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

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, James F. Wilson, Peter K. Joshi and Nicholas M. Morton ()
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Katherine A. Kentistou: University of Edinburgh
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
John R. Speakman: University of Aberdeen
Nicholas J. Wareham: University of Cambridge
Timothy J. Kendall: University of Edinburgh
Claudia Langenberg: University of Cambridge
James F. Wilson: University of Edinburgh
Peter K. Joshi: University of Edinburgh
Nicholas M. Morton: University of Edinburgh

Nature Communications, 2023, vol. 14, issue 1, 1-12

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-022-35563-0

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