Genetic architecture of human obesity traits in the rhesus macaque

OBJECTIVE: While the metabolic consequences of obesity have been studied extensively in the rhesus macaque, corollary genetic studies of obesity are non-existent. Here, we assess genetic contributions to spontaneous adiposity in this species. METHODS: We assessed phenotypic variation by age-class and sex for body mass index, waist-to-height ratio, waist-to-thigh ratio, and waist circumference in 583 macaques. We estimated total and sex-specific heritability for all traits, including waist-to-thigh ratio adjusted for BMI, as well as genotypic and phenotypic correlations. We also assessed functional genetic variation at BDNF, FTO, LEP, LEPR, MC4R, PCSK1, POMC, and SIM1 in 4 animals with extreme spontaneous adiposity. RESULTS: Trait heritability in the combined sample was low-to-moderate (0.14–0.32), while sex-specific heritability was more substantial (0.20–0.67). Heritability was greater in females for all traits except BMI. All traits were robustly correlated, with genetic correlations of 0.63–0.93 indicating substantial pleiotropy. We discovered likely functional variants in the 4 macaques at all 8 human obesity genes, including 6 missense mutations in BDNF, FTO, LEP, LEPR, and PCSK1, and notably, 1 nonsense mutation in LEPR. CONCLUSIONS: We find a moderate polygenic contribution to adiposity in rhesus macaques, and mutations with potentially larger effects in multiple genes that influence obesity in humans.