Causal Associations of Circulating Micronutrients With the Risk of Infertility: A Mendelian Randomization Study

Infertility impacts 48 million couples globally, and accumulating evidence suggests that micronutrients potentially influence reproductive health. This Mendelian randomization study investigates causal relationships between 15 micronutrients and infertility in both males and females, aiming to complement existing nutritional epidemiology insights. Genetic association estimates for micronutrient biomarkers (including selenium, iron, β-carotene, calcium, magnesium, phosphorus, folate, vitamins B₆, B₁₂, C, D, zinc, copper, iodine, and manganese) and infertility phenotypes were derived from European-ancestry genome-wide association study (GWAS) cohorts. For causal inference, inverse-variance weighted MR served as the primary analytical method, supplemented by MR-Egger and weighted median approaches. In female, genetically predicted higher levels of selenium (OR = 0.94; 95% CI = 0.90-0.99; p = 0.019), iron (OR = 0.89; 95% CI = 0.80-0.98; p = 0.023), and β-carotene (OR = 0.87; 95% CI = 0.80-0.96; p = 0.005) demonstrated inverse associations with risk, suggesting potential protective effects. In males, higher phosphorus exhibited a strong positive correlation with infertility (OR = 4.05; 95% CI = 1.37-11.96; p = 0.011). No significant associations were observed for the remaining micronutrients. This Mendelian randomization study comprehensively evaluates the causal effects of 15 micronutrients on infertility in both sexes. The findings highlight potential protective roles of selenium, iron, and β-carotene in female infertility and identify phosphorus as a risk factor for male infertility. These results support the development of sex-specific nutritional strategies for fertility improvement.