Abstract

Hundreds of genetic variants have been associated with Body Mass Index (BMI) through genome-wide association studies (GWAS) using observational cohorts. However, the genetic contribution to efficient weight loss in response to dietary intervention remains unknown. We perform a GWAS in two large low-caloric diet intervention cohorts of obese participants. Two loci close to NKX6.3/MIR486 and RBSG4 are identified in the Canadian discovery cohort (n = 1166) and replicated in the DiOGenes cohort (n = 789). Modulation of HGTX (NKX6.3 ortholog) levels in Drosophila melanogaster leads to significantly altered triglyceride levels. Additional tissue-specific experiments demonstrate an action through the oenocytes, fly hepatocyte-like cells that regulate lipid metabolism. Our results identify genetic variants associated with the efficacy of weight loss in obese subjects and identify a role for NKX6.3 in lipid metabolism, and thereby possibly weight control.

Individuals show large variability in their capacity to lose weight and maintain this weight. Here, the authors perform GWAS in two weight loss intervention cohorts and identify two genetic loci associated with weight loss that are taken forward for Bayesian fine-mapping and functional assessment in flies.

Details

Title
Genome-wide gene-based analyses of weight loss interventions identify a potential role for NKX6.3 in metabolism
Author
Valsesia Armand 1 ; Qiao-Ping, Wang 2 ; Gheldof Nele 1 ; Carayol Jérôme 1   VIAFID ORCID Logo  ; Ruffieux Hélène 3 ; Clark Teleri 4 ; Shenton, Victoria 4 ; Oyston, Lisa J 4 ; Lefebvre, Gregory 1 ; Metairon Sylviane 1   VIAFID ORCID Logo  ; Chabert, Christian 1 ; Walter Ondine 1 ; Mironova Polina 1 ; Lau, Paulina 5 ; Descombes, Patrick 1   VIAFID ORCID Logo  ; Viguerie Nathalie 6   VIAFID ORCID Logo  ; Langin Dominique 7   VIAFID ORCID Logo  ; Harper, Mary-Ellen 8   VIAFID ORCID Logo  ; Astrup Arne 9   VIAFID ORCID Logo  ; Saris, Wim H 10   VIAFID ORCID Logo  ; Dent, Robert 11 ; Neely, Greg G 4 ; Hager Jörg 1 

1  Nestlé Institute of Health Sciences, Lausanne, Switzerland (GRID:grid.419905.0) (ISNI:0000 0001 0066 4948) 
2  Functional Genomics group, Charles Perkins Centre, University of Sydney, Sydney, Australia (GRID:grid.1013.3) (ISNI:0000 0004 1936 834X); School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Guangzhou, China (GRID:grid.12981.33) (ISNI:0000 0001 2360 039X) 
3  Nestlé Institute of Health Sciences, Lausanne, Switzerland (GRID:grid.419905.0) (ISNI:0000 0001 0066 4948); Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland (GRID:grid.5333.6) (ISNI:0000000121839049) 
4  Functional Genomics group, Charles Perkins Centre, University of Sydney, Sydney, Australia (GRID:grid.1013.3) (ISNI:0000 0004 1936 834X) 
5  Ottawa Hospital Weight Management Clinic, The Ottawa Hospital, Ottawa, Canada (GRID:grid.412687.e) (ISNI:0000 0000 9606 5108) 
6  Institute of Metabolic and Cardiovascular Diseases, INSERM, Paul Sabatier University, UMR 1048, Obesity Research Laboratory, University of Toulouse, Toulouse, France (GRID:grid.11417.32) (ISNI:0000 0001 2353 1689) 
7  Institute of Metabolic and Cardiovascular Diseases, INSERM, Paul Sabatier University, UMR 1048, Obesity Research Laboratory, University of Toulouse, Toulouse, France (GRID:grid.11417.32) (ISNI:0000 0001 2353 1689); Toulouse University Hospitals, Department of Clinical Biochemistry, Toulouse, France (GRID:grid.11417.32) (ISNI:0000 0001 2353 1689) 
8  Faculty of Medicine, University of Ottawa, Department of Biochemistry, Microbiology and Immunology, Ottawa, Canada (GRID:grid.28046.38) (ISNI:0000 0001 2182 2255) 
9  Faculty of Science, University of Copenhagen, Department of Nutrition, Exercise and Sports, Copenhagen, Denmark (GRID:grid.5254.6) (ISNI:0000 0001 0674 042X) 
10  Maastricht University Medical Centre+(MUMC+), Department of Human Biology, NUTRIM, School of Nutrition and Translational Research in Metabolism, Maastricht, The Netherlands (GRID:grid.412966.e) (ISNI:0000 0004 0480 1382) 
11  Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland (GRID:grid.5333.6) (ISNI:0000000121839049) 
Publication year
2019
Publication date
Feb 2019
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-019-08492-8
ProQuest document ID
2174745236
Copyright
This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.