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Multivariate genome-wide analyses of insulin resistance unravel novel loci and therapeutic targets for cardiometabolic health

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Listed:
  • Chaojie Ye

    (Shanghai Jiao Tong University School of Medicine
    Shanghai Jiao Tong University School of Medicine)

  • Chun Dou

    (Shanghai Jiao Tong University School of Medicine
    Shanghai Jiao Tong University School of Medicine)

  • Dong Liu

    (Shanghai Jiao Tong University School of Medicine
    Shanghai Jiao Tong University School of Medicine)

  • Lijie Kong

    (Shanghai Jiao Tong University School of Medicine
    Shanghai Jiao Tong University School of Medicine)

  • Mingling Chen

    (Shanghai Jiao Tong University School of Medicine
    Shanghai Jiao Tong University School of Medicine)

  • Min Xu

    (Shanghai Jiao Tong University School of Medicine
    Shanghai Jiao Tong University School of Medicine)

  • Yu Xu

    (Shanghai Jiao Tong University School of Medicine
    Shanghai Jiao Tong University School of Medicine)

  • Mian Li

    (Shanghai Jiao Tong University School of Medicine
    Shanghai Jiao Tong University School of Medicine)

  • Zhiyun Zhao

    (Shanghai Jiao Tong University School of Medicine
    Shanghai Jiao Tong University School of Medicine)

  • Jie Zheng

    (Shanghai Jiao Tong University School of Medicine
    Shanghai Jiao Tong University School of Medicine)

  • Jieli Lu

    (Shanghai Jiao Tong University School of Medicine
    Shanghai Jiao Tong University School of Medicine)

  • Yuhong Chen

    (Shanghai Jiao Tong University School of Medicine
    Shanghai Jiao Tong University School of Medicine)

  • Guang Ning

    (Shanghai Jiao Tong University School of Medicine
    Shanghai Jiao Tong University School of Medicine)

  • Weiqing Wang

    (Shanghai Jiao Tong University School of Medicine
    Shanghai Jiao Tong University School of Medicine)

  • Yufang Bi

    (Shanghai Jiao Tong University School of Medicine
    Shanghai Jiao Tong University School of Medicine)

  • Tiange Wang

    (Shanghai Jiao Tong University School of Medicine
    Shanghai Jiao Tong University School of Medicine)

Abstract

Limited identification of insulin resistance-associated loci hinders understanding of its role in cardiometabolic health, impeding therapeutic strategies. We apply three multivariate genome-wide association study approaches on homeostatic model assessment for insulin resistance, insulin resistance index, fasting insulin, and ratio of triglycerides to high-density lipoprotein cholesterol from MAGIC and UK Biobank to develop a comprehensive phenotype (‘mvIR’), and identify 217 independent loci, including 24 novel loci. The mvIR is causally associated with higher risks of 17 cardiometabolic diseases and five aging phenotypes, independent of adiposity and sarcopenia. We outline 21 of 2644 druggable genes for insulin resistance by Mendelian randomization and colocalization, where six genes (AKT1, ERBB3, FCGR1A, FGFR1, LPL, NR1H3) encode targets for approved drugs with consistent directions in alleviating insulin resistance, with no significant side effects revealed by phenome-wide association study. This study uncovers novel loci and therapeutic targets to inform strategies promoting insulin resistance-centered cardiometabolic health and longevity.

Suggested Citation

  • Chaojie Ye & Chun Dou & Dong Liu & Lijie Kong & Mingling Chen & Min Xu & Yu Xu & Mian Li & Zhiyun Zhao & Jie Zheng & Jieli Lu & Yuhong Chen & Guang Ning & Weiqing Wang & Yufang Bi & Tiange Wang, 2025. "Multivariate genome-wide analyses of insulin resistance unravel novel loci and therapeutic targets for cardiometabolic health," Nature Communications, Nature, vol. 16(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-64985-9
    DOI: 10.1038/s41467-025-64985-9
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    References listed on IDEAS

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    1. Chaojie Ye & Chun Dou & Dong Liu & Lijie Kong & Mingling Chen & Min Xu & Yu Xu & Mian Li & Zhiyun Zhao & Jie Zheng & Jieli Lu & Yuhong Chen & Guang Ning & Weiqing Wang & Yufang Bi & Tiange Wang, 2025. "Multivariate genome-wide analyses of insulin resistance unravel novel loci and therapeutic targets for cardiometabolic health," Nature Communications, Nature, vol. 16(1), pages 1-13, December.

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