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

Published version
Peer-reviewed

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Authors

Kentistou, Katherine A  ORCID logo  https://orcid.org/0000-0002-5816-664X
Wittemans, Laura BL 

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.

Description

Keywords

Article, /631/208/205/2138, /631/208/457/649, /13, /14, /45/43, /64/60, /82/51, article

Journal Title

Nat Commun

Conference Name

Journal ISSN

2041-1723
2041-1723

Volume Title

Publisher

Springer Science and Business Media LLC
Sponsorship
Medical Research Council (MC_UU_12015/1)
Medical Research Council (MR/N003284/1)