Age-related cataract (ARC) also known as senile cataract, is the most common form of cataract and a leading cause of vision impairment worldwide (1). It is characterized by the progressive formation of an opaque lens that eventually leads to loss of vision and eventual blindness (2, 3). It typically affects people over the age of 60, but can also affect younger people (1). Sight can be restored through cataract removal surgery, in which the clouded lens is removed and an artificial lens is implanted. Although the success rate of cataract surgery is high, there are risks associated with cataract surgery, including lens fragments, vitreous detachment or traction, retinal detachment, intraocular inflammation or hemorrhage, corneal edema, infection, and increased intraocular pressure (4–6). In addition, the cost of cataract surgery to remove ARC remains a significant burden for many families. Statistics show that nearly 2 million cataract surgeries are performed every year in the United States at a cost of approximately $60 billion, and that delaying the onset of ARC by 10 years can reduce the number of people requiring surgery by 45 percent (6, 7). Therefore, it is essential to identify potential risk factors for delaying or preventing ARC in order to improve patients’ quality of life and reduce the immense social and economic burden.

As a type of bioregulatory hormone, thyroid hormone (TH) plays crucial roles in human growth and development, metabolism, cardiovascular function, and temperature regulation (8). It circulates in the balance between the biologically active free form and the protein-bound form, the production and release of which is primarily regulated by the hypothalamus and pituitary gland (9). TH may play a crucial role in the pathogenesis of eye diseases. TH signaling has been shown to play a critical role in the regulation of retinal development and is a key regulator of S- and M-cone opsins (10). Additionally, the absence of TH during embryonic and early postnatal development can also affect the formation of the eyeball and the proliferation of all retinal cells (11, 12). Even when an individual’s thyroid function is within the normal range, higher FT4 levels are associated with an increased risk of age-related macular degeneration (AMD), according to recent research (13). However, the function of TH in ARC has been studied little. A case-control study of risk factors for ARC showed that moderate cortical opacities were associated with higher levels of thyroid hormone use (14). In another study, it was also found that metabolic cataracts could be treated with TH supplements (15). Although both studies attempted to control for potential confounding variables, the causal relationship between thyroid dysfunction and ARC remains unclear.

Mendelian Randomization (MR) is a statistical method in epidemiology that uses genetic variation as instrumental variables (IVs) to infer causal relationships between exposures and outcomes (16). During gamete formation, alleles are segregated and are randomly distributed to offspring according to Mendel’s law of independent assortment (17). This suggests that modifying exposure through genetic variation will have an identical effect on the outcome. A number of conditions, such as atrial fibrillation, renal function, anemia, sex hormones and function, and major depressive disorder and its subtypes, have been predicted to be affected by thyroid dysfunction (18–21). There are currently no Mendelian Randomization (MR) studies investigating the causal relationship between thyroid dysfunction, specifically hypothyroidism, and the risk of ARC. To determine the causal relationship between thyroid dysfunction (including hypothyroidism, hyperthyroidism, circulating fT4 and TSH levels) and ARC risk, we performed an MR study using Single Nucleotide Polymorphisms (SNPs) as IVs.

Previous studies have shown that thyroid dysfunction and ARC are two unrelated conditions, and their relationship has rarely been investigated. Although total thyroidectomy has been reported to cause cataracts, researchers believe that disruption of calcium and phosphorus metabolism due to removal of the parathyroid glands is the primary cause (31). Through a MR method, we found for the first time that genetically determined hypothyroidism increases the risk of developing ARC. We provided genetic support that hypothyroidism increases the risk of ARC in the European population. In sensitivity analyses, neither forest plots nor leave-one-out plots revealed SNPs that significantly influenced the results. There was no pleiotropy according to the MR-Egger intercept test and the MR-PRESSO test. In addition, the MR Steiger test indicated that there was no inverse causality with hypothyroidism and ARC.

Cataracts are the leading cause of blindness in older people, accounting for up to 51% of all cases of blindness, making them a serious global public health problem (32). Age is considered to be the most important risk factor for cataracts, which typically appear between the ages of 40 and 50, progress slowly, and typically do not affect vision until the age of 60 (2). However, age alone does not fully explain the development of ARC. Physiologically, the human lens is composed of 63% water and 35% protein (33, 34). Changes in water content and protein aggregation abnormalities in cataracts are the result of exposure to ultraviolet and x-ray radiation, steroids, and other chemicals and drugs, as well as the presence of local or systemic diseases such as diabetes, smoking, and malnutrition, rendering the normally transparent lens opaque (1, 4). Oxidative stress has also been implicated in the pathogenesis of cataract (35). Oxidative stress causes a decrease in the glutathione levels in the lens, an increase in the level of glutathione disulfide (the oxidised form of the antioxidant glutathione), and ultimately the accumulation of lens-ageing proteins, including disulfide-bound proteins (36, 37). In addition, a number of studies suggest that nutrient, vitamin and mineral intake is also associated with lens ageing (38). High protein and vitamin C intake (approximately twice the recommended levels) may delay lens ageing, and the use of various vitamin supplements and trace minerals such as selenium may be beneficial in maintaining lens health, particularly in minimizing the risk of nuclear and cortical cataracts (39, 40). These findings have implications for the prevention and treatment of cataract.

