The causal effects of lifestyle, circulating, pigment, and metabolic factors on early age-related macular degeneration: a comprehensive Mendelian randomization study

Purpose: Early detection of lifestyle factors, skin and hair color, circulating parameters, and metabolic comorbidities is crucial for personalized prevention and treatment of early age-related macular degeneration (AMD). This study aimed to assess the relationships between genetically predicted comprehensive risk factors and early AMD.

Methods and results: Publicly available genome-wide association study (GWAS) data were utilized to identify genetic variants significantly associated with each trait. We applied a Bonferroni-corrected significance level of P < 0.0017. P values between 0.0017 and 0.05 were considered suggestive associations. Univariable Mendelian randomization (MR) analyses revealed that elevated serum HDL-C, lower serum TG, and decreased three circulating fatty acids levels were robust indicators of an increased risk of early AMD (all P < 0.0017), with odds ratios (ORs) and 95% confidence intervals (CIs) of 1.218 (1.140-1.303), 0.784 (0.734-0.837), 0.772 (0.698-0.855), 0.776 (0.706-0.852), and 0.877 (0.798-0.963), respectively. Additionally, the "never eat wheat products", "age started wearing glasses", and "skin color" were significantly associated with the risk of early AMD (both P < 0.0017), with ORs (95% CIs) of 23.853 (2.731-208.323), 1.605 (1.269-2.030) and 1.190 (1.076-1.317), respectively. Multivariable MR analysis confirmed that elevated serum HDL-C (OR = 1.187, 1.064-1.324) increased the risk of early AMD, while higher serum TG (OR = 0.838, 0.738-0.950) was associated with a significantly lower risk. Furthermore, validation results indicated that serum HDL-C 1.201 (1.101-1.310) and TG 0.795 (0.732-0.864) were significantly associated with the risk of early AMD. There were suggestive associations of smoothies, chronotype, and hair color (0.0017 < P < 0.05), but sun/UV protection, smoking, BMI, diabetes, high blood pressure, cardiovascular diseases, fresh fruit intake, fish oil/cod liver oil supplement, sleeplessness, serum C-reactive protein level, and iron level were not associated with the risk of early AMD.

Conclusions: Our comprehensive MR analysis demonstrated that elevated circulating HDL-C levels increase the risk of early AMD, while TG and fatty acid levels are associated with a decreased risk. These findings provide robust evidence for improved diagnosis and personalized prevention and treatment of early AMD.