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Abstract

Objective

To investigate the causal effects of physical activity and sedentary traits on risk of Age-related macular degeneration (AMD).

Methods

A two-sample Mendelian randomization (MR) analysis was used to investigate the causal relationship between physical activity and risk of AMD. We used genome-wide association studies (GWAS) summary statistics from two publicly available biobank-scale cohorts: UK Biobank and FinnGen. Physical activity data were self-reported by 703,901 UK Biobank participants and sedentary behaviour data were gathered from 159,606 FinnGen participants. Our analysis primarily used the inverse variance weighted (IVW) method.

Result

Engaging in moderate-to-vigorous physical activity significantly reduced the risk of AMD with an odds ratio of 0.77 (95% CI: 0.66–0.89). However, leisure screen time showed a slight but non-statistically significant upward trend. Sedentary behaviour at work, sedentary commuting showed no causal effects on AMD risk.

Conclusions

This study used MR analysis to examine the causal relationship between physical activity, sedentary behaviour, and AMD. It offers genetic evidence suggesting that physical activity may protect against AMD, emphasizing the significance of lifestyle factors in maintaining ocular health.

Keywords

Introduction

Age-related macular degeneration (AMD) is a leading cause of significant vision loss and blindness, severely impacting the quality of life for the elderly worldwide.¹ Projections suggest that by 2040, around 288 million people globally may be affected by this condition.² Clinically, there is no complete cure for AMD, which primarily affects the macula and progresses through three stages: early, intermediate, and advanced.³ Advanced AMD is categorized into dry AMD (atrophic AMD) and wet AMD (exudative or neovascular AMD).⁴ The wet type is often linked to more significant vision deterioration. Although recent advancements in the treatment of wet AMD, like intraocular anti-anti–vascular endothelial growth factor (VEGF) therapy, show promise, this approach still has its limitations. Patients may face side effects, serious complications like endophthalmitis, inconsistent treatment responses, high costs, and the risk of worsening geographic atrophy, leading to further vision loss.^5–7 These challenges highlight the urgent need for effective prevention strategies for both forms of AMD. However, the task is complicated by the lack of clearly defined protective factors, making it a difficult undertaking

Physical activity offers a promising approach to tackling this challenge and has received considerable backing from medical experts and researchers. Physical activity encompasses a wide range of movements initiated by skeletal muscles, leading to energy expenditure, and includes tasks related to work, recreation, and daily life.⁸ Regular participation in physical activity has been shown to provide protective benefits against various eye conditions, such as glaucoma,⁹ myopia,¹⁰ dry eye disease,¹¹ and may also reduce the risk of visual impairment. However, the evidence regarding the impact of physical activity on AMD is inconsistent.¹² The sample sizes in observational studies are often too small to provide sufficient statistical power.^13,14 Some studies suggest a protective effect of physical activity against AMD,^14–17 while others report no significant association or highlight differing outcomes based on the sex of the patients.¹⁸

Mendelian randomization (MR) overcomes the methodological challenges of traditional studies by applying genetic variants as instrumental variables (IVs) to identify causal effects.¹⁹ This approach functions like a natural randomized controlled trial, as genetic variants are randomly assigned at conception and remain constant throughout an individual's lifetime. This intrinsic stability reduces the risks of confounding and reverse causality, thus strengthening the inference of causal relationships.²⁰ This present study used MR to investigate the causal relationship between physical activity and risk of AMD using data from two large genome-wide association studies (GWAS). By using genetic variants as IVs, MR minimizes confounding and reverse causality, providing valuable insights for the development of effective AMD prevention strategies.

Methods

Study design

We used a two-sample MR approach, a robust statistical method that determines causality through the use of genetic variants as IVs, to investigate the causal relationship between physical activity and risk of AMD. The Strengthening the Reporting of Observational Studies in Epidemiology using MR (STROBE-MR) guideline was rigorously adhered to in the reporting of this MR study.²¹ This design exploits the principle that single nucleotide polymorphisms (SNPs) are randomly assigned during meiosis, similar to a randomized clinical trial (RCT) which minimizes confounding factors such as age, sex, and reverse causality. Three basic assumptions were met to ensure reliable causal inference.²² Firstly, genetic variants display a strong correlation with the targeted exposure. Secondly, genetic variants and potential confounders are mutually independent. Thirdly, genetic variants influence outcomes only via exposure and cannot affect outcome through any other pathways (Figure 1). Various rigorous sensitivity analysis methods were applied to assess potential violations of the above assumptions, thereby increasing the reliability of the results. We used GWAS summary statistics from two publicly available biobank-scale cohorts: UK Biobank²³ and FinnGen.²⁴ Physical activity data were self-reported by 703,901 UK Biobank participants using the international physical activity questionnaire summary. Sedentary behaviour data were gathered from 159,606 participants through various questionnaires, which covered aspects like sedentary work habits, commuting, and leisure screen time. Cohort specificity was defined to maximize the use of existing data while maintaining consistency among studies.²⁴ This study used publicly available anonymised data and so ethical approval was not required.

