Canine genome-wide association study identifies DENND1B as an obesity gene in dogs and humans

• 成果类型: Article
• 署名作者: Wallis, Natalie J.; Mcclellan, Alyce; Morseburg, Alexander; Kentistou, Katherine A.; Jamaluddin, Aqfan; Dowsett, Georgina K. C.; Schofield, Ellen; Morros-Nuevo, Anna; Saeed, Sadia; Lam, Brian Y. H.; Sumanasekera, Natasha T.; Chan, Justine; Kumar, Sambhavi S.; Zhang, Rey M.; Wainwright, Jodie F.; Dittmann, Marie; Lakatos, Gabriella; Rainbow, Kara; Withers, David; Bounds, Rebecca; Ma, Marcella; German, Alexander J.; Ladlow, Jane; Sargan, David; Froguel, Philippe; Farooqi, I. Sadaf; Ong, Ken K.; Yeo, Giles S. H.; Tadross, John A.; Perry, John R. B.; Gorvin, Caroline M.; Raffan, Eleanor
• 署名单位: University of Cambridge; University of Cambridge; University of Cambridge; University of Cambridge; University of Birmingham; University of Birmingham; University of Nottingham; University of Cambridge; Institut National de la Sante et de la Recherche Medicale (Inserm); Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute for Biology (INSB); Universite de Lille; Pasteur Network; Institut Pasteur Lille; Universite de Lille; CHU Lille; Imperial College London; University of Liverpool; University of Liverpool; University of Cambridge; University of Cambridge
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8103
• DOI: 10.1126/science.ads2145
• 发表日期: 2025-03-28
• 关键词: melanocyte-stimulating hormone; severe childhood obesity; mixed-model analysis; body condition; variants; tissue; heritability; population; resource; weight

摘要

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 (DENND1B). Each copy of the alternate allele was associated with similar to 7% 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.