TY - JOUR
T1 - Large scale phenotype imputation and in vivo functional validation implicate ADAMTS14 as an adiposity gene
AU - Kentistou, Katherine
AU - Luan, Jian'an
AU - Wittemans, Laura B L
AU - Hambly, Catherine
AU - Klaric, Lucija
AU - Kutalik, Zoltan
AU - Speakman, John R.
AU - Wareham, Nicholas J
AU - Kendall, Timothy J.
AU - Langenberg, Claudia
AU - Wilson, James F.
AU - Joshi, Peter K
AU - Morton, Nicholas M
N1 - Funding Information:
K.A.K. acknowledges funding from the MRC Doctoral Training Programme in Precision Medicine (MR/N013166/1). L.K. was supported by an RCUK Innovation Fellowship from the National Productivity Investment Fund (MR/R026408/1). Z.K. was supported by the Swiss National Science Foundation (310030-189147). J.F.W. acknowledges funding from the MRC Human Genetics Unit programme grant Quantitative Traits in Health and Disease (U. MC_UU_00007/10). N.M.M. was supported by a Wellcome Trust New Investigator Award (100981/Z/13/Z). We kindly thank Alain Colige and colleagues at the University of Liege for the provision of Adamts14+ /–mouse sperm. We would also like to thank the researchers, funders and participants of all the contributing cohorts. Specifically, we thank the UK Biobank Resource, approved under application 19655. ORCADES was supported by the Chief Scientist Office of the Scottish Government (CZB/4/276, CZB/4/710), the Royal Society, the MRC Human Genetics Unit, Arthritis Research UK and the European Union framework program 6 EUROSPAN project (contract no. LSHG-CT-2006-018947). DNA extractions were performed at the Clinical Research Facility in Edinburgh. We would like to acknowledge the invaluable contributions of the research nurses in Orkney, the administrative team in Edinburgh and the people of Orkney. The EPIC-Norfolk study (https://doi.org/10.22025/2019.10.105.00004) has received funding from the Medical Research Council (MR/N003284/1 and MC-UU_12015/1) and Cancer Research UK (C864/A14136). The genetics work in the EPIC-Norfolk study was funded by the Medical Research Council (MC_PC_13048). We are grateful to all the participants who have been part of the project and to the many members of the study teams at the University of Cambridge who have enabled this research. The Fenland Study (10.22025/2017.10.101.00001) is funded by the Medical Research Council (MC_UU_12015/1). We are grateful to all the volunteers and to the General Practitioners and practice staff for assistance with recruitment. We thank the Fenland Study Investigators, Fenland Study Co-ordination team and the Epidemiology Field, Data and Laboratory teams. We further acknowledge support for genomics from the Medical Research Council (MC_PC_13046).
Funding Information:
K.A.K. acknowledges funding from the MRC Doctoral Training Programme in Precision Medicine (MR/N013166/1). L.K. was supported by an RCUK Innovation Fellowship from the National Productivity Investment Fund (MR/R026408/1). Z.K. was supported by the Swiss National Science Foundation (310030-189147). J.F.W. acknowledges funding from the MRC Human Genetics Unit programme grant Quantitative Traits in Health and Disease (U. MC_UU_00007/10). N.M.M. was supported by a Wellcome Trust New Investigator Award (100981/Z/13/Z). We kindly thank Alain Colige and colleagues at the University of Liege for the provision of Adamts14 mouse sperm. We would also like to thank the researchers, funders and participants of all the contributing cohorts. Specifically, we thank the UK Biobank Resource, approved under application 19655. ORCADES was supported by the Chief Scientist Office of the Scottish Government (CZB/4/276, CZB/4/710), the Royal Society, the MRC Human Genetics Unit, Arthritis Research UK and the European Union framework program 6 EUROSPAN project (contract no. LSHG-CT-2006-018947). DNA extractions were performed at the Clinical Research Facility in Edinburgh. We would like to acknowledge the invaluable contributions of the research nurses in Orkney, the administrative team in Edinburgh and the people of Orkney. The EPIC-Norfolk study ( https://doi.org/10.22025/2019.10.105.00004 ) has received funding from the Medical Research Council (MR/N003284/1 and MC-UU_12015/1) and Cancer Research UK (C864/A14136). The genetics work in the EPIC-Norfolk study was funded by the Medical Research Council (MC_PC_13048). We are grateful to all the participants who have been part of the project and to the many members of the study teams at the University of Cambridge who have enabled this research. The Fenland Study (10.22025/2017.10.101.00001) is funded by the Medical Research Council (MC_UU_12015/1). We are grateful to all the volunteers and to the General Practitioners and practice staff for assistance with recruitment. We thank the Fenland Study Investigators, Fenland Study Co-ordination team and the Epidemiology Field, Data and Laboratory teams. We further acknowledge support for genomics from the Medical Research Council (MC_PC_13046). +/–
Publisher Copyright:
© 2022, The Author(s).
PY - 2023/1/19
Y1 - 2023/1/19
N2 - 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 imputed DXA adiposity phenotypes in UK Biobank from the 4,366 directly measured participants onto the rest of the cohort, greatly increasing our discovery power. GWAS on these imputed phenotypes in 392,535 participants yielded hundreds of associations, six of which were replicated in independent DXA cohorts. The leading causal gene candidate, ADAMTS14, was further investigated in a mouse knockout model. Concordant with the GWAS data, the Adamts14–/– mice exhibited reduced adiposity and weight-gain under obesogenic conditions, alongside an improved metabolic rate and health. Phenotypic imputation at scale has offered deeper biological insights into the genetics of human adiposity that could lead to therapeutic targets.
AB - 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 imputed DXA adiposity phenotypes in UK Biobank from the 4,366 directly measured participants onto the rest of the cohort, greatly increasing our discovery power. GWAS on these imputed phenotypes in 392,535 participants yielded hundreds of associations, six of which were replicated in independent DXA cohorts. The leading causal gene candidate, ADAMTS14, was further investigated in a mouse knockout model. Concordant with the GWAS data, the Adamts14–/– mice exhibited reduced adiposity and weight-gain under obesogenic conditions, alongside an improved metabolic rate and health. Phenotypic imputation at scale has offered deeper biological insights into the genetics of human adiposity that could lead to therapeutic targets.
U2 - 10.1038/s41467-022-35563-0
DO - 10.1038/s41467-022-35563-0
M3 - Article
SN - 2041-1723
JO - Nature Communications
JF - Nature Communications
ER -