A recent study published in Nature Communications has unveiled significant genetic and biological pathways contributing to the development of age-related cataracts.1 Leveraging a genome-wide association study (GWAS) meta-analysis involving over 940,000 participants, the research findings promise to reshape our understanding of cataract etiology and open doors to innovative prevention and treatment strategies.
Age-related cataracts, which cause the lens of the eye to become cloudy, account for 90% of cataract cases globally. They disproportionately affect adults over 60, with prevalence as high as 40% in some regions, such as sub-Saharan Africa. While environmental factors like ultraviolet (UV) exposure and conditions such as diabetes have long been recognized as contributors, the interplay between genetic predisposition and these risk factors remains poorly understood.1-5
This new study—the largest of its kind—sought to bridge this knowledge gap. By integrating multi-ancestry datasets from diverse cohorts and advanced analytical tools, the researchers ensured high reliability and generalizability of their findings. Polygenic risk scores (PRS) validated the genetic associations in independent cohorts, further strengthening the study’s conclusions.
Here are the key findings:
- Expanding the genetic landscape. The researchers identified 101 genetic loci associated with cataracts. Notably, 57 of these loci had not been previously linked to the condition. These discoveries double the number of known cataract-associated loci, marking a major step forward in genetic research.
- Biological pathways and gene function. Functional analysis revealed that the newly identified genes are enriched in pathways related to pericyte cell differentiation and lipid biosynthesis regulation—processes that align with the disruption of lens proteins and the lens opacification observed in cataracts. For instance, the lipid biosynthesis pathways have potential therapeutic implications, as lipid dysregulation is a known contributor to lens degeneration.
- Drug-gene interactions. The study identified four key drug-gene interactions (GNL3, JAG1, METTL21A, and CREB1) involving eight drugs, including citalopram and hydrocortisone. These findings suggest potential pathways for therapeutic interventions, although further research is needed to validate these connections.
- Type 1 diabetes as a risk factor. Through Mendelian randomization, the study established a causal link between type 1 diabetes and cataracts, with an odds ratio of 1.01. This finding emphasizes the need for better diabetes management to mitigate cataract risk.
- The role of UV exposure. UV-related damage emerged as a significant risk factor for cataracts, particularly in older adults. Although a PRS analysis showed mixed results across age groups, the link between UV exposure and cataract development remains a key focus for prevention strategies.
- Metabolites and protective factors. Among 249 metabolites analyzed, β-Hydroxybutyric acid stood out as potentially protective against cataracts, showing an odds ratio of 0.41. This finding highlights a new avenue for exploring metabolic interventions.
The study’s comprehensive approach sheds light on the complex genetic architecture of cataracts and suggests potential therapeutic targets. For instance, drugs influencing lipid metabolism could be repurposed or developed to address cataract risk. Additionally, the established link between Type 1 diabetes and cataracts underscores the importance of systemic health in eye care.
While the findings are groundbreaking, they also raise new questions. For example, how do environmental and genetic factors interact over a lifetime to influence cataract risk? And how can the identified drug-gene interaction be translated to effective therapies? Addressing these questions will require further studies, including clinical trials and longitudinal research.
Nonetheless, by doubling the number of known genetic loci associated with cataracts and uncovering novel biological pathways, this study marks a turning point in cataract research. Its insights not only deepen our understanding of cataract formation but also pave the way for innovative interventions.
References
- Diaz-Torres S, Lee SSY, Garcia-Marin LM, et al. Uncovering genetic loci and biological pathways associated with age-related cataracts through GWAS meta-analysis. Nature Communications. 2024;15:9116.
- Hashemi H, Pakzad R, Yekta A, et al. Global and regional prevalence of age-related cataract: a comprehensive systematic review and meta-analysis. Eye (Lond). 2020;34(8):1357-1370.
- Khoza LB, Nunu WN, Tshivhase SE, et al. Survey on prevalence of cataract in selected communities in Limpopo Province of South Africa. Scientific African. 2020;8:e00352.
- Roberts JE. Ultraviolet radiation as a risk factor for cataract and macular degeneration. Eye Contact Lens. 2011;37(4):246-249.
- Lu WL, Shen PC, Lee CH, et al. High risk of early cataracts in young Type 1 diabetes group: A nationwide cohort study. Int J Endocrinol. 2020;2020:8160256.
