Abstract：
BACKGROUND: Recent research highlights the importance of muscular strength as a key factor in physical fitness, a strong indicator of overall mortality risk, and a vital target for preventing chronic diseases. This study used a proteome-wide Mendelian randomization analysis plus colocalization analysis for low hand grip strength to explore potential therapeutic targets for muscle weakness.
METHODS: We conducted two two-sample Mendelian randomization analyses from four cohorts to identify and validate the causal relationship between plasma proteins and low grip strength. We also employed bidirectional Mendelian randomization analysis with Steiger filtering, Bayesian co-localization, and phenotype scanning to detect reverse causality, thereby consolidating our Mendelian randomization findings. Downstream analyses were also undertaken of identified proteins, including knockout models, enrichment analyses, and protein-protein interaction networks. Finally, we assessed the druggability of the identified proteins.
RESULTS: At Bonferroni significance (P < 6.82 × 10-5), Mendelian randomization analysis revealed that three proteins were causally associated with low grip strength. Increased MGP (OR = 0.85) and HP (OR = 0.96) decreased the risk of low grip strength, whereas elevated ART4 (OR = 1.06) increased the risk of low grip strength. None of the three proteins had reverse causality with low grip strength. Bayesian co-localization suggested that MGP shared the same variant with low grip strength (coloc.abf-PPH4 = 0.826). Further downstream analyses showed that MGP, which is highly expressed in musculoskeletal system, is a potential novel target for muscle weakness.
CONCLUSIONS: The proteome-wide Mendelian randomization investigation identified three proteins associated with the risk of muscle weakness. MGP, HP, and ART4 deserve further investigation as potential therapeutic targets for muscle weakness.
METHODS: We conducted two two-sample Mendelian randomization analyses from four cohorts to identify and validate the causal relationship between plasma proteins and low grip strength. We also employed bidirectional Mendelian randomization analysis with Steiger filtering, Bayesian co-localization, and phenotype scanning to detect reverse causality, thereby consolidating our Mendelian randomization findings. Downstream analyses were also undertaken of identified proteins, including knockout models, enrichment analyses, and protein-protein interaction networks. Finally, we assessed the druggability of the identified proteins.
RESULTS: At Bonferroni significance (P < 6.82 × 10-5), Mendelian randomization analysis revealed that three proteins were causally associated with low grip strength. Increased MGP (OR = 0.85) and HP (OR = 0.96) decreased the risk of low grip strength, whereas elevated ART4 (OR = 1.06) increased the risk of low grip strength. None of the three proteins had reverse causality with low grip strength. Bayesian co-localization suggested that MGP shared the same variant with low grip strength (coloc.abf-PPH4 = 0.826). Further downstream analyses showed that MGP, which is highly expressed in musculoskeletal system, is a potential novel target for muscle weakness.
CONCLUSIONS: The proteome-wide Mendelian randomization investigation identified three proteins associated with the risk of muscle weakness. MGP, HP, and ART4 deserve further investigation as potential therapeutic targets for muscle weakness.
摘要：
背景：最近的研究强调了肌肉力量作为身体健康的关键因素的重要性，总死亡率风险的有力指标，和预防慢性病的重要目标。这项研究使用了蛋白质组范围的孟德尔随机化分析和低握力的共定位分析来探索肌肉无力的潜在治疗目标。
方法：我们从四个队列中进行了两个孟德尔随机样本分析，以确定和验证血浆蛋白与低握力之间的因果关系。我们还采用了双向孟德尔随机化分析与Steiger滤波，贝叶斯协同定位，和表型扫描来检测反向因果关系，从而巩固我们的孟德尔随机化研究结果。还对鉴定的蛋白质进行了下游分析，包括淘汰赛模型，富集分析，和蛋白质-蛋白质相互作用网络。最后,我们评估了鉴定的蛋白质的可药用性.
结果：在Bonferroni意义上（P<6.82×10-5），孟德尔随机化分析显示，三种蛋白质与低握力有因果关系。增加MGP（OR=0.85）和HP（OR=0.96）降低了低握力的风险，而升高的ART4（OR=1.06）增加了低握力的风险。这三种蛋白质在低握力下都没有反向因果关系。贝叶斯共定位表明，MGP共享具有低握力的相同变体（coloc。abf-PPH4=0.826)。进一步的下游分析表明，MGP，在肌肉骨骼系统中高度表达，是肌肉无力的潜在新目标。
结论：全蛋白质组孟德尔随机化研究发现了三种与肌肉无力风险相关的蛋白质。MGP,HP,ART4作为肌无力的潜在治疗靶点值得进一步研究.
方法：我们从四个队列中进行了两个孟德尔随机样本分析，以确定和验证血浆蛋白与低握力之间的因果关系。我们还采用了双向孟德尔随机化分析与Steiger滤波，贝叶斯协同定位，和表型扫描来检测反向因果关系，从而巩固我们的孟德尔随机化研究结果。还对鉴定的蛋白质进行了下游分析，包括淘汰赛模型，富集分析，和蛋白质-蛋白质相互作用网络。最后,我们评估了鉴定的蛋白质的可药用性.
结果：在Bonferroni意义上（P<6.82×10-5），孟德尔随机化分析显示，三种蛋白质与低握力有因果关系。增加MGP（OR=0.85）和HP（OR=0.96）降低了低握力的风险，而升高的ART4（OR=1.06）增加了低握力的风险。这三种蛋白质在低握力下都没有反向因果关系。贝叶斯共定位表明，MGP共享具有低握力的相同变体（coloc。abf-PPH4=0.826)。进一步的下游分析表明，MGP，在肌肉骨骼系统中高度表达，是肌肉无力的潜在新目标。
结论：全蛋白质组孟德尔随机化研究发现了三种与肌肉无力风险相关的蛋白质。MGP,HP,ART4作为肌无力的潜在治疗靶点值得进一步研究.
