Previous observational studies suggested that sarcopenia is associated with Parkinson disease (PD), but it is unclear whether this association is causal. The objective of this study was to examine causal associations between sarcopenia-related traits and the risk or progression of PD using a Mendelian randomization (MR) approach. Two-sample bidirectional MR analyses were conducted to evaluate causal relationships. Genome-wide association study (GWAS) summary statistics for sarcopenia-related traits, including right handgrip strength (n = 461,089), left handgrip strength (n = 461,026), and appendicular lean mass (n = 450,243), were retrieved from the IEU OpenGWAS database. GWAS data for the risk of PD were derived from the FinnGen database (4235 cases; 373,042 controls). Summary-level data for progression of PD, including progression to Hoehn and Yahr stage 3, progression to dementia, and development of levodopa-induced dyskinesia, were obtained from a recent GWAS publication on progression of PD in 4093 patients from 12 longitudinal cohorts. Significant causal associations identified in MR analysis were verified through a polygenic score (PGS)-based approach and pathway enrichment analysis using genotype data from the Parkinson’s Progression Markers Initiative. MR results supported a significant causal influence of right handgrip strength (odds ratio [OR] = 0.152, 95% confidence interval [CI] = 0.055–0.423, adjusted P = 0.0036) and appendicular lean mass (OR = 0.597, 95% CI = 0.440–0.810, adjusted P = 0.0111) on development of levodopa-induced dyskinesia. In Cox proportional hazard analysis, higher PGSs for right handgrip strength (hazard ratio [HR] = 0.225, 95% CI = 0.095–0.530, adjusted P = 0.0019) and left handgrip strength (HR = 0.303, 95% CI = 0.121–0.59, adjusted P = 0.0323) were significantly associated with a lower risk of developing levodopa-induced dyskinesia, after adjusting for covariates. Pathway enrichment analysis revealed that genome-wide significant single-nucleotide polymorphisms for right handgrip strength were substantially enriched in biological pathways involved in the control of synaptic plasticity. This study provides genetic evidence of the protective role of handgrip strength or appendicular lean mass on the development of levodopa-induced dyskinesia in PD. Sarcopenia-related traits can be promising prognostic markers for levodopa-induced dyskinesia and potential therapeutic targets for preventing levodopa-induced dyskinesia in patients with PD.

先前的观察性研究表明，肌肉减少症与帕金森病（PD）有关，但尚不清楚这种关联是否存在因果关系。本研究的目的是使用孟德尔随机化 (MR) 方法检查肌肉减少症相关特征与 PD 风险或进展之间的因果关系。进行两个样本双向 MR 分析来评估因果关系。从 IEU 检索肌肉减少症相关特征的全基因组关联研究 (GWAS) 汇总统计数据，包括右手握力 ( n = 461,089)、左手握力 ( n = 461,026) 和四肢瘦肉质量 ( n = 450,243) OpenGWAS 数据库。 PD 风险的 GWAS 数据来自 FinnGen 数据库（4235 例病例；373,042 例对照）。 PD 进展的汇总数据，包括进展为 Hoehn 和 Yahr 3 期、进展为痴呆以及左旋多巴诱发的运动障碍的发展，均来自最近 GWAS 发表的关于来自 12 个纵向队列的 4093 名患者的 PD 进展的数据。 MR 分析中确定的显着因果关联通过基于多基因评分 (PGS) 的方法和使用来自帕金森病进展标记计划的基因型数据的通路富集分析进行了验证。 MR 结果支持右手握力（优势比 [OR] = 0.152，95% 置信区间 [CI] = 0.055–0.423，调整后P = 0.0036）和四肢瘦肉质量（OR = 0.597，95% CI = 0.440–0.810，调整后的P = 0.0111）对左旋多巴引起的运动障碍的发展。在 Cox 比例风险分析中，右手握力的 PGS 较高（风险比 [HR] = 0.225，95% CI = 0.095–0。530，调整后的P = 0.0019）和左手握力（HR = 0.303，95% CI = 0.121-0.59，调整后的P = 0.0323）在调整协变量后与左旋多巴诱发的运动障碍的较低风险显着相关。通路富集分析表明，右手握力的全基因组显着单核苷酸多态性在涉及突触可塑性控制的生物通路中显着富集。这项研究提供了握力或四肢瘦肉质量对帕金森病中左旋多巴引起的运动障碍的保护作用的遗传证据。肌肉减少症相关特征可能是左旋多巴诱发的运动障碍的有前景的预后标志物，也是预防 PD 患者左旋多巴诱发的运动障碍的潜在治疗靶点。