Canine genome-wide association study identifies <i>DENND1B</i> as an obesity gene in dogs and humans
Obesity is a heritable disease, but its genetic basis is incompletely understood. Canine population history facilitates trait mapping. We performed a canine genome-wide association study for body condition score-a measure of obesity-in 241 Labrador retrievers. Using a cross-species approach, we showed that canine obesity genes are also associated with rare and common forms of obesity in humans. The lead canine association was within the gene DENN domain containing 1B (<i>DENND1B</i>). Each copy of the alternate allele was associated with ~7.5% greater body fat. We demonstrate a role for this gene in regulating signaling and trafficking of melanocortin 4 receptor, a critical controller of energy homeostasis. Thus, canine genetics identified obesity genes and mechanisms relevant to both dogs and humans.
Authors
- Gabriella Lakatos (ORCID: https://orcid.org/0000-0003-1436-7324)
- Alyce McClellan (ORCID: https://orcid.org/0000-0003-0658-4812)
- Natalie Wallis (ORCID: https://orcid.org/0000-0001-9543-3711)
- I. Sadaf Farooqi (ORCID: https://orcid.org/0000-0001-7609-3504)
- Rey M. Zhang (ORCID: https://orcid.org/0000-0003-1755-0407)
- Philippe Froguel (ORCID: https://orcid.org/0000-0003-2972-0784)
- Caroline M. Gorvin (ORCID: https://orcid.org/0000-0002-1361-9174)
- David R. Sargan (ORCID: https://orcid.org/0000-0001-9897-2489)
- Marcella Ma (ORCID: https://orcid.org/0000-0002-2228-7466)
- Rebecca Bounds (ORCID: https://orcid.org/0000-0001-8830-9456)
- Ken K. Ong (ORCID: https://orcid.org/0000-0003-4689-7530)
- Alexander J. German (ORCID: https://orcid.org/0000-0002-3017-7988)
- Brian Y.H. Lam (ORCID: https://orcid.org/0000-0002-3638-9025)
- Marie T. Dittmann
- Eleanor Raffan (ORCID: https://orcid.org/0000-0002-1403-3538)
- John R. B. Perry (ORCID: https://orcid.org/0000-0001-6483-3771)
- Aqfan Jamaluddin (ORCID: https://orcid.org/0000-0003-4934-3277)
- David Withers
- Kara Rainbow (ORCID: https://orcid.org/0000-0002-8089-0693)
- Georgina K.C. Dowsett (ORCID: https://orcid.org/0000-0002-2134-8554)
- Sadia Saeed (ORCID: https://orcid.org/0000-0003-3144-7772)
- Jane Ladlow (ORCID: https://orcid.org/0000-0002-8076-4021)
- Katherine A. Kentistou (ORCID: https://orcid.org/0000-0002-5816-664X)
- Giles S.H. Yeo (ORCID: https://orcid.org/0000-0001-8823-3615)
- Ellen Schofield (ORCID: https://orcid.org/0000-0003-0648-1418)
- Alexander Mörseburg (ORCID: https://orcid.org/0000-0003-4832-4007)
- John A. Tadross (ORCID: https://orcid.org/0000-0002-8424-1252)
- Jodie Wainwright (ORCID: https://orcid.org/0009-0004-1726-2442)
- Natasha T. Sumanasekera
- Anna Morros‐Nuevo (ORCID: https://orcid.org/0009-0007-0309-3811)
- Sanjeev Kumar
- J. Chan (ORCID: https://orcid.org/0000-0002-2151-8031)
Institutions
- Centre National de la Recherche Scientifique (FR)
- University of Liverpool (GB)
- Inserm (FR)
- Université de Lille (FR)
- University of Cambridge (GB)
- Cambridge University Hospitals NHS Foundation Trust (GB)
- National Institute for Health and Care Research (GB)
- Wellcome/MRC Institute of Metabolic Science (GB)
- MRC Epidemiology Unit (GB)
- European Genomic Institute for Diabetes (FR)
- NIHR Cambridge Biomedical Research Centre (GB)
- Imperial College London (GB)
- University of Birmingham (GB)
Publication Details
- Journal
- Science
- Published
- 2025-03-06
- DOI
- https://doi.org/10.1126/science.ads2145
- Citations
- 11
- Primary Topic
- Diet and metabolism studies
- Type
- article
- Field-Weighted Citation Impact
- 12.81
Funders
- Medical Research Council
- Biotechnology and Biological Sciences Research Council