Understanding the Genetic Basis of Obesity: Lessons from Man’s Best Friend

Obesity is an increasingly prevalent and complex disorder which poses a serious threat to canine and human health. Obesity is ultimately caused by caloric excess, and results from the complex interplay between environmental, behavioural, and genetic factors. Study of human obesity has been extensive whilst that in dogs has been limited. Past data on how biological risk factors impact canine obesity have been contradictory and the genetic basis of canine obesity is poorly understood. The heritability of human obesity is estimated at 40-70% and, despite considerable study, the majority of genetic variants responsible for this heritability are yet to be uncovered. Therefore, the understanding of obesity genetics across species is incomplete. In dogs, selective breeding and population bottlenecks simplify gene mapping for complex disease, offering the chance to unpick the ‘missing heritability’ of obesity in both dogs and humans. The studies of this thesis aim to better understand the development of canine obesity and gain insight into obesity genetics across species. First, biological risk factors for obesity were investigated in a population of British pet Labrador retrievers (n = 521), an obesity-prone dog breed. Linear regression was used to assess known and novel risk factors for canine obesity. Findings demonstrated a nuanced effect of known risk factors, with neutering and age having sex-dependent effects on obesity outcome. Chocolate coat colour was discovered as a novel risk factor for Labrador obesity. Some of these risk factors were mediated through an increase in food motivation, providing valuable insight into underlying mechanisms of action in canine obesity. Subsequently, a genome wide association study (GWAS) for obesity in Labrador retrievers was conducted. Multiple obesity-associated loci were identified, and regions of interest harboured candidate genes and variants. Candidate genes were interrogated using cross-species resources, and mechanisms of action hypothesised. Similarities between canine and human obesity means genetic associations in dogs can prioritise and identify obesity genes in human genomic studies. Syntenic human regions and genes were explored through GWAS and rare variant enrichment analyses in large scale human cohorts. Canine obesity loci of large effect served to highlight human loci implicated in common obesity, including genes *CDH8*, *CARD11* and *DENND1B*. Variants in *CSNK1A1* were also found to be associated with monogenic cases of severe, early onset obesity in humans. Carriers were pursued through familial investigation and deep clinical phenotyping. Further, a canine GWAS association of large effect at the *SEMA3D* locus provides strong orthogonal evidence of its importance in energy homeostasis. Canine GWAS summary statistics were used to construct a canine polygenic risk score method for obesity, something not previously achieved in dogs. Genetic scores for obesity predicted phenotypes in related but not unrelated dog breeds. Polygenic scores also provided insight into known within-breed variation in canine obesity risk, explaining associations with coat colour. Polygenic background was shown to influence the penetrance of a well characterised canine *POMC* mutation that affects obesity risk by altering hypothalamic leptin-melanocortin signalling. Additionally, polygenic background affected how owner management practices impact obesity outcome in dogs. This thesis provides novel insight into canine and human obesity, including the identification of new obesity-related genes. An improved understanding of canine obesity risk factors is established and highlights areas for further investigation, particularly through intra-breed study. Findings demonstrate the benefits of studying complex disease in non-traditional animal models such as the dog. This work informs the treatment and prevention of obesity in both human and veterinary medicine.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2023

Author dc:creator

• Wallis, Natalie

Advisor dc:contributor.advisor

• Raffan, Eleanor

• Canine
• Companion animal
• Comparative genomics
• Cross-species
• Dog
• Genetics
• Genomics
• Metabolic disease
• Obesity

Licence

• https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/e413f60c-3fcc-44e2-a1a7-d2094f6dd7da/download
• https://www.rioxx.net/licenses/all-rights-reserved/

Language dc:language

eng

Author Identifier

0000-0001-9543-3711

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/367274