Identifying genetic determinants of sarcopenia-related traits: a Mendelian randomization study of druggable genes

IF 10.8 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Metabolism: clinical and experimental Pub Date : 2024-08-06 DOI:10.1016/j.metabol.2024.155994
Jihao Wu , Xiong Chen , Ruijun Li , Qiying Lu , Yucheng Ba , Jiayun Fang , Yilin Liu , Ruijie Li , Yixuan Liu , Yiling Wang , Jinsi Chen , Yanbing Li , Yinong Huang
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Abstract

Background

Sarcopenia, characterized by progressive muscle mass and function loss, particularly affects the elderly, and leads to severe consequences such as falls and mortality. Despite its prevalence, targeted pharmacotherapies for sarcopenia are lacking. Utilizing large-sample genome-wide association studies (GWAS) data is crucial for cost-effective drug discovery.

Methods

Herein, we conducted four studies to understand the putative causal effects of genetic components on muscle mass and function. Study 1 employed a two-sample Mendelian randomization (MR) on 15,944 potential druggable genes, investigating their potential causality with muscle quantity and quality in a European population (N up to 461,089). Study 2 validated MR results through sensitivity analyses and colocalization analyses. Study 3 extended validation across other European cohorts, and study 4 conducted quantitative in vivo verification.

Results

MR analysis revealed significant causality between four genes (BLOC-1 related complex subunit 7, BORCS7; peptidase m20 domain containing 1, PM20D1; nuclear casein kinase and cyclin dependent kinase substrate 1, NUCKS1 and ubiquinol-cytochrome c reductase complex assembly factor 1, UQCC1) and muscle mass and function (p-values range 5.98 × 10−6 to 9.26 × 10−55). To be specific, BORCS7 and UQCC1 negatively regulated muscle quantity and quality, whereas enhancing PM20D1 and NUCKS1 expression showed promise in promoting muscle mass and function. Causal relationships remained robust across sensitivity analyses, with UQCC1 exhibiting notable colocalization effects (PP·H4 93.4 % to 95.8 %). Further validation and in vivo replication verified the potential causality between these genes and muscle mass as well as function.

Conclusions

Our druggable genome-wide MR analysis identifies BORCS7, PM20D1, NUCKS1, and UQCC1 as causally associated with muscle mass and function. These findings offer insights into the genetic basis of sarcopenia, paving the way for these genes to become promising drug targets in mitigating this debilitating condition.

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确定肌肉疏松症相关特征的遗传决定因素:对可药用基因的孟德尔随机化研究。
背景:肌肉疏松症的特点是肌肉质量和功能逐渐丧失,尤其影响老年人,并导致跌倒和死亡等严重后果。尽管肌肉疏松症普遍存在,但却缺乏针对肌肉疏松症的药物疗法。利用大样本全基因组关联研究(GWAS)数据对于发现具有成本效益的药物至关重要。方法:在此,我们进行了四项研究,以了解基因成分对肌肉质量和功能的推定因果效应。研究 1 对 15,944 个潜在的可药用基因采用了双样本孟德尔随机法(MR),调查了欧洲人群(样本数达 461,089 个)中这些基因与肌肉数量和质量的潜在因果关系。研究 2 通过敏感性分析和共定位分析验证了 MR 结果。研究 3 将验证范围扩大到其他欧洲队列,研究 4 则进行了定量活体验证:MR分析表明,四个基因(BLOC-1相关复合体亚基7,BORCS7;含有m20结构域的肽酶1,PM20D1;核酪蛋白激酶和细胞周期蛋白依赖激酶底物1,NUCKS1和泛醌-细胞色素c还原酶复合体组装因子1,UQCC1)与肌肉质量和功能之间存在明显的因果关系(P值范围为5.98 × 10-6至9.26 × 10-55)。具体而言,BORCS7 和 UQCC1 对肌肉的数量和质量有负面调节作用,而提高 PM20D1 和 NUCKS1 的表达则有望促进肌肉的质量和功能。在各种敏感性分析中,因果关系保持稳健,UQCC1表现出显著的共定位效应(PP-H4 93.4%至95.8%)。进一步的验证和体内复制验证了这些基因与肌肉质量和功能之间的潜在因果关系:我们的可药用全基因组磁共振分析确定了 BORCS7、PM20D1、NUCKS1 和 UQCC1 与肌肉质量和功能的因果关系。这些发现深入揭示了肌肉疏松症的遗传基础,为这些基因成为药物靶点以减轻这种令人衰弱的病症铺平了道路。
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来源期刊
Metabolism: clinical and experimental
Metabolism: clinical and experimental 医学-内分泌学与代谢
CiteScore
18.90
自引率
3.10%
发文量
310
审稿时长
16 days
期刊介绍: Metabolism upholds research excellence by disseminating high-quality original research, reviews, editorials, and commentaries covering all facets of human metabolism. Consideration for publication in Metabolism extends to studies in humans, animal, and cellular models, with a particular emphasis on work demonstrating strong translational potential. The journal addresses a range of topics, including: - Energy Expenditure and Obesity - Metabolic Syndrome, Prediabetes, and Diabetes - Nutrition, Exercise, and the Environment - Genetics and Genomics, Proteomics, and Metabolomics - Carbohydrate, Lipid, and Protein Metabolism - Endocrinology and Hypertension - Mineral and Bone Metabolism - Cardiovascular Diseases and Malignancies - Inflammation in metabolism and immunometabolism
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