Molecular Genetics of Glaucoma: Subtype and Ethnicity Considerations

• Main Authors: Ryan Zukerman, Alon Harris, Alice Verticchio Vercellin, Brent Siesky, Louis R. Pasquale, Thomas A. Ciulla
• Format: Article
• Language: English
• Published: MDPI AG 2021-12-01
• Series: Genes
• Subjects: glaucoma; genetics; genome-wide association study; genetic/polygenic risk score; primary open-angle glaucoma; exfoliation syndrome
• Online Access: https://www.mdpi.com/2073-4425/12/1/55

Glaucoma, the world’s leading cause of irreversible blindness, is a complex disease, with differential presentation as well as ethnic and geographic disparities. The multifactorial nature of glaucoma complicates the study of genetics and genetic involvement in the disease process. This review synthesizes the current literature on glaucoma and genetics, as stratified by glaucoma subtype and ethnicity. Primary open-angle glaucoma (POAG) is the most common cause of glaucoma worldwide, with the only treatable risk factor (RF) being the reduction of intraocular pressure (IOP). Genes associated with elevated IOP or POAG risk include: <i>ABCA1</i>, <i>AFAP1</i>, <i>ARHGEF12, ATXN2</i>, <i>CAV1</i>, <i>CDKN2B</i>-<i>AS1</i>, <i>FOXC1</i>, <i>GAS7</i>, <i>GMDS</i>, <i>SIX1</i>/<i>SIX6</i>, <i>TMCO1</i>, and <i>TXNRD2</i>. However, there are variations in RF and genetic factors based on ethnic and geographic differences; it is clear that unified molecular pathways accounting for POAG pathogenesis remain uncertain, although inflammation and senescence likely play an important role. There are similar ethnic and geographic complexities in primary angle closure glaucoma (PACG), but several genes have been associated with this disorder, including<i> MMP9</i>, <i>HGF</i>, <i>HSP70</i>, <i>MFRP</i>, and <i>eNOS</i>. In exfoliation glaucoma (XFG), genes implicated include <i>LOXL1</i>, <i>CACNA1A</i>, <i>POMP, TMEM136, AGPAT1, RBMS3, </i>and <i>SEMA6A</i>. Despite tremendous progress, major gaps remain in resolving the genetic architecture for the various glaucoma subtypes across ancestries. Large scale carefully designed studies are required to advance understanding of genetic loci as RF in glaucoma pathophysiology and to improve diagnosis and treatment options.