Unraveling Glaucoma’s Genetic Tapestry

Glaucoma has long been recognized as a disease underpinned by a complex interplay of genetic and environmental factors. Over the past 25 years, the field of glaucoma genetics has evolved from constructing glaucoma family trees for gene discovery using linkage analysis and gene screening, through to large population and cohort studies for genome-wide association studies (GWAS) and developing polygenic risk scores – all of which could have profound implications for clinical practice.

At the outset, our understanding of glaucoma genetics was anchored by identifying specific genes with Mendelian inheritance patterns, such as myocilin and CYP1B1. These discoveries, heralded as breakthroughs at the time, offered valuable insights into the genetic underpinnings of the disease. Myocilin genetic testing in families could identify those carrying mutations and at high risk of developing glaucoma, and even today we are still weighing evidence as to whether one of hundreds of variations in myocilin are disease-causing mutations, benign polymorphisms, or variants of unknown significance (1).

Relatively early on, it became apparent that the Mendelian genes accounted for only a fraction of glaucoma cases. The advent of GWAS established a new era in glaucoma genetics, enabling researchers to cast a wider net in their quest for genetic determinants of the disease. Through GWAS, hundreds of genetic loci associated with glaucoma have now been discovered. From the LOXL1 gene implicated in exfoliation glaucoma, to the TMCO1 and CDKN2BAS genes linked to primary open-angle glaucoma (POAG), the genetic landscape for glaucoma has expanded exponentially, with hundreds of genes contributing to the polygenic nature of POAG (2).

Polygenic risk scores have emerged as a powerful tool in the armamentarium of glaucoma genetics; indeed, an individual’s risk score provides a nuanced assessment of genetic susceptibility to the disease. By integrating information from multiple genetic variants, a polygenic risk score can provide personalized risk estimates, enabling more targeted approaches to screening, prevention, and treatment (3). However, the utility of these scores hinge on their validation across diverse populations; notably, most studies to date have predominantly focused on Northern European cohorts.

Taking this into account, it is important to note that ethnic diversity in genetic studies is paramount for ensuring the generalizability and equitable application of genetic findings. Despite the disproportionate burden of glaucoma among individuals of African ancestry, their representation in genetic research remains inadequate  – a fact that highlights systemic disparities in research funding and participation. As such, efforts to address these disparities are imperative to guarantee that genetic insights are applicable across diverse populations, so that they can inform tailored approaches to glaucoma management – wherever it is most needed (4).

In the clinical arena, the integration of genetic information could revolutionize patient care. From risk stratification to personalized treatment algorithms, genetics has the potential to usher in a new era of precision medicine in glaucoma. But challenges abound – from the interpretation of genetic variants to the ethical implications of genetic testing and counseling.

With all of these factors to consider, several key questions loom large in the glaucoma genetics space: How do we translate genetic discoveries into actionable insights for clinical practice? What are the implications of genetic testing for disease screening and management? And how do we ensure equitable access to genetic testing and its benefits across diverse populations?

If we’re able to answer these questions, collaborations between glaucoma geneticists, researchers, and clinicians could help us achieve a realistic future in which there are no cases of glaucoma-associated blindness.