{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,24]],"date-time":"2026-04-24T05:41:29Z","timestamp":1777009289043,"version":"3.51.4"},"reference-count":55,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T00:00:00Z","timestamp":1776124800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Most glaucoma genetic data derive from European and East Asian cohorts, leaving high-consanguinity Middle Eastern populations under-characterized. This review synthesizes 33 Saudi-specific genetic studies (2014\u20132024, &gt;9000 participants) to define a population-level glaucoma genetic architecture that diverges substantially from global models and carries direct precision medicine implications. Three findings distinguish the Saudi landscape. First, CYP1B1 functions as the dominant causal gene across both primary congenital glaucoma (PCG) and juvenile-onset open-angle glaucoma (JOAG), accounting for 76\u201386% of cases, with two founder alleles, p.G61E (penetrance 87.7%) and p.R469W (penetrance 93%), driving severe, early-onset phenotypes. Critically, MYOC and LTBP2, the primary JOAG genes in other populations, carry no pathogenic variants in Saudi cohorts, rendering standard multi-ethnic gene panels inadequate for this population. Second, adult-onset glaucoma follows a distinct polygenic architecture where APOE \u03b52 confers a near five-fold risk for primary angle-closure glaucoma (OR = 4.82), an effect absent or inconsistent in global datasets, and NOS3 variants associate with primary open-angle glaucoma specifically in men, a sex-stratified signal unreported outside Saudi cohorts. The MTHFR T\/T genotype, common in European and Asian POAG patients, is entirely absent locally, indicating population-specific allelic distributions that alter folate-metabolism-related optic nerve susceptibility. Third, ACVR1 rs12997 associates across POAG, PACG, and pseudoexfoliation glaucoma (PXG), positioning BMP\/TGF-\u03b2 signaling as a shared mechanistic pathway spanning multiple subtypes. These findings argue for Saudi-specific genetic panels, CYP1B1-centered cascade testing in consanguineous families, and polygenic risk models incorporating local allele frequencies rather than globally derived weights.<\/jats:p>","DOI":"10.3390\/ijms27083506","type":"journal-article","created":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T14:24:58Z","timestamp":1776176698000},"page":"3506","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Genetic Risk Factors and Clinical Implications of Glaucoma in the Saudi Population: A Review"],"prefix":"10.3390","volume":"27","author":[{"given":"Abdullah Faisal","family":"Alotaibi","sequence":"first","affiliation":[{"name":"Glaucoma Division, King Khaled Eye Specialist Hospital and Research Center, Riyadh 11462, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lojain Mohammed A.","family":"Maawadh","sequence":"additional","affiliation":[{"name":"College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam 31441, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-8434-3148","authenticated-orcid":false,"given":"Mohammed Naji Obaid","family":"Almutairi","sequence":"additional","affiliation":[{"name":"College of Medicine, King Saud bin Abdulaziz University for Health Sciences, Riyadh 11481, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-2746-0784","authenticated-orcid":false,"given":"Syed","family":"Hameed","sequence":"additional","affiliation":[{"name":"Research Department, King Khaled Eye Specialist Hospital and Research Center, Riyadh 11462, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rizwan","family":"Malik","sequence":"additional","affiliation":[{"name":"Research Department, King Khaled Eye Specialist Hospital and Research Center, Riyadh 11462, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Khaled K.","family":"Abu-Amero","sequence":"additional","affiliation":[{"name":"Research Department, King Khaled Eye Specialist Hospital and Research Center, Riyadh 11462, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,14]]},"reference":[{"key":"ref_1","first-page":"225","article-title":"The Diagnosis and Treatment of Glaucoma","volume":"117","author":"Schuster","year":"2020","journal-title":"Dtsch. 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