Showing papers by "Claude Bouchard published in 2017"

Genome-wide physical activity interactions in adiposity. A meta-analysis of 200,452 adults

Abstract: Physical activity (PA) may modify the genetic effects that give rise to increased risk of obesity. To identify adiposity loci whose effects are modified by PA, we performed genome-wide interaction meta-analyses of BMI and BMI-adjusted waist circumference and waist-hip ratio from up to 200,452 adults of European (n = 180,423) or other ancestry (n = 20,029). We standardized PA by categorizing it into a dichotomous variable where, on average, 23% of participants were categorized as inactive and 77% as physically active. While we replicate the interaction with PA for the strongest known obesity-risk locus in the FTO gene, of which the effect is attenuated by ~30% in physically active individuals compared to inactive individuals, we do not identify additional loci that are sensitive to PA. In additional genome-wide meta-analyses adjusting for PA and interaction with PA, we identify 11 novel adiposity loci, suggesting that accounting for PA or other environmental factors that contribute to variation in adiposity may facilitate gene discovery.

Genome-wide meta-analysis of 241,258 adults accounting for smoking behaviour identifies novel loci for obesity traits

Abstract: Few genome-wide association studies (GWAS) account for environmental exposures, like smoking, potentially impacting the overall trait variance when investigating the genetic contribution to obesity-related traits. Here, we use GWAS data from 51,080 current smokers and 190,178 nonsmokers (87% European descent) to identify loci influencing BMI and central adiposity, measured as waist circumference and waist-to-hip ratio both adjusted for BMI. We identify 23 novel genetic loci, and 9 loci with convincing evidence of gene-smoking interaction (GxSMK) on obesity-related traits. We show consistent direction of effect for all identified loci and significance for 18 novel and for 5 interaction loci in an independent study sample. These loci highlight novel biological functions, including response to oxidative stress, addictive behaviour, and regulatory functions emphasizing the importance of accounting for environment in genetic analyses. Our results suggest that tobacco smoking may alter the genetic susceptibility to overall adiposity and body fat distribution.

Genome-wide meta-analysis of 241,258 adults accounting for smoking behaviour identifies novel loci for obesity traits

Abstract: Few genome-wide association studies (GWAS) account for environmental exposures, like smoking, potentially impacting the overall trait variance when investigating the genetic contribution to obesity-related traits. Here, we use GWAS data from 51,080 current smokers and 190,178 nonsmokers (87% European descent) to identify loci influencing BMI and central adiposity, measured as waist circumference and waist-to-hip ratio both adjusted for BMI. We identify 23 novel genetic loci, and 9 loci with convincing evidence of gene-smoking interaction (GxSMK) on obesity-related traits. We show consistent direction of effect for all identified loci and significance for 18 novel and for 5 interaction loci in an independent study sample. These loci highlight novel biological functions, including response to oxidative stress, addictive behaviour, and regulatory functions emphasizing the importance of accounting for environment in genetic analyses. Our results suggest that tobacco smoking may alter the genetic susceptibility to overall adiposity and body fat distribution.

Convergence between biological, behavioural and genetic determinants of obesity.

Abstract: Multiple biological, behavioural and genetic determinants or correlates of obesity have been identified to date. Genome-wide association studies (GWAS) have contributed to the identification of more than 100 obesity-associated genetic variants, but their roles in causal processes leading to obesity remain largely unknown. Most variants are likely to have tissue-specific regulatory roles through joint contributions to biological pathways and networks, through changes in gene expression that influence quantitative traits, or through the regulation of the epigenome. The recent availability of large-scale functional genomics resources provides an opportunity to re-examine obesity GWAS data to begin elucidating the function of genetic variants. Interrogation of knockout mouse phenotype resources provides a further avenue to test for evidence of convergence between genetic variation and biological or behavioural determinants of obesity.

Prevalence of Risk Factors for Metabolic Syndrome in Adolescents

Abstract: Main Outcome Measures: Metabolic syndrome was defined as having 3 or more disorders in the following measurements: waist circumference, blood pressure, fasting triglycerides, high-density lipoprotein serum cholesterol, and glucose. Results: About half of the participants had at least 1 disordered measurement, with an overall metabolic syndrome prevalence of 8.6% (95% confidence interval, 6.5%10.6%). Prevalence was higher in males (10.8%) than females (6.1%), and in Hispanic (11.2%) and white (8.9%) individuals than in black individuals (4.0%). In black females, there was a high prevalence of a large waist circumference (23.3%), but no component of metabolic syndrome dominated its diagnosis in black adolescents of either sex. A large waist circumference and high fasting triglyceride and low high-density lipoprotein serum cholesterol concentrations were salient factors in Hispanic and white adolescents of both sexes; high glucose concentrations were prominent among Hispanic and white males.

Biological/Genetic Regulation of Physical Activity Level: Consensus from GenBioPAC

Abstract: PurposePhysical activity unquestionably maintains and improves health; however, physical activity levels globally are low and not rising despite all the resources devoted to this goal. Attention in both the research literature and the public policy domain has focused on social–behavioral fac

Genomic and transcriptomic predictors of response levels to endurance exercise training.

