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

• Published in: Nature communications Vol. 14; no. 1; pp. 307 - 12
• Main Authors: Kentistou, Katherine A., Luan, Jian’an, Wittemans, Laura B. L., Hambly, Catherine, Klaric, Lucija, Kutalik, Zoltán, Speakman, John R., Wareham, Nicholas J., Kendall, Timothy J., Langenberg, Claudia, Wilson, James F., Joshi, Peter K., Morton, Nicholas M.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 19.01.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 14; 45/43; 631/208/205/2138; 631/208/457/649; 64/60; 82/51; ADAMTS Proteins - genetics; Adipose tissue; Adiposity - genetics; Animals; Biobanks; Body fat; Body Mass Index; Body weight gain; Gene loci; Genetics; Genome; Genomes; Global health; Health risks; Humanities and Social Sciences; Humans; Metabolic rate; Metabolism; Mice; Mice, Knockout; Mortality risk; multidisciplinary; Obesity; Obesity - genetics; Phenotype; Phenotypes; Public health; Science; Science (multidisciplinary); Therapeutic targets; Weight Gain - genetics
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-35563-0

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. Our understanding of the genetic contribution to human adiposity is incomplete, as few studies measure adiposity directly. Here, the authors impute whole-body imaging adiposity phenotypes in large biobanks, enhancing their power to discover genes driving human adiposity, and further investigate one such gene using a mouse model.