SFEBES2025 Oral Communications Metabolism, Obesity and Diabetes (6 abstracts)
Canine genome-wide association study identifies DENND1B as a canine and human obesity gene which regulates melanocortin signalling
Natalie Wallis 1 , Alyce McClellan 1 , Alexander Mörseburg 1 , Katherine Kentistou 1 , Aqfan Jamaluddin 2 , Georgina Dowsett 1 , Ellen Schofield 1 , Anna Morros-Nuevo 1 , Sadia Saeed 3,4 , Brian Lam 1 , Natasha Sumanasekera 1 , Justine Chan 1 , Sambhavi Kumar 1 , Rey Zhang 1 , Jodie Wainwright 1 , Marie Dittmann 1 , Gabriella Lakatos 1 , Kara Rainbow 1 , David Withers 1 , Rebecca Bounds 1 , Marcella Ma 1 , Alexander German 5 , Jane Ladlow 1 , David Sargan 1 , Philippe Froguel 3,4 , I. Sadaf Farooqi 1 , Ken Ong 1 , Giles Yeo 1 , John Tadross 1,6 , John Perry 1 , Caroline Gorvin 2 & Eleanor Raffan 1
1University of Cambridge, Cambridge, United Kingdom; 2University of Birmingham, Birmingham, United Kingdom; 3University of Lille, Lille, France; 4Imperial College, London, United Kingdom; 5University of Liverpool, Liverpool, United Kingdom; 6Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom
Obesity is an important heritable disease, but its genetic basis is not clearly understood. In dogs, selective breeding renders some breeds, including Labrador retrievers, particularly susceptible to obesity and makes trait mapping tractable. We performed a canine genome-wide association study (GWAS) for obesity in 241 Labrador retrievers. We showed polygenic risk affects individual susceptibility to weight gain in an obesogenic environment and that owners of at risk dogs must exercise greater restraint to keep at-risk dogs slim. To test if genes identified on the canine GWAS were relevant to human obesity, we examined regions orthologous to those mapped in dogs in human data sets. Specifically, we tested for association with BMI in a GWAS on 806,834 participants from the GIANT study; an exome-wide association study (ExWAS) of rare, deleterious exome variants from 454,787 individuals from the UK Biobank study; rare variant enrichment tests in the Severe Childhood Onset Obesity Project; and the Severe Obesity in Pakistani Population (SOPP) cohort. This approach identified some form of genetic association with human obesity for each of the top five canine loci. The lead association in dogs was with rs24430444 within the gene DENN domain containing 1B (DENND1B) with the risk SNP being associated with ~7% greater body fat. In humans, DENND1B was significantly associated with BMI in the GWAS and ExWAS studies and a homozygous variant found in DENND1B was a candidate for causing severe obesity in a patient from SOPP. We demonstrated that DENND1B regulates signalling and trafficking of MC4R, a hypothalamic receptor which has a central role in energy homeostasis. In summary, our work used canine genetics to identify novel obesity genes and mechanisms relevant to both dogs and humans.
Volume 109
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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