Abstract: Predicting the responsiveness to regular exercise is a topic of great relevance due to its potential role in personalized exercise medicine applications. The present review focuses on cardiorespiratory fitness (commonly measured by maximal oxygen uptake, VO2 max ), a trait with wide-ranging impact on health and performance indicators. Gains in VO2 max demonstrate large inter-individual variation even in response to standardized exercise training programmes. The estimated ΔVO2 max heritability of 47% suggests that genomic-based predictors alone are insufficient to account for the total trainability variance. Candidate gene and genome-wide linkage studies have not significantly contributed to our understanding of the molecular basis of trainability. A genome-wide association study suggested that VO2 max trainability is influenced by multiple genes of small effects, but these findings still await rigorous replication. Valuable evidence, however, has been obtained by combining skeletal muscle transcript abundance profiles with common DNA variants for the prediction of the VO2 max response to exercise training. Although the physiological determinants of VO2 max measured at a given time are largely enunciated, what is poorly understood are the details of tissue-specific molecular mechanisms that limit VO2 max and related signalling pathways in response to exercise training. Bioinformatics explorations based on thousands of variants have been used to interrogate pathways and systems instead of single variants and genes, and the main findings, along with those from exercise experimental studies, have been summarized here in a working model of VO2 max trainability.

Adropin: An endocrine link between the biological clock and cholesterol homeostasis

Abstract: Objective Identify determinants of plasma adropin concentrations, a secreted peptide translated from the Energy Homeostasis Associated (ENHO) gene linked to metabolic control and vascular function. Methods Associations between plasma adropin concentrations, demographics (sex, age, BMI) and circulating biomarkers of lipid and glucose metabolism were assessed in plasma obtained after an overnight fast in humans. The regulation of adropin expression was then assessed in silico, in cultured human cells, and in animal models. Results In humans, plasma adropin concentrations are inversely related to atherogenic LDL-cholesterol (LDL-C) levels in men (n = 349), but not in women (n = 401). Analysis of hepatic Enho expression in male mice suggests control by the biological clock. Expression is rhythmic, peaking during maximal food consumption in the dark correlating with transcriptional activation by RORα/γ. The nadir in the light phase coincides with the rest phase and repression by Rev-erb. Plasma adropin concentrations in nonhuman primates (rhesus monkeys) also exhibit peaks coinciding with feeding times (07:00 h, 15:00 h). The ROR inverse agonists SR1001 and the 7-oxygenated sterols 7-β-hydroxysterol and 7-ketocholesterol, or the Rev-erb agonist SR9009, suppress ENHO expression in cultured human HepG2 cells. Consumption of high-cholesterol diets suppress expression of the adropin transcript in mouse liver. However, adropin over expression does not prevent hypercholesterolemia resulting from a high cholesterol diet and/or LDL receptor mutations. Conclusions In humans, associations between plasma adropin concentrations and LDL-C suggest a link with hepatic lipid metabolism. Mouse studies suggest that the relationship between adropin and cholesterol metabolism is unidirectional, and predominantly involves suppression of adropin expression by cholesterol and 7-oxygenated sterols. Sensing of fatty acids, cholesterol and oxysterols by the RORα/γ ligand-binding domain suggests a plausible functional link between adropin expression and cellular lipid metabolism. Furthermore, the nuclear receptors RORα/γ and Rev-erb may couple adropin synthesis with circadian rhythms in carbohydrate and lipid metabolism.

Correction: Genome-wide physical activity interactions in adiposity - A meta-analysis of 200,452 adults.

Abstract: [This corrects the article DOI: 10.1371/journal.pgen.1006528.].

Genome-wide physical activity interactions in adiposity. A meta-analysis of 200,452 adults

Abstract: Physical activity (PA) may modify the genetic effects that give rise to increased risk of obesity. To identify adiposity loci whose effects are modified by PA, we performed genome-wide interaction meta-analyses of BMI and BMI-adjusted waist circumference and waist-hip ratio from up to 200,452 adults of European (n = 180,423) or other ancestry (n = 20,029). We standardized PA by categorizing it into a dichotomous variable where, on average, 23% of participants were categorized as inactive and 77% as physically active. While we replicate the interaction with PA for the strongest known obesity-risk locus in the FTO gene, of which the effect is attenuated by ~30% in physically active individuals compared to inactive individuals, we do not identify additional loci that are sensitive to PA. In additional genome-wide meta-analyses adjusting for PA and interaction with PA, we identify 11 novel adiposity loci, suggesting that accounting for PA or other environmental factors that contribute to variation in adiposity may facilitate gene discovery.

Plasma Steroids and Cardiorespiratory Fitness Response to Regular Exercise

Abstract: The aim of this report is to evaluate the relationships between baseline levels of adrenal, gonadal and conjugated steroids and baseline cardiorespiratory fitness, as assessed by maximal oxygen uptake (VO2max), as well as its response to a standardized exercise program. To address this aim we used a subset of the HERITAGE Family Study (N = 448). In men, significant positive associations were found between baseline VO2max/kg weight and plasma levels of androsterone glucuronide (ADTG), dihydrotesterone (DHT), 17 hydroxy progesterone (OHPROG), sex hormone binding globulin (SHBG), and testosterone (TESTO), and negative association with aldosterone (ALDO). In women, only the free androgen index (FAI) was negatively associated with baseline VO2max/kg weight. Neither baseline plasma steroid levels nor SHBG concentrations were associated with the gains in VO2max resulting from exposure to the 20-week aerobic exercise program after adjustment for baseline values, age and ethnicity (white or black). We conclude that baseline plasma steroid levels are only weakly associated with individual differences in cardiorespiratory fitness in the sedentary state in men but not in women, whereas no association could be detected with trainability, as defined by the change in VO2max with the exercise program.