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

## TL;DR

This study finds that high homocysteine levels are causally linked to sarcopenia traits like low grip strength and lean mass, suggesting Hcy interventions may help prevent sarcopenia.

## Contribution

The study provides causal evidence linking genetically predicted homocysteine levels to sarcopenia-related traits using Mendelian randomization and longitudinal data.

## Key findings

- Genetically predicted higher homocysteine levels are causally associated with lower grip strength and appendicular lean mass.
- Individuals with medium or high stable homocysteine levels have significantly increased sarcopenia risk compared to low-level groups.
- A dose–response relationship was observed between baseline homocysteine levels and sarcopenia risk.

## 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 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, 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.

We employed Mendelian randomization analysis and longitudinal cohort data to identify a causal relationship between genetically predicted high Hcy levels and low grip strength as well as low appendicular lean mass. In the clinical cohort, individuals with persistent medium and high levels of Hcy had a significantly increased risk of sarcopenia, and a dose–response relationship was observed. No consistent causal evidence was found between B vitamins and the characteristics of sarcopenia.