Shared genetic architecture of type 2 diabetes with muscle mass and function and frailty reveals comorbidity etiology and pleiotropic druggable targets

Chun Dou; Dong Liu; Lijie Kong; Mingling Chen; Chaojie Ye; Zheng Zhu; Jie Zheng; Min Xu; Yu Xu; Mian Li; Zhiyun Zhao; Jieli Lu; Yuhong Chen; Guang Ning; Weiqing Wang; Yufang Bi; Tiange Wang

doi:10.1016/j.metabol.2024.156112

Shared genetic architecture of type 2 diabetes with muscle mass and function and frailty reveals comorbidity etiology and pleiotropic druggable targets

Metabolism. 2024 Dec 20:156112. doi: 10.1016/j.metabol.2024.156112. Online ahead of print.

Authors

Chun Dou¹, Dong Liu¹, Lijie Kong¹, Mingling Chen¹, Chaojie Ye¹, Zheng Zhu¹, Jie Zheng¹, Min Xu¹, Yu Xu¹, Mian Li¹, Zhiyun Zhao¹, Jieli Lu¹, Yuhong Chen¹, Guang Ning¹, Weiqing Wang¹, Yufang Bi¹, Tiange Wang²

Affiliations

¹ 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.
² 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. Electronic address: tiange.wang@shsmu.edu.cn.

PMID: 39710002
DOI: 10.1016/j.metabol.2024.156112

Abstract

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 APFH), 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.

Keywords: Frailty; Muscle mass and function; Pleiotropic druggable genes; Shared genetic architecture; Type 2 diabetes.