Figure 1.

An illustration of three basic assumptions of Mendelian randomization. (1) the genetic instrument is strongly associated with the physical activity/sedentary traits; (2) the genetic instrument is not associated with any potential confounder in the physical activity/sedentary traits-to- age-related macular degeneration (AMD) relationship and (3) the genetic variants should only affect the risk of AMD through physical activity/sedentary traits.

Selection of genetic instruments

MR analysis considered vertical and horizontal pleiotropy to ensure the validity of IVs.²⁵ SNPs were selected for physical activity and sedentary traits based on strict criteria, including those with genome-wide significance (P < 5 × 10⁻⁶), while excluding those significantly linked to AMD. To minimize linkage disequilibrium, clumping was applied with an r² threshold of 0.001 and a clumping distance of 10,000 kb, while SNPs with pleiotropic effects were excluded.²⁶ Additionally, the F statistic (F = beta2/se2) was calculated to assess the strength of the IVs and address potential biases from weak instruments; an F statistic less than 10 was deemed to indicate an invalid instrument.^27,28 To ensure accuracy, ambiguous and palindromic SNPs were harmonized, while Steiger filtering was used to remove SNPs that showed stronger associations with outcomes than with exposures.²⁹

GWAS summary statistics for AMD

To avoid participant overlap, the GWAS analysis of AMD outcomes used genomic data from 9, 721 cases and 381, 339 controls sourced from the FinnGen Biobank. The median age of AMD cases at time of initial diagnosis was 76 years, which was obtained from analysis of hospital discharge records or death data.³⁰ AMD classification used the ICD-10 codes, H35. 31 (i.e., nonexudative age-related macular degeneration) and H35. 32 (i.e., exudative age-related macular degeneration.

Statistical analyses

MR analyses were performed in R (v4. 3. 1) using the Two Sample MR package (v0. 5. 8) and MR-PRESSO (v1. 0) package. A P value <0.05 was considered to indicate statistical significance. In the primary analysis, the inverse variance weighted (IVW) method was used in the absence of heterogeneity. A meta-analysis of the Wald ratio for individual SNPs was used to evaluate the link between exposure and outcome.³¹ If there was SNP heterogeneity, then a random-effects model was used, weighting each effect by its standard error.³² Bayesian Weighted MR (BWMR) addressed the uncertainty caused by pleiotropy by using Bayesian-weighted outlier detection to correct for violations of instrumental variable assumptions, effectively tackling the issues of ‘weak instruments' and ‘weak horizontal pleiotropy’.³³ The robust adjusted profile score (RAPS) enhanced causal inference reliability by modifying the profile score to resist pleiotropy and measurement error.^34,35 Additionally, we applied complementary methods such as MR-Egger,³⁶ weighted median,³⁷ and MR-PRESSO.

Sensitivity analysis was performed using a multi-step approach to assess Assumption ii. and Assumption iii (Figure 1). Firstly, Cochran's Q test was used to assess heterogeneity among the independent variables.³⁸ Afterwards the potential horizontal pleiotropy of the IVs was examined using MR-Egger regression and the MR-PRESSO global test.³⁶ Finally, the leave-one-out method was applied for exclusion analysis, sequentially removing each SNP to evaluate the impact of significant horizontal pleiotropic SNPs on MR estimates and to detect any abnormal SNPs.³⁹

Results

In total, we used 112 SNPs as IVs for moderate-to-vigorous physical activity, 15 SNPs for sedentary commuting, 253 SNPs for leisure screen time, and 53 SNPs for total sedentary time. All genetic instruments had F-statistics greater than 62.67, indicating the absence of instrument bias.

