaucoma is driven by a range of mechanisms. While high eye pressure from blocked aqueous drainage is the most common cause, nerve damage can also be caused by poor blood flow, immune factors, and genetic susceptibilities. The risk of glaucoma is higher in people who are older, of certain ethnicities, have a family history, or carry particular gene mutations (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Emerging evidence casts glaucoma as a neurodegenerative condition, with oxidative stress, inflammation, and even the gut microbiome contributing to disease. Understanding these causes — from molecular pathways to systemic influences — helps doctors identify who is at most risk and points to new treatments beyond pressure lowering. Vigilant screening of at-risk individuals (family members, patients on steroids, those with anatomy risks) combined with managing IOP and systemic health offers the best chance to prevent this “sneak thief of sight.”