TY - JOUR
T1 - Genetic Architecture of Human Obesity Traits in the Rhesus Macaque
AU - Raboin, Michael J.
AU - Letaw, John
AU - Mitchell, Asia D.
AU - Toffey, David
AU - McKelvey, Jessica
AU - Roberts, Charles T.
AU - Curran, Joanne E.
AU - Vinson, Amanda
N1 - Funding Information:
Funding agencies: This work was supported by P51 OD011092 for operation of the Oregon National Primate Research Center and by support provided to AV from the Human Genetics Initiative and the Knight Cardiovascular Institute at Oregon Health & Science University, Portland, Oregon. Disclosure: The authors declared no conflicts of interest. Additional Supporting Information may be found in the online version of this article. Received: 20 June 2018; Accepted: 31 October 2018; Published online 11 February 2019. doi:10.1002/oby.22392
Funding Information:
agencies: This work was supported by P51 OD011092 for operation of the Oregon National Primate Research Center and by support provided to AV from the Human Genetics Initiative and the Knight Cardiovascular Institute at Oregon Health & Science University, Portland, Oregon.We thank Vincent Diego, PhD, of the Department of Human Genetics at the University of Texas Rio Grande Valley, and Dr Kamm Prongay, DVM, MCR, for helpful discussions of sex-specific heritability and of growth and adiposity in macaques, respectively. We are also grateful to the animal care personnel at the Oregon National Primate Research Center for their assistance in our collection of all phenotypic measures.
Publisher Copyright:
© 2019 The Obesity Society
PY - 2019/3
Y1 - 2019/3
N2 - Objective: Whereas the metabolic consequences of obesity have been studied extensively in the rhesus macaque, corollary genetic studies of obesity are nonexistent. This study assessed genetic contributions to spontaneous adiposity in this species. Methods: Phenotypic variation by age class and sex for BMI, waist to height ratio, waist to thigh ratio, and waist circumference was assessed in 583 macaques. Total and sex-specific heritability for all traits was estimated, including waist to thigh ratio adjusted for BMI, as well as genotypic and phenotypic correlations. In addition, functional genetic variation at BDNF, FTO, LEP, LEPR, MC4R, PCSK1, POMC, and SIM1 was assessed in four animals with extreme spontaneous adiposity. Results: Trait heritability in the combined sample was low to moderate (0.14-0.32), whereas 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 to 0.93 indicating substantial pleiotropy. Likely functional variants were discovered in the four macaques at all eight human obesity genes, including six missense mutations in BDNF, FTO, LEP, LEPR, and PCSK1 and, notably, one nonsense mutation in LEPR. Conclusions: A moderate polygenic contribution to adiposity in rhesus macaques was found, as well as mutations with potentially larger effects in multiple genes that influence obesity in humans.
AB - Objective: Whereas the metabolic consequences of obesity have been studied extensively in the rhesus macaque, corollary genetic studies of obesity are nonexistent. This study assessed genetic contributions to spontaneous adiposity in this species. Methods: Phenotypic variation by age class and sex for BMI, waist to height ratio, waist to thigh ratio, and waist circumference was assessed in 583 macaques. Total and sex-specific heritability for all traits was estimated, including waist to thigh ratio adjusted for BMI, as well as genotypic and phenotypic correlations. In addition, functional genetic variation at BDNF, FTO, LEP, LEPR, MC4R, PCSK1, POMC, and SIM1 was assessed in four animals with extreme spontaneous adiposity. Results: Trait heritability in the combined sample was low to moderate (0.14-0.32), whereas 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 to 0.93 indicating substantial pleiotropy. Likely functional variants were discovered in the four macaques at all eight human obesity genes, including six missense mutations in BDNF, FTO, LEP, LEPR, and PCSK1 and, notably, one nonsense mutation in LEPR. Conclusions: A moderate polygenic contribution to adiposity in rhesus macaques was found, as well as mutations with potentially larger effects in multiple genes that influence obesity in humans.
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U2 - 10.1002/oby.22392
DO - 10.1002/oby.22392
M3 - Article
C2 - 30741480
AN - SCOPUS:85061452264
VL - 27
SP - 479
EP - 488
JO - Obesity
JF - Obesity
SN - 1930-7381
IS - 3
ER -