Metabolome-Wide Mendelian Randomization Assessing the Causal Relationship Between Blood Metabolites and Sarcopenia-Related Traits.

Sarcopenia is among the most common musculoskeletal illnesses, yet its underlying biochemical mechanisms remain incompletely understood. In this study, we used Mendelian randomization (MR) to investigate the causal relationship between the genetically determined blood metabolites and sarcopenia, with the overall objective of identifying likely molecular pathways for sarcopenia. We used 2-sample MR to investigate the effects of blood metabolites on sarcopenia-related traits. 452 metabolites were exposure, and 3 sarcopenia-related traits as the outcomes: handgrip strength, appendicular lean mass, and walking pace. The inverse-variance weighted (IVW) causal estimates were determined. For sensitivity analysis, methods such as MR-Egger regression, the weighted median, the weighted mode, and the heterogeneity test were used. Additionally, for complementation, we performed replication, meta-analysis, and metabolic pathway analyses. Candidate biomarkers were defined by meeting one of the following criteria: (1) significant metabolites are defined as pIVW < pBonferroni [1.11 × 10-4 (.05/452)]; (2) strong metabolites are defined as 4 MR methods p < .05; and (3) suggestive metabolites are defined as passing sensitivity analysis. Three metabolites (creatine, 1-arachidonoylglycerophosphocholine, and pentadecanoate [15:0]) with significant causality, 3 metabolites (glycine, 1-arachidonoylglycerophosphocholine, and epiandrosterone sulfate) with strong causality, and 25 metabolites (including leucylleucin, pyruvic acid, etc.) with suggestive causality were associated with sarcopenia-related traits. After further replication analyses and meta-analysis, these metabolites maintained substantial effects on sarcopenia-related traits. We additionally identified 14 important sarcopenia-related trait metabolic pathways. By combining metabolomics with genomics, these candidate metabolites and metabolic pathways identified in our study may provide new clues regarding the mechanisms underlying sarcopenia.

Chen S ，Dong Y ，Aiheti N ，Wang J ，Yan S ，Kuribanjiang K ，Li H ，Peng X ，Wupuer A ，Li Y ，Yang L ，Zhao J ... -  《-》

Causality between urate levels with sarcopenia-related traits: a bi-directional Mendelian randomization study.

Observational studies have suggested associations between serum urate levels and sarcopenia, but the causality underlying this correlation remains uncertain. The principal objective of this study is to investigate a causal relationship of serum urate levels with sarcopenia-related traits (hand grip strength, lean mass, walking pace) using bidirectional two-sample Mendelian randomization (MR) approach. The utilization of MR methodology serves to minimize bias caused by reverse causality and confounding factors from observational studies. The summary statistics of serum urate levels were derived from a cohort consisting of 288,659 individuals participating in CKDGen study. The parameters of right-hand grip strength (N=461,089), left-hand grip strength (N=461,026), appendicular lean mass (ALM) (N=450,243), whole-body lean mass(N=454,850),right-leg fat-free mass(FFM;N=454,835),left-leg FFM(N=454,805), right-arm FFM(N=454,753),left-arm FFM(N=454,672) and walking pace (N=459,915)were sourced from the UK Biobank. MR analysis was conducted utilizing inverse variance weighted (IVW), weighted median, and MR-Egger to evaluate causality. Sensitivity analysis was performed using Cochran's Q test, MR-Egger intercept test, leave-one-out analysis and the funnel plot. IVW estimates demonstrated that serum urate levels exhibited no causal association with sarcopenia-related traits. In the inverse MR investigation, we had exclusively discerned an inverse correlation between walking pace and serum urate levels. No compelling evidence had surfaced to substantiate any association of other sarcopenia-related traits with serum urate. Supplemental MR methods consistently validated the findings obtained from the primary analysis. Sensitivity analysis demonstrated the robustness of findings. Our MR study revealed the absence of the bidirectional causal relationship between serum urate levels and sarcopenia. It is imperative to acknowledge that advanced age and an individual's health status are pivotal determinants influencing urate level and the initiation and advancement of sarcopenia. However, it is worth underscoring that these aspects remain unexamined within the purview of this study. Thus, future investigations should delve deeper into these intricate facets.

Lin Y ，Wang X ，Yao W ，Sun Y ，Zhou J ，Feng F ... -  《Frontiers in Endocrinology》

The causal relationship of human blood metabolites with the components of Sarcopenia: a two-sample Mendelian randomization analysis.