Causal association between PA, sedentary traits, and AMD

Analysis of fixed-effects IVW showed a significant protective effect of moderate-to-vigorous physical activity against AMD, with an odds ratio of 0.77 (95% CI, 0.66–0.89; P = 0.001) (Figure 2). Similar results were found when using random-effects IVW, weighted median, MR-PRESSO, RAPS, and BWMR (Figure 2). Although the MR-Egger method produced results in the same direction, they did not reach statistical significance (Figure 2).

Figure 2.

Forest plot illustrating Mendelian randomization (MR) analysis results for the relationship between physical activity, sedentary traits, and age-related macular degeneration (AMD).

No causal association was found between genetic predisposition toward sedentary traits, such as leisure screen time, sedentary behaviour at work, sedentary commuting, and risk of AMD. However, it is worth noting that the leisure screen time showed a slight but non-statistically significant upward trend.

Sensitivity analyses

The findings for heterogeneity and horizontal pleiotropy are shown in Table 1. Cochran Q tests yielded P-values >0.05, indicating no significant heterogeneity. Scatter plots and leave-one-out analyses showed a few potential SNP outliers. The Egger intercept and MR-PRESSO global tests yielded P-values >0.05, suggesting no evidence of horizontal pleiotropy between moderate-to-vigorous physical activity, sedentary behaviour at work, leisure screen time.

Table 1.

Pleiotropy and heterogeneity tests of Mendelian randomization.

Exposure	Test	Method	Effect size	Statistical significance
Moderate-to-vigorous physical activity	Heterogeneity	Cochran’s Q test (MR Egger)	120.659	ns
	Heterogeneity	Cochran’s Q test (IVW)	120.715	ns
	Pleiotropy	MR-Egger regression (egger_intercept)	0.001	ns
	Pleiotropy	MR-PRESSO global test	122.763	ns
Leisure screen time	Heterogeneity	Cochran’s Q test (MR Egger)	210.826	ns
	Heterogeneity	Cochran’s Q test (IVW)	213.857	ns
	Pleiotropy	MR-Egger regression (egger_intercept)	−0.008	ns
	Pleiotropy	MR-PRESSO global test	215.606	ns
Sedentary behaviour at work	Heterogeneity	Cochran’s Q test (MR Egger)	62.041	ns
	Heterogeneity	Cochran’s Q test (IVW)	62.082	ns
	Pleiotropy	MR-Egger regression (egger_intercept)	−0.002	ns
	Pleiotropy	MR-PRESSO global test	64.401	ns
Sedentary commuting	Heterogeneity	Cochran’s Q test (MR Egger)	15.085	ns
	Heterogeneity	Cochran’s Q test (IVW)	15.627	ns
	Pleiotropy	MR-Egger regression (egger_intercept)	0.014	ns
	Pleiotropy	MR-PRESSO global test	18.021	ns

MR, Mendelian randomization; IVW, inverse variance weighted; ns, not statistically significant.

Discussion

This study conducted MR analysis using GWAS data to assess the relationship between genetic prediction of moderate-to-vigorous physical activity, sedentary traits, and AMD risk. The findings indicated that engaging in moderate-to-vigorous physical activity significantly reduce the risk of AMD. Supporting these findings, a 7-year prospective study of 41, 708 participants reported that higher levels of vigorous exercise, particularly average running distances of 4 km/day or more, were associated with a 42% to 54% reduction in adjusted AMD risk.⁴⁰ In addition, an Australian cohort study found that engaging in at least 20 minutes of vigorous exercise per week, regardless of the frequency (≥3 times/week or 1–2 times/week) through activities such as swimming, tennis, or basketball, was associated with reduced odds of developing intermediate and advanced AMD.¹⁸ Moreover, a systematic review and meta-analysis found that individuals with high physical activity levels had reduced odds of developing early and advanced AMD.⁴¹ Indeed, multiple studies have confirmed these findings.^14–16 Interestingly, additional studies have showed that patients with advanced AMD are less likely to participate in physical activity.^16,42 While these aforementioned studies highlight an association between physical activity and reduced risk of AMD, direct evidence of causality remains elusive. Compared with large-scale prospective clinical trials that require long-term follow-up and are often less feasible, MR studies offer a more efficient, cost-effective approach, providing new insights into the potential causal link between physical activity and AMD.²⁰

While our study did not identify a causal link between sedentary traits and risk of AMD, previous studies have suggested an association between sedentary traits and AMD. For example, a 15-year prospective study showed that sedentary individuals had a 70% higher risk of developing exudative AMD compared to their more active counterparts, even after adjusting for age, sex, and other factors.¹⁶ Similarly, a cross-sectional study found a notable increase in AMD risk among participants who spent the most time sitting each week, compared to those who engaged in 7 to 12 hours of physical activity weekly.¹⁷ However, while these studies suggest a correlation, they are often influenced by confounding variables and may be subject to reverse causality. By contrast, using an MR design, our study offered causal evidence suggesting that reducing sedentary time does not directly impact AMD risk.