The positive causal relationship between hypothyroidism and ARC may be due to the fact that thyroid hormone deficiency affects the formation of lens proteins. In previous observational studies, patients with congenital hypothyroidism often had concomitant cataracts (41). Congenital hypothyroidism may cause thyroid hormone levels to be too low during the embryonic period, thereby affecting the normal development of ocular structures, including the lens. Alternatively, some genes may be involved in both thyroid hormone synthesis and eye development, allowing the two disorders to coexist in children with certain congenital malformations (42, 43). This is consistent with the genetic evidence we provide. In addition, THs regulate the body’s water balance, and lens water transport is a critical physiological process for maintaining lens function and image quality. The effect of THs on systemic and local water balance is important in lens lesions (34). We hypothesize that one of the reasons hypothyroidism increases the risk of ARC is due to the disruption of water metabolism associated with thyroid hormone deficiency, and that water retention may have an effect on ocular tissues and the lens.

Oxidative stress is considered to be one of the key mechanisms of cataract (35). Studies have shown that hypothyroidism increases oxidative stress, which influences the apoptosis of structural cells and inflammatory cells and alters the cytokine microenvironment balance, thereby contributing to the pathogenesis of cataract. The study by Huang et al. showed that TH can increase the lipid saturation and membrane raft lipids in human lens epithelial cell lines, thereby decreasing mitochondrial-generated reactive oxygen species and increasing the total antioxidant capacity of lens epithelial cells (44, 45). This also supports the previously held belief that mitochondrial dysfunction and metabolic dysregulation may be associated with cataracts, and that reducing the production of damaging mitochondrial ROS may ameliorate ageing eye tissue and cataract disease (46). Furthermore, THs characterise the basic metabolism of the body, particularly in relation to gastrointestinal function and visceral organs. In addition to central appetite suppression, hypothyroid patients often experience various digestive disorders, such as oesophageal dysmotility, interstitial oedema of the gastrointestinal muscular layer, and impaired liver function (47). This means that hypothyroid patients consume fewer nutrients, vitamins, and minerals than the normal population, disrupting the nutritional metabolic balance of the lens and accelerating its degeneration. Further research is needed to determine whether hypothyroidism mediates systemic diseases that contribute to the onset or progression of ARC.

However, there are some limitations to this study that need to be considered. First, all of the participants in this study were of European ancestry, so our findings may not be applicable to people of other ancestries. Second, because we used aggregated GWAS data rather than individual-level data, we were unable to stratify for factors such as age and sex to further explore the causal relationship between hypothyroidism and ARC. Next, the traits of hypothyroidism and hyperthyroidism were derived from public GWAS datasets as non-cancer disease self-report codes rather than diagnosis codes; The use of self-reported codes may lead to greater characterization of hypothyroidism and hyperthyroidism, which may increase the impact of potential heterogeneity. Fortunately, we found no significant heterogeneity through a series of quality analyses. Additionally, there are relatively few SNPs as IVs for hyperthyroidism, which may increase the risk of type II error and thus limits the ability to detect true associations between genetic factors and hyperthyroidism. Future GWAS datasets of larger, more specific diagnosis codes will improve statistical power. Finally, although MR uses genetic variation for studies that are not subject to traditional confounders such as environment and behavior, the effects of clinical interventions cannot be determined by MR analysis. Further studies are needed to explore the relationship between hypothyroidism and ARC.

Our study provides strong evidence that hypothyroidism is a causal determinant of ARC risk.

The original contributions presented in the study are included in the article/ Supplementary Material , further inquiries can be directed to the corresponding authors.

Ethical review and approval were not required for this study in human subjects in accordance with the local laws and institutional requirements. Written informed consent for participation was not required for this study in accordance with national laws and institutional requirements.

SL: Writing – original draft, Writing – review & editing, Data curation, Methodology, Conceptualization. QS: Writing – original draft, Writing – review & editing, Formal analysis, Software. QG: Writing – review & editing, Formal analysis. YB: Writing – review & editing, Investigation. WW: Software. XQ: Writing – original draft, Supervision, Project administration, Funding acquisition, Resources. XY: Writing – original draft, Supervision, Project administration, Funding acquisition, Resources.