Identifying genetic overlaps in obesity and metabolic disorders unlocking unique and shared mechanistic insights

IF 7.1 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Free Radical Biology and Medicine Pub Date : 2025-02-23 DOI:10.1016/j.freeradbiomed.2025.02.033

Liwan Fu , Xiaodi Han , Yuquan Wang , Yue-Qing Hu

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引用次数: 0

Abstract

Objective

Obesity has a high heritability and frequently co-occurs with metabolic disorders, indicating shared genetic susceptibility. The underlying causative genes and biological mechanisms of obesity and metabolic disorders remain predominantly elusive.

Methods

The FinnGen R11 dataset, including over 450,000 subjects, was employed in conjunction with the Genotype-Tissue Expression Project (GTEx) v8 eQTls dataset to conduct cross-tissue transcriptome association studies, Functional Summary-based Imputation in single tissues, and Gene Analysis combined with Multimarker Analysis of Genomic Annotation, respectively, for identifying distinct and shared genetic architectures of obesity and metabolic disorders. We also employed RHOGE to ascertain the genetic correlation and putative causal directions between them. Subsequent Mendelian randomization, colocalization analyses, and other cell and tissue enrichment analyses were employed to enhance our understanding of the functional implications of these susceptibility genes.

Results

A total of 35 genes were identified as obesity susceptibility and 10 genes linked to metabolic disorder susceptibility. Of these, three genes (MCM6, MAPRE3 and UBXN4) were identified as being shared. Mendelian randomization and colocalization analyses revealed the three shared genes have causal associations with obesity and metabolic disorders and serve as independent signals. Subsequent analyses indicated MCM6 may influence obesity and metabolic disorder risk by regulating DNA replication, cell proliferation, and interactions with chemical responses. MAPRE3 may confer protective effects against obesity and metabolic disorders through PAK Pathway, while UBXN4 may involve in regulating cholesterol metabolism.

Conclusion

Our study provides insight into the novel shared genetic mechanism between obesity and metabolic disorders and identifies potential targets for pharmacological intervention.

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来源期刊

Free Radical Biology and Medicine 医学-内分泌学与代谢

CiteScore

14.00

自引率

4.10%

发文量

850

审稿时长

22 days

期刊介绍： Free Radical Biology and Medicine is a leading journal in the field of redox biology, which is the study of the role of reactive oxygen species (ROS) and other oxidizing agents in biological systems. The journal serves as a premier forum for publishing innovative and groundbreaking research that explores the redox biology of health and disease, covering a wide range of topics and disciplines. Free Radical Biology and Medicine also commissions Special Issues that highlight recent advances in both basic and clinical research, with a particular emphasis on the mechanisms underlying altered metabolism and redox signaling. These Special Issues aim to provide a focused platform for the latest research in the field, fostering collaboration and knowledge exchange among researchers and clinicians.