Physical activity also provides important advantages, such as reducing the likelihood of developing obesity and coronary heart disease.^43–46 Numerous studies recognize these conditions as risk factors for AMD.^47,48 Obesity may act as a mediating factor between physical activity and AMD, contributing to adverse effects like dyslipidaemia and increased circulating VEGF levels.^49–52 Observational data show that patients with advanced AMD often have abnormal VEGF levels in their tears and circulation,⁵³ and several studies have confirmed that elevated intraocular VEGF is vital for AMD development and progression.^54–57 Both systemic and local inflammatory responses are strongly linked to AMD.^51–54 Exercise decreases systemic inflammatory markers, including interleukin (IL)-6, tumour necrosis factor alpha (TNF-α), and soluble TNF-α receptors, across different age groups, with a strong impact in older adults.⁵⁸ In addition, exercise induces the release of anti-inflammatory agents from skeletal muscles, including glucocorticoids and IL-10, which can suppress pro-inflammatory factors such as TNF-α and IL-1β.^58,59 Observational studies indicate that regular physical activity in the elderly correlates with high IL-10 and adiponectin levels, which are protective against AMD.^60–66 Moreover, MR analyses indicate that high circulating C-reactive protein (CRP) levels may increase the risk of AMD.^67,68 A meta-analysis of seven studies involving 275 participants demonstrated that exercise interventions effectively lowered CRP levels in hospitalized elderly individuals.⁶⁹ Another meta-analysis, which included 38 randomized controlled trials, confirmed that aerobic exercise reduced inflammatory markers including CRP and TNF-α.⁷⁰

In terms of ocular effects, a study using a running wheel model that subjected C57 mice to four weeks of exercise followed by laser-induced choroidal neovascularization, found a reduction in neovascularization volume and a decrease in macrophage accumulation at the lesion site.⁷¹ In addition, physical activity may reduce the release of pro-inflammatory factors associated with AMD by affecting endothelial cell function, thereby reducing its risk. During exercise, increased tissue perfusion exposes endothelial cells to high levels of laminar shear stress, which modulates key molecules involved in inflammatory responses such as vascular cell adhesion molecule-1 (VCAM-1), nuclear factor-κB (NF-κB), mitogen-activated protein kinases (MAPK) and cyclooxygenase-2 (COX-2).^72,73 In addition, animal studies have shown that exercise training significantly downregulates the expression of intercellular cell adhesion molecule-1 (ICAM-1) and NF-κB in large vessels in mice.^74,75 After exposing aortic endothelial cells to laminar shear stress for four hours, VCAM-1 expression was significantly reduced.⁷⁶ These studies collectively provide theoretical evidence linking routine physical activity to reduced risk of AMD. Importantly, regular physical activity may mitigate AMD risk by addressing chronic disease and inflammation.

Conventional research designs have limitations in effectively accounting for reverse causality and confounding variables that maybe present in observational studies.^77,78 These limitations can introduce association bias, which may impact the validity of the conclusions drawn. RCTs provide a robust approach to assess the theoretical efficacy or effectiveness of clinical interventions. Recognized as the gold standard in clinical research, RCTs minimize selection bias and confounding, making them the most reliable method for establishing causal relationships.^78–80

However, applying RCTs to investigate the causal link between physical activity and risk of AMD presents significant challenges. Despite the methodological strength of RCTs, ethical and practical concerns often make them unrealistic in this context. While observational studies can easily identify associations between environmental factors and disease, confirming causality is more complex. The key challenges include: (1) the presence of uncontrolled external factors that may interfere; (2) the risk of confounding factors creating ‘false causality,' where a demonstrated correlation may not indicate a true cause-and-effect relationship; and (3) the need to consider not only causation from cause to effect but also the possibility of reverse causality, where the effect could influence the cause. Although regression models can eliminate some confounders, if they are unobserved or numerous, it becomes difficult for regression analysis to fully eliminate bias. Additionally, because reverse causality leads to simultaneous changes in both the dependent and independent variables, conventional regression analysis cannot always provide reliable results.⁸⁰

