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Large scale phenotype imputation and in vivo functional validation implicate ADAMTS14 as an adiposity gene

Author

Listed:
  • Katherine A. Kentistou

    (University of Edinburgh
    University of Edinburgh
    University of Cambridge)

  • Jian’an Luan

    (University of Cambridge)

  • Laura B. L. Wittemans

    (University of Cambridge)

  • Catherine Hambly

    (University of Aberdeen)

  • Lucija Klaric

    (University of Edinburgh)

  • Zoltán Kutalik

    (University of Lausanne
    Swiss Institute of Bioinformatics)

  • John R. Speakman

    (University of Aberdeen
    Chinese Academy of Sciences
    CAS Centre of Excellence in Animal Evolution and Genetics)

  • Nicholas J. Wareham

    (University of Cambridge)

  • Timothy J. Kendall

    (University of Edinburgh)

  • Claudia Langenberg

    (University of Cambridge
    Berlin Institute of Health (BIH) Charité University Medicine)

  • James F. Wilson

    (University of Edinburgh
    University of Edinburgh)

  • Peter K. Joshi

    (University of Edinburgh)

  • Nicholas M. Morton

    (University of Edinburgh)

Abstract

Obesity remains an unmet global health burden. Detrimental anatomical distribution of body fat is a major driver of obesity-mediated mortality risk and is demonstrably heritable. However, our understanding of the full genetic contribution to human adiposity is incomplete, as few studies measure adiposity directly. To address this, we impute whole-body imaging adiposity phenotypes in UK Biobank from the 4,366 directly measured participants onto the rest of the cohort, greatly increasing our discovery power. Using these imputed phenotypes in 392,535 participants yielded hundreds of genome-wide significant associations, six of which replicate in independent cohorts. The leading causal gene candidate, ADAMTS14, is further investigated in a mouse knockout model. Concordant with the human association data, the Adamts14−/− mice exhibit reduced adiposity and weight-gain under obesogenic conditions, alongside an improved metabolic rate and health. Thus, we show that phenotypic imputation at scale offers deeper biological insights into the genetics of human adiposity that could lead to therapeutic targets.

Suggested Citation

  • Katherine A. Kentistou & Jian’an Luan & Laura B. L. Wittemans & Catherine Hambly & Lucija Klaric & Zoltán Kutalik & John R. Speakman & Nicholas J. Wareham & Timothy J. Kendall & Claudia Langenberg & J, 2023. "Large scale phenotype imputation and in vivo functional validation implicate ADAMTS14 as an adiposity gene," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-022-35563-0
    DOI: 10.1038/s41467-022-35563-0
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    References listed on IDEAS

    as
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