背景:肌肉减少症,以进行性肌肉质量和功能丧失为特征,尤其影响老年人,并导致严重的后果,如跌倒和死亡。尽管流行,缺乏针对肌肉减少症的靶向药物治疗.利用大样本全基因组关联研究(GWAS)数据对于具有成本效益的药物发现至关重要。
方法:这里,我们进行了四项研究,以了解遗传成分对肌肉质量和功能的假定因果效应。研究1对15,944个潜在的可药用基因进行了双样本孟德尔随机化(MR),调查他们与欧洲人群肌肉数量和质量的潜在因果关系(N高达461,089)。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在其他欧洲队列中扩展了验证,并对研究4进行了体内定量验证。
结果:MR分析揭示了四个基因(BLOC-1相关的复合物亚基7,BORCS7;包含1的肽酶m20结构域,PM20D1;核酪蛋白激酶和细胞周期蛋白依赖性激酶底物1,NUCKS1和泛醇-细胞色素c还原酶复合物组装因子1,UQCC1)与肌肉质量和功能之间存在显着因果关系(p值范围为5.98×9.10至具体而言,BORCS7和UQCC1负调节肌肉数量和质量,而增强PM20D1和NUCKS1表达显示出促进肌肉质量和功能的前景。因果关系在敏感性分析中保持稳健,UQCC1表现出显着的共定位效应(PP·H493.4%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以及功能之间的潜在因果关系。
结论:我们的药物全基因组MR分析确定BORCS7、PM20D1、NUCKS1和UQCC1与肌肉质量和功能有因果关系。这些发现为肌少症的遗传基础提供了见解,为这些基因成为缓解这种衰弱状况的有希望的药物靶标铺平了道路。
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.