Sarcopenia is a progressive loss of muscle mass and function. Since skeletal muscle plays a critical role in metabolic homeostasis, identifying the relationship of blood metabolites with sarcopenia components would help understand the etiology of sarcopenia. A two-sample Mendelian randomization study was conducted to examine the causal relationship of blood metabolites with the components of sarcopenia. Summary genetic association data for 309 known metabolites were obtained from the Twins UK cohort and KORA F4 study (7824 participants). The summary statistics for sarcopenia components [hand grip strength (HGS), walking pace (WP), and appendicular lean mass (ALM)] were obtained from the IEU Open GWAS project (461,089 participants). The inverse variance weighted method was used, and the MR-Egger, weighted median, and MR-PRESSO were used for the sensitivity analyses. Metabolic pathways analysis was further performed. Fifty-four metabolites associated with sarcopenia components were selected from 275 known metabolites pool. Metabolites that are causally linked to the sarcopenia components were mainly enriched in amino sugar and nucleotide sugar metabolism, galactose metabolism, fructose and mannose metabolism, carnitine synthesis, and biotin metabolism. The associations of pentadecanoate (15:0) with ALM, and 3-dehydrocarnitine and isovalerylcarnitine with HGS were significant after Bonferroni correction with a threshold of P < 1.82 × 10- 4 (0.05/275). Meanwhile, the association of hyodeoxycholate and glycine with the right HGS, and androsterone sulfate with ALM were significant in the sensitivity analyses. Blood metabolites from different metabolism pathways were causally related to the components of sarcopenia. These findings might benefit the understanding of the biological mechanisms of sarcopenia and targeted drugs development for muscle health.

Peng W ，Xia Z ，Guo Y ，Li L ，He J ，Su Y ... -  《-》

Genetically Predicted Levels of Serum Metabolites and Risk of Sarcopenia: A Mendelian Randomization Study.

Sha T ，Wang N ，Wei J ，He H ，Wang Y ，Zeng C ，Lei G ... -  《Nutrients》

Causal relationship between sarcopenia with osteoarthritis and the mediating role of obesity: a univariate, multivariate, two-step Mendelian randomization study.

Recent genetic evidence supports a causal role for sarcopenia in osteoarthritis, which may be mediated by the occurrence of obesity or changes in circulating inflammatory protein levels. Here, we leveraged publicly available genome-wide association study data to investigate the intrinsic causal relationship between sarcopenia, obesity, circulating inflammatory protein levels, and osteoarthritis. In this study, we used Mendelian randomization analyses to explore the causal relationship between sarcopenia phenotypes (Appendicular lean mass [ALM], Low hand-grip strength [LHG], and usual walking pace [UWP]) and osteoarthritis (Knee osteoarthritis [KOA], and Hip osteoarthritis [HOA]). Univariable Mendelian randomization (UVMR) analyses were performed using the inverse variance weighted (IVW) method, MR-Egger, weighted median method, simple mode, and weighted mode, with the IVW method being the primary analytical technique. Subsequently, the independent causal effects of sarcopenia phenotype on osteoarthritis were investigated using multivariate Mendelian randomization (MVMR) analysis. To further explore the mechanisms involved, obesity and circulating inflammatory proteins were introduced as the mediator variables, and a two-step Mendelian randomization analysis was used to explore the mediating effects of obesity and circulating inflammatory proteins between ALM and KOA as well as the mediating proportions. UVMR analysis showed a causal relationship between ALM, LHG, UWP and KOA [(OR = 1.151, 95% CI: 1.087-1.218, P = 1.19 × 10-6, PFDR = 7.14 × 10-6) (OR = 1.215, 95% CI: 1.004-1.470; P = 0.046, PFDR = 0.055) (OR = 0.503, 95% CI: 0.292-0.867; P = 0.013, PFDR = 0.027)], and a causal relationship between ALM, UWP and HOA [(OR = 1.181, 95% CI: 1.103-1.265, P = 2.05 × 10-6, PFDR = 6.15 × 10-6) (OR = 0.438, 95% CI: 0.226-0.849, P = 0.014, PFDR = 0.022)]. In the MVMR analyses adjusting for confounders (body mass index, insomnia, sedentary behavior, and bone density), causal relationships were observed between ALM, LHG, UWP and KOA [(ALM: OR = 1.323, 95%CI: 1.224- 1.431, P = 2.07 × 10-12), (LHG: OR = 1.161, 95%CI: 1.044- 1.292, P = 0.006), (UWP: OR = 0.511, 95%CI: 0.290- 0.899, P = 0.020)], and between ALM and HOA (ALM: OR = 1.245, 95%CI: 1.149- 1.348, P = 7.65 × 10-8). In a two-step MR analysis, obesity was identified to play a potential mediating role in ALM and KOA (proportion mediated: 5.9%). The results of this study suggest that decreased appendicular lean mass, grip strength, and walking speed increase the risk of KOA and decreased appendicular lean mass increases the risk of HOA in patients with sarcopenia in a European population. Obesity plays a mediator role in the occurrence of KOA due to appendicular lean body mass reduction.

Jin Z ，Wang R ，Jin L ，Wan L ，Li Y ... -  《BMC Geriatrics》