Genetically Predicted Homocysteine Levels and B Vitamins on Sarcopenia‐Related Traits: Insights From an Observational and Mendelian Randomization Analysis

Sarcopenia is a significant public health concern that adversely affects the health and quality of life of older adults. The causal and longitudinal relationships between homocysteine (Hcy), B vitamins, and sarcopenia remain unclear. This study integrated genetic evidence with clinical cohort data to investigate these associations using a two-stage design. First, we performed a two-sample Mendelian randomization (MR) analysis using summary data from large-scale genome-wide association studies (GWAS) of European ancestry. We examined the potential causal effects of Hcy, Vit B₆, folate, and Vit B₁₂ on sarcopenia-related phenotypes, including appendicular lean mass (ALM), grip strength, and walking pace, using the inverse-variance weighted (IVW) method as the primary analysis. Second, to validate these genetic findings and examine their longitudinal relevance, we established an independent retrospective clinical cohort of 1322 individuals. Group-based trajectory modeling identified distinct Hcy trajectory groups, and multivariable Cox regression with restricted cubic splines was used to assess longitudinal associations and dose-response relationships with incident sarcopenia. The MR analysis showed that genetically predicted higher Hcy levels were causally associated with low grip strength (OR = 1.133, 95% CI: 1.016-1.263, <i>p</i> = 0.025) and lower ALM (<i>β</i> = -0.043, 95% CI: -0.069 - -0.016, <i>p</i> = 0.001). In the clinical cohort, individuals in the medium-stable and high-stable Hcy trajectory groups had a 1.965-fold (95% CI: 1.027-3.759) and 2.832-fold (95% CI: 1.608-4.987) higher risk of developing sarcopenia, respectively, compared to the low-stable group. A continuous, incremental dose-response relationship was observed between baseline Hcy levels and sarcopenia risk (<i>p</i> < 0.05). No robust genetic evidence supported causal roles for B vitamins in sarcopenia. This study provides evidence that Hcy is associated with sarcopenia risk, suggesting that interventions targeting Hcy may help prevent or delay sarcopenia onset.