This study first investigated the potential impact of physical activity on reducing AMD risk using a two-sample MR approach, which helps minimize biases related to reverse causation and confounding factors often present in observational studies. We also conducted sensitivity analyses to confirm the validity of the MR assumptions, thereby minimizing the risk of biased results. Horizontal pleiotropy occurs when IVs influence the outcome independently of the exposure. The IVW method, which was the primary analysis in this study, provides more statistical power than other MR approaches. However, each SNP must be free from horizontal pleiotropy, making it more vulnerable to pleiotropic effects if present.⁸¹ To address potential pleiotropy, we used MR-Egger regression and the MR-PRESSO global test to strengthen the reliability of our findings. The reduced statistical power of the MR-Egger analysis, as indicated by wider confidence intervals and lack of statistical significance, was expected.⁸² By using multiple analytical methods to explore causal relationships, we were able to draw more comprehensive and robust conclusions. We also ensured that the beta direction remained consistent across all MR approaches, further enhancing the reliability of our results.

The study had several limitations. For example, the findings may have limited applicability to other ethnic groups, as the dataset consisted mainly of individuals of European descent, who may have specific cultural practices and lifestyles. Additionally, while we used pooled data from the largest AMD genomic study to date, the number of AMD cases was still relatively small compared to other outcomes commonly analysed in MR studies, such as cardiovascular disease. The small sample size may reduce statistical power, potentially making it more difficult to detect associations with certain exposures. Furthermore, targeted horizontal pleiotropy poses an additional challenge in MR analyses, as genetic variants may affect AMD independently of the risk factors being studied. Despite these limitations, our findings have significant implications for public health, particularly in the context of an aging population and the increasing prevalence of AMD. Promoting physical activity as a preventative measure may be a valuable addition to current strategies for this condition.

In conclusion, physical activity may protect against AMD, emphasizing the significance of lifestyle factors in eye health. Further research is required to clarify the biological pathways involved and verify whether this relationship is causal. Expanding these investigations will help to better understand the mechanisms at play and provide more robust evidence supporting causality.

Supplemental Material

sj-pdf-1-imr-10.1177_03000605251318198 - Supplemental material for Genetically determined physical activity levels, sedentary behaviours, and their association with the risk of age-related macular degeneration

Supplemental material, sj-pdf-1-imr-10.1177_03000605251318198 for Genetically determined physical activity levels, sedentary behaviours, and their association with the risk of age-related macular degeneration by Xiangpeng Zhou, Jiang Wu, Yingjiao Shen, Shucheng He, Hanyi Guan and Lijun Shen in Journal of International Medical Research

Supplemental Material

sj-pdf-2-imr-10.1177_03000605251318198 - Supplemental material for Genetically determined physical activity levels, sedentary behaviours, and their association with the risk of age-related macular degeneration

Supplemental material, sj-pdf-2-imr-10.1177_03000605251318198 for Genetically determined physical activity levels, sedentary behaviours, and their association with the risk of age-related macular degeneration by Xiangpeng Zhou, Jiang Wu, Yingjiao Shen, Shucheng He, Hanyi Guan and Lijun Shen in Journal of International Medical Research

Footnotes

Data availability statement

The datasets including FinnGen Biobank (https://r10.finngen.fi/) and UK biobank (UKB) from GWAS catalogue () analysed in this study are publicly available.

Declaration of conflicting interest

The authors declare there are no conflicts of interest.

Funding

This study was supported by the National Key Research and Development Program of China (2022YFC2404305).

ORCID iD

Xiangpeng Zhou

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Supplementary Material

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Genetically determined physical activity levels,sedentary behaviours,and their association with the risk of age-related macular degeneration

Abstract

Objective

Methods

Result

Conclusions

Keywords

Introduction

Methods

Study design

Selection of genetic instruments

GWAS summary statistics for AMD

Statistical analyses

Results

Causal association between PA, sedentary traits, and AMD

Sensitivity analyses

Discussion

Supplemental Material

sj-pdf-1-imr-10.1177_03000605251318198 - Supplemental material for Genetically determined physical activity levels, sedentary behaviours, and their association with the risk of age-related macular degeneration

Supplemental Material

sj-pdf-2-imr-10.1177_03000605251318198 - Supplemental material for Genetically determined physical activity levels, sedentary behaviours, and their association with the risk of age-related macular degeneration

Footnotes

Data availability statement

Declaration of conflicting interest

Funding

ORCID iD

References

Supplementary Material