Analysis Suggests Causal Link Between AMD, Rheumatoid Arthritis

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Mendelian randomization analysis demonstrated a direct connection between rheumatoid arthritis and an increased risk of age-related macular degeneration.

A Mendelian randomization analysis identified a causal relationship between age-related macular degeneration (AMD) and rheumatoid arthritis (RA), with the presence of RA demonstrated to increase the risk of AMD.

The investigation was preceded in recent years by several retrospective clinical observation studies pointing to the association between RA and AMD.2 By contrast, these results from the two-sample Mendelian randomization investigation revealed a causal link between the two conditions.1

“The existence of a causal link, in contrast to epidemiologic studies, may imply that the detection rate of AMD among RA patients in our study is far from reality or that RA treatment strategies are effective in preventing AMD,” wrote the investigative team, led by Yue Feng, Chengdu University of Traditional Chinese Medicine.

Epidemiological data have shown both RA and AMD are diseases becoming more prevalent globally, including in non-European populations.2 Some research has claimed a connection between the two diseases, but no study has reported evidence of a potential causal relationship.3 As its impact remains unknown, Feng and colleagues used Mendelian randomization to test the hypothesis of a two-sample causal relationship between RA and AMD.1

Summary data from genome-wide association studies (GWAS) for RA and AMD in individuals with European ancestry were obtained from the IEU GWAS database. GWAS summary statistics of 14,361 individuals with RA and 43,923 healthy controls were enrolled in the analysis. Summary statistics of 14,034 patients with AMD and 91,214 healthy controls also participated in the research.

After the selection of instrumental variables in association with Mendelian randomization, Feng and colleagues used multiple approaches to validate the causal relationship between RA and AMD, including the Mendelian Randomization-Egger (MR-Egger), weighted median, and inverse variance weighting techniques (IVW).

In sensitivity analysis, the MR-Egger intercept and MR-Polyvalent Residuals and Outliers approaches were utilized to assess the effects of horizontal pleiotropy. Investigators used the leave-one-out strategy to prevent bias caused by some single nucleotide polymorphism (SNPs).

According to strict exclusion criteria, the analysis included 50 SNPs for RA—investigators identified no heterogeneity using the Cochran Q test (P >.05). Upon analysis, the correlation between AMD and RA was found to be statistically significant, according to the IVW (odds ratio [OR], 1.056; 95% CI, 1.02 - 1.09; P = 5.44E-04), weighted median (OR, 1.085; 95% CI, 1.04 - 1.14; P = 4.05E–04), and MR-Egger (OR, 1.074; 95% CI, 1.01 - 1.14; P = 2.18 E–2) approaches.

However, Feng and colleagues noted there are limitations in interpreting these data. Feng and colleagues noted, that although the causal association was observed in consistent data, the OR was ultimately low. In addition, they pointed to the lack of stratification between patients with RA and wet and dry AMD, respectively.

To improve the power of the analysis, Feng and colleagues indicated a larger GWAS with a bigger sample size, and SNPs are needed to replicate these results. As RA and AMD are both widespread illnesses, with rising frequency in non-European populations, the sample may need to be more diverse to confirm the findings.

“For RA patients, routine visual acuity screening is advised,” they wrote. “Future research on RA and AMD could focus on the mechanisms by which RA affects AMD.”


  1. Zhang M, Duan L, Feng Y. Causal association between rheumatoid arthritis and an increased risk of age-related macular degeneration: A Mendelian randomization study. Medicine (Baltimore). 2024;103(15):e37753. doi:10.1097/MD.0000000000037753
  2. Finckh A, Gilbert B, Hodkinson B, et al. Global epidemiology of rheumatoid arthritis. Nat Rev Rheumatol. 2022;18(10):591-602. doi:10.1038/s41584-022-00827-y
  3. Schultz NM, Bhardwaj S, Barclay C, Gaspar L, Schwartz J. Global Burden of Dry Age-Related Macular Degeneration: A Targeted Literature Review. Clin Ther. 2021;43(10):1792-1818. doi:10.1016/j.clinthera.2021.08.011