BackgroundThere are no effective pharmacological treatments for sarcopenia. We aim to identify potential therapeutic targets for sarcopenia by integrating various publicly available datasets.MethodsWe integrated druggable genome data, cis‐eQTL/cis‐pQTL from human blood and skeletal muscle tissue, and GWAS summary data of sarcopenia‐related traits to analyse the potential causal relationships between drug target genes and sarcopenia using the Mendelian Randomization (MR) method. Sensitivity analyses and Bayesian colocalization were employed to validate the causal relationships. We also assessed the side effects or additional indications of the identified drug targets using a phenome‐wide MR (Phe‐MR) approach and investigated actionable drugs for target genes using available databases.ResultsMR analysis identified 17 druggable genes with potential causation to sarcopenia in human blood or skeletal muscle tissue. Six of them (HP, HLA‐DRA, MAP 3K3, MFGE8, COL15A1, and AURKA) were further confirmed by Bayesian colocalization (PPH4 > 90%). The up‐regulation of HP [higher ALM (beta: 0.012, 95% CI: 0.007–0.018, P = 1.2*10−5) and higher grip strength (OR: 0.96, 95% CI: 0.94–0.98, P = 4.2*10−5)], MAP 3K3 [higher ALM (beta: 0.24, 95% CI: 0.21–0.26, P = 1.8*10−94), higher grip strength (OR: 0.82, 95% CI: 0.75–0.90, P = 2.1*10−5), and faster walking pace (beta: 0.03, 95% CI: 0.02–0.05, P = 8.5*10−6)], and MFGE8 [higher ALM (muscle eQTL, beta: 0.09, 95% CI: 0.06–0.11, P = 6.1*10−13; blood pQTL, beta: 0.05, 95% CI: 0.03–0.07, P = 3.8*10−09)], as well as the down‐regulation of HLA‐DRA [lower ALM (beta: ‐0.09, 95% CI: −0.11 to −0.08, P = 5.4*10−36) and lower grip strength (OR: 1.13, 95% CI: 1.07–1.20, P = 1.8*10−5)] and COL15A1 [higher ALM (muscle eQTL, beta: ‐0.07, 95% CI: −0.10 to −0.04, P = 3.4*10−07; blood pQTL, beta: ‐0.05, 95% CI: −0.06 to −0.03, P = 1.6*10−07)], decreased the risk of sarcopenia. AURKA in blood (beta: ‐0.16, 95% CI: −0.22 to −0.09, P = 2.1*10−06) and skeletal muscle (beta: 0.03, 95% CI: 0.02 to 0.05, P = 5.3*10−05) tissues showed an inverse relationship with sarcopenia risk. The Phe‐MR indicated that the six potential therapeutic targets for sarcopenia had no significant adverse effects. Drug repurposing analysis supported zinc supplementation and collagenase clostridium histolyticum might be potential therapeutics for sarcopenia by activating HP and inhibiting COL15A1, respectively.ConclusionsOur research indicated MAP 3K3, MFGE8, COL15A1, HP, and HLA‐DRA may serve as promising targets for sarcopenia, while the effectiveness of zinc supplementation and collagenase clostridium histolyticum for sarcopenia requires further validation.

中文翻译：

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系统性药物全基因组孟德尔随机化确定了肌肉减少症的治疗靶点

背景对于肌肉减少症没有有效的药物治疗。我们的目标是通过整合各种公开可用的数据集来确定肌肉减少症的潜在治疗靶点。方法我们整合了可药物基因组数据、来自人类血液和骨骼肌组织的 cis-eQTL/cis-pQTL 以及肌肉减少症相关性状的 GWAS 摘要数据来分析潜在的治疗靶点使用孟德尔随机化 (MR) 方法分析药物靶基因与肌肉减少症之间的因果关系。采用敏感性分析和贝叶斯共定位来验证因果关系。我们还使用全表型 MR (Phe-MR) 方法评估了已确定药物靶标的副作用或其他适应症，并使用可用数据库研究了针对靶基因的可操作药物。结果 MR 分析确定了 17 个可能导致人类肌肉减少症的可药物基因血液或骨骼肌组织。其中六个（生命值,HLA-DRA,地图3K3,MFGE8,科尔15A1， 和奥卡）通过贝叶斯共定位进一步证实（PPH4 > 90%）。上调调节生命值[更高的 ALM（β：0.012，95% CI：0.007–0.018，磷= 1.2*10−5）和更高的握力（OR：0.96，95% CI：0.94–0.98，磷= 4.2*10−5)],地图3K3[较高的 ALM（β：0.24，95% CI：0.21–0.26，磷= 1.8*10−94）、更高的握力（OR：0.82，95% CI：0.75–0.90，磷= 2.1*10−5）和更快的步行速度（β：0.03，95% CI：0.02–0.05，磷= 8.5*10−6）]， 和MFGE8[更高的 ALM（肌肉 eQTL，β：0.09，95% CI：0.06–0.11，磷= 6.1*10−13;血液 pQTL，β：0.05，95% CI：0.03–0.07，磷= 3.8*10−09)]，以及下调HLA-DRA[较低的 ALM（β：‐0.09，95% CI：-0.11 至 -0.08，磷= 5.4*10−36）和较低的握力（OR：1.13，95% CI：1.07–1.20，磷= 1.8*10−5）] 和科尔15A1[更高的 ALM（肌肉 eQTL，β：‐0.07，95% CI：-0.10 至 -0.04，磷= 3.4*10−07;血液 pQTL，β：‐0.05，95% CI：-0.06 至 -0.03，磷= 1.6*10−07)]，降低了肌肉减少症的风险。奥卡血液中（β：‐0.16，95% CI：-0.22 至 -0.09，磷= 2.1*10−06）和骨骼肌（β：0.03，95% CI：0.02 至 0.05，磷= 5.3*10−05）组织与肌肉减少症风险呈负相关。 Phe-MR 表明肌少症的六种潜在治疗靶点没有显着的副作用。药物再利用分析支持锌补充剂和胶原酶溶组织梭菌可能是通过激活肌肉减少症的潜在疗法生命值并抑制科尔15A1，分别。结论我们的研究表明地图3K3,MFGE8,科尔15A1,生命值， 和HLA-DRA可能作为肌肉减少症的有希望的目标，而补锌和胶原酶的有效性溶组织梭菌对于肌少症需要进一步验证。