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

ABSTRACT 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 B 6 , folate, and Vit B 12 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, p = 0.025) and lower ALM ( β = −0.043, 95% CI: −0.069 – −0.016, p = 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 ( p < 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.