Abstract
Objective:In humans, the ontogeny of obesity throughout the life course and the genetics underlying it has been historically difficult to study. We compared, in a non-human primate model, the lifelong growth trajectories of obese and non-obese adults to assess the heritability of and map potential genomic regions implicated in growth and obesity.Study population:A total of 905 African green monkeys, or vervets (Chlorocebus aethiops sabaeus) (472 females, 433 males) from a pedigreed captive colony.Methods:We measured fasted body weight (BW), crown-to-rump length (CRL), body-mass index (BMI) and waist circumference (WC) from 2000 to 2015. We used a longitudinal clustering algorithm to detect obesogenic growth, and logistic growth curves implemented in nonlinear mixed effects models to estimate three growth parameters. We used maximum likelihood variance decomposition methods to estimate the genetic contributions to obesity-related traits and growth parameters, including a test for the effects of a calorie-restricted dietary intervention. We used multipoint linkage analysis to map implicated genomic regions.Results:All measurements were significantly influenced by sex, and with the exception of WC, also influenced by maternal and post-natal diet. Chronic obesity outcomes were significantly associated with a pattern of extended growth duration with slow growth rates for BW. After accounting for environmental influences, all measurements were found to have a significant genetic component to variability. Linkage analysis revealed several regions suggested to be linked to obesity-related traits that are also implicated in human obesity and metabolic disorders.Conclusions:As in humans, growth patterns in vervets have a significant impact on adult obesity and are largely under genetic control with some evidence for maternal and dietary programming. These results largely mirror findings from human research, but reflect shorter developmental periods, suggesting that the vervet offers a strong genetic model for elucidating the ontogeny of human obesity.
Highlights
The mechanisms by which longitudinal and developmental processes contribute to risk for adult obesity outcomes remain largely unclear, but available evidence suggests the importance of critical periods during which high or low caloric intake, body weight (BW) and weight gain influence adult obesity.[1]
Obesity is highly heritable (h2 of ~ 40–70%), and human genome-wide association studies (GWAS) have identified dozens of replicable loci showing associations with obesity-related phenotypes,[4,5,6,7] these loci do not explain the majority of the heritability for these traits.[7]
Based on our analytical criteria, of the 1665 individuals measured in the Vervet Research Colony (VRC) from 2000 to 2015, a total of 905 were suitable to assess either adult obesity traits, growth patterns or both
Summary
The mechanisms by which longitudinal and developmental processes contribute to risk for adult obesity outcomes remain largely unclear, but available evidence suggests the importance of critical periods during which high or low caloric intake, body weight (BW) and weight gain influence adult obesity.[1]. Obesity is highly heritable (h2 of ~ 40–70%), and human genome-wide association studies (GWAS) have identified dozens of replicable loci showing associations with obesity-related phenotypes,[4,5,6,7] these loci do not explain the majority of the heritability for these traits.[7] Some of these loci appear to act in an age-dependent manner, suggesting that the ontogeny of obesity is both genetically dynamic and pleiotropic.[8,9,10,11] Relatively few projects have sought to both characterize long-term ontogenetic patterns associated with adult obesity while examining the potential genetic basis of such patterns.[11]
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