This study identified 85 independent genome-wide significant loci associated with cataracts, of which 37 are novel, expanding our understanding of the genetic basis of this condition. The PRS analysis showed an association between these genome-wide independent loci and the risk of cataracts in independent datasets, providing further evidence for an association between these loci and the disease.
We used MAGMA to perform gene enrichment analysis and found that 126 genes were associated with cataracts. Additionally, we identified two biological processes, tendon development and the negative regulation of the lipid biosynthetic process, that were associated with age-related cataracts. These results are consistent with previous studies that implicate lipid accumulation in disrupting the structure and function of lens proteins 29,30 by affecting homeostasis and the biosynthesis process of lipids, which leads to an opacification of the lens.
Negative regulation of lipid biosynthesis has also been linked to the development of metabolic disorders such as type 2 diabetes 31,32, where a dysregulation of lipid biosynthesis can lead to the accumulation of lipids such as triglycerides and cholesterol in several organ tissues 33,34. Lipids are also an important component of the lens membranes and dysregulation of the lipid metabolism has been associated with the development of cataracts 35. Drugs that target negative regulation of lipid biosynthesis have shown promise as potential treatments for cataracts 36 by modulating lipid metabolism and reducing the accumulation of lipids in the lens, which is a hallmark of cataract formation.
Drug-gene interactions can aid in the identification of potential risk factors for cataract development and in uncovering the mechanisms of interaction with drugs, which, through methods such as drug repurposing, hold promise as novel treatments for cataracts. Our results suggest that specific interactions between genes and drugs may play a crucial role in the development of cataracts. In particular, the gene CREB1 exhibits interactions with lithium, nicotine, and alcohol, indicating their potential relevance to cataract formation. Consistently, previous studies have linked lithium 37, nicotine 38, and alcohol consumption 39 with an increased risk of developing cataracts. Citalopram, an antidepressant known as a selective serotonin reuptake inhibitor 40, has been associated with an increased risk of cataract surgery 41. The interaction between METTL21A and CREB1 with citalopram could be highlighting a mechanism that is triggered by citalopram and leads to an increased risk of cataracts.
Meanwhile, the interaction of JAG1 with hydrocortisone underlines a potential drug that could be used for the treatment of cataracts. Hydrocortisone is a corticosteroid drug that has been evaluated for its potential as an anti-cataract steroidal drug 42, which is consistent with the findings of this study. The mechanism of interaction with other drugs such as epirubicin, cyclophosphamide, and fluorouracil is not well understood, so further research is needed to determine if this interaction could lead to potential treatments. This information sheds light on the complex genetic basis of cataracts and provides new insights into the underlying mechanisms behind gene-drug interaction.
We observed a potential causal association between genetic predisposition to type 1 diabetes and an increased risk for cataracts. Despite the already well-established high prevalence of cataracts among patients with diabetes, this is a noteworthy finding as it suggests that the genetic variants associated with type 1 diabetes may also increase the risk of cataracts. This is consistent with previously published research that identified a potential causal association between type 2 diabetes and cataracts 43, likely pointing to a common underlying mechanism between the etiology of the two conditions. However, patients diagnosed with diabetes often undergo frequent eye examinations 44. More frequent and careful examinations could lead to a higher diagnosis rate within the disease subgroups which could inflate the association between type 1 diabetes and cataracts. As such, additional research incorporating a wider sample is imperative to establish the persistence of the causal relationship.
The PRS cross-trait analyses indicated an association between the risk of developing cataract and increased CUVAF area in young adults, while results in older adults were nominally significant. These findings are consistent with the hypothesis that early-life exposure to sunlight may influence the development of cataracts later in life. Thus, this implicates UVR, specifically CUVAF area, as a marker of cataract risk in young adults.
This study contributes to our understanding of the genetic basis of cataracts and has yielded several noteworthy findings. Our analysis identified 85 loci and 126 genes associated with cataracts, doubling the number of known loci. Notably, we have identified a potential overlap between negative regulation of lipid biosynthesis and the development of cataracts, as well as drug-gene interactions that may expand the range of therapeutic options available for the treatment of cataracts. Furthermore, our findings provided evidence of a putative causal relationship between genetic predisposition to type 1 diabetes and an increased risk of cataracts. Finally, we identified an association between early-life exposure to UVR and risk to develop age-related cataracts; however, further research is required to establish the reliability of this as a marker of cataract risk. The results of this study have important implications for both the diagnosis and treatment of cataracts and open up exciting research avenues for future research.