2型糖尿病与肌肉质量、功能及衰弱的共享遗传结构揭示了共病病因及多效性可药物靶向。
Shared genetic architecture of type 2 diabetes with muscle mass and function and frailty reveals comorbidity etiology and pleiotropic druggable targets.
作者信息
Dou Chun, Liu Dong, Kong Lijie, Chen Mingling, Ye Chaojie, Zhu Zheng, Zheng Jie, Xu Min, Xu Yu, Li Mian, Zhao Zhiyun, Lu Jieli, Chen Yuhong, Ning Guang, Wang Weiqing, Bi Yufang, Wang Tiange
机构信息
Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
出版信息
Metabolism. 2025 Mar;164:156112. doi: 10.1016/j.metabol.2024.156112. Epub 2024 Dec 20.
BACKGROUND
Delineating the shared genetic architecture of type 2 diabetes with muscle mass and function and frailty is essential for unraveling the common etiology and developing holistic therapeutic strategies for these co-existing conditions.
METHODS
In this genome-wide pleiotropic association study, we performed multi-level pairwise trait pleiotropic analyses using genome-wide association study summary statistics from up to 461,026 European ancestry individuals to dissect the shared genetic factors and causal relationships of type 2 diabetes and seven glycemic traits with four muscle mass- and function-related phenotypes and the frailty index.
RESULTS
We first identified 27 pairs with significant genetic correlations through the linkage disequilibrium score regression and high-definition likelihood analysis. Then we determined 79 pleiotropic loci and 109 pleiotropic genes across linkage pairs via the pleiotropic analysis under the composite null hypothesis (PLACO), the colocalization, and the Multi-marker Analysis of GenoMic Annotation (MAGMA) analyses. We subsequently performed transcriptome-wide association study (TWAS) analyses using joint-tissue imputation, refined by gene-based integrative fine-mapping through a conditional TWAS approach, and identified 44 unique causal shared genes across 13 tissues in linkage pairs, including eight druggable genes (ABO, AOC1, FTO, GCKR, MTOR, POLK, PPARG, and APEH), with MTOR and PPARG categorized as clinically actionable. Two-sample Mendelian randomization analysis supported bidirectional causality between diabetes and frailty index and unidirectional causal effects of muscle phenotypes on glycemic profiles.
CONCLUSIONS
Our findings highlight the common genetic underpinnings between type 2 diabetes and muscle loss and frailty and inform drug targets with pleiotropic effects on both of these aging-related challenges.
背景
明确2型糖尿病与肌肉质量、功能以及虚弱之间的共同遗传结构，对于揭示这些共存疾病的共同病因并制定整体治疗策略至关重要。
方法
在这项全基因组多效性关联研究中，我们利用多达461,026名欧洲血统个体的全基因组关联研究汇总统计数据，进行了多层次的成对性状多效性分析，以剖析2型糖尿病和七种血糖性状与四种肌肉质量和功能相关表型以及虚弱指数之间的共同遗传因素和因果关系。
结果
我们首先通过连锁不平衡评分回归和高清似然性分析确定了27对具有显著遗传相关性的性状对。然后，我们通过复合零假设下的多效性分析（PLACO）、共定位分析以及基因组注释多标记分析（MAGMA），在连锁对中确定了79个多效性位点和109个多效性基因。随后，我们使用联合组织归因进行转录组范围的关联研究（TWAS）分析，并通过条件TWAS方法进行基于基因的综合精细定位来优化，在连锁对中的13个组织中确定了44个独特的因果共享基因，包括八个可成药基因（ABO、AOC1、FTO、GCKR、MTOR、POLK、PPARG和APEH），其中MTOR和PPARG被归类为具有临床可操作性。两样本孟德尔随机化分析支持糖尿病与虚弱指数之间的双向因果关系以及肌肉表型对血糖谱的单向因果效应。
结论
我们的研究结果突出了2型糖尿病与肌肉流失和虚弱之间的共同遗传基础，并为应对这两种与衰老相关挑战均具有多效性作用的药物靶点提供了信息。
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