Showing papers by "Claude Bouchard published in 2021"

Genetics of Obesity: What We Have Learned Over Decades of Research.

Abstract: There is a genetic component to human obesity that accounts for 40% to 50% of the variability in body weight status but that is lower among normal weight individuals (about 30%) and substantially higher in the subpopulation of individuals with obesity and severe obesity (about 60%-80%). The appreciation that heritability varies across classes of BMI represents an important advance. After controlling for BMI, ectopic fat and fat distribution traits are characterized by heritability levels ranging from 30% to 55%. Defects in at least 15 genes are the cause of monogenic obesity cases, resulting mostly from deficiencies in the leptin-melanocortin signaling pathway. Approximately two-thirds of the BMI heritability can be imputed to common DNA variants, whereas low-frequency and rare variants explain the remaining fraction. Diminishing allele effect size is observed as the number of obesity-associated variants expands, with most BMI-increasing or -decreasing alleles contributing only a few grams or less to body weight. Obesity-promoting alleles exert minimal effects in normal weight individuals but have larger effects in individuals with a proneness to obesity, suggesting a higher penetrance; however, it is not known whether these larger effect sizes precede obesity or are caused by an obese state. The obesity genetic risk is conditioned by thousands of DNA variants that make genetically based obesity prevention and treatment a major challenge.

Human plasma proteomic profiles indicative of cardiorespiratory fitness

Abstract: Maximal oxygen uptake (VO2max) is a direct measure of human cardiorespiratory fitness and is associated with health. However, the molecular determinants of interindividual differences in baseline (intrinsic) VO2max, and of increases of VO2max in response to exercise training (ΔVO2max), are largely unknown. Here, we measure ~5,000 plasma proteins using an affinity-based platform in over 650 sedentary adults before and after a 20-week endurance-exercise intervention and identify 147 proteins and 102 proteins whose plasma levels are associated with baseline VO2max and ΔVO2max, respectively. Addition of a protein biomarker score derived from these proteins to a score based on clinical traits improves the prediction of an individual’s ΔVO2max. We validate findings in a separate exercise cohort, further link 21 proteins to incident all-cause mortality in a community-based cohort and reproduce the specificity of ~75% of our key findings using antibody-based assays. Taken together, our data shed light on biological pathways relevant to cardiorespiratory fitness and highlight the potential additive value of protein biomarkers in identifying exercise responsiveness in humans. Plasma proteomic profiles from 650 adult humans are measured before and after a 20-week exercise regimen to determine proteins associated with baseline cardiorespiratory fitness and improvements in response to exercise.

Gene-educational attainment interactions in a multi-ancestry genome-wide meta-analysis identify novel blood pressure loci

Abstract: Educational attainment is widely used as a surrogate for socioeconomic status (SES). Low SES is a risk factor for hypertension and high blood pressure (BP). To identify novel BP loci, we performed multi-ancestry meta-analyses accounting for gene-educational attainment interactions using two variables, "Some College" (yes/no) and "Graduated College" (yes/no). Interactions were evaluated using both a 1 degree of freedom (DF) interaction term and a 2DF joint test of genetic and interaction effects. Analyses were performed for systolic BP, diastolic BP, mean arterial pressure, and pulse pressure. We pursued genome-wide interrogation in Stage 1 studies (N = 117 438) and follow-up on promising variants in Stage 2 studies (N = 293 787) in five ancestry groups. Through combined meta-analyses of Stages 1 and 2, we identified 84 known and 18 novel BP loci at genome-wide significance level (P < 5 x 10(-8)). Two novel loci were identified based on the 1DF test of interaction with educational attainment, while the remaining 16 loci were identified through the 2DF joint test of genetic and interaction effects. Ten novel loci were identified in individuals of African ancestry. Several novel loci show strong biological plausibility since they involve physiologic systems implicated in BP regulation. They include genes involved in the central nervous system-adrenal signaling axis (ZDHHC17, CADPS, PIK3C2G), vascular structure and function (GNB3, CDON), and renal function (HAS2 and HAS2-AS1, SLIT3). Collectively, these findings suggest a role of educational attainment or SES in further dissection of the genetic architecture of BP.

Whole Genome Sequence Analysis of the Plasma Proteome in Black Adults Provides Novel Insights into Cardiovascular Disease.

Abstract: Background: Plasma proteins are critical mediators of cardiovascular processes and are the targets of many drugs. Previous efforts to characterize the genetic architecture of the plasma proteome ha...

HRR and V˙O2R Fractions Are Not Equivalent: Is It Time to Rethink Aerobic Exercise Prescription Methods?

Abstract: INTRODUCTION According to current guidelines, the intensity of health-enhancing aerobic exercise should be prescribed using a percentage of heart rate reserve (%HRR), which is considered to be more closely associated (showing a 1:1 relation) with the percentage of oxygen uptake reserve (%V˙O2R) rather than with the percentage of maximal oxygen uptake (%V˙O2max) during incremental exercise. However, the associations between %HRR and %V˙O2R and between %HRR and %V˙O2max are under debate; hence, their actual relationships were investigated in this study. METHODS Data from each stage of a maximal incremental exercise test performed by 737 healthy and physically inactive participants of the HERITAGE Family Study were screened and filtered then used to calculate the individual linear regressions between %HRR and either %V˙O2R or %V˙O2max. For each relationship, the mean slope and intercept of the individual linear regression were compared with 1 and 0 (i.e., the identity line), respectively, using one-sample t-tests. The individual root mean square errors of the actual versus the 1:1 predicted %HRR were calculated for both relationships and compared using a paired-sample t-test. RESULTS The mean slopes (%HRR-%V˙O2R, 0.972 ± 0.189; %HRR-%V˙O2max, 1.096 ± 0.216) and intercepts (%HRR-%V˙O2R, 8.855 ± 16.022; %HRR-%V˙O2max, -3.616 ± 18.993) of both relationships were significantly different from 1 and 0, respectively, with high interindividual variability. The average root mean square errors were high and revealed that the %HRR-%V˙O2max relationship was more similar to the identity line (P < 0.001) than the %HRR-%V˙O2R relationship (7.78% ± 4.49% vs 9.25% ± 5.54%). CONCLUSIONS Because both relationships are different from the identity line and using a single equation may not be appropriate to predict exercise intensity at the individual level, a rethinking of the relationships between the intensity variables may be necessary to ensure that the most suitable health-enhancing aerobic exercise intensity is prescribed.

Multi-ancestry genome-wide gene-sleep interactions identify novel loci for blood pressure.

Abstract: Long and short sleep duration are associated with elevated blood pressure (BP), possibly through effects on molecular pathways that influence neuroendocrine and vascular systems. To gain new insights into the genetic basis of sleep-related BP variation, we performed genome-wide gene by short or long sleep duration interaction analyses on four BP traits (systolic BP, diastolic BP, mean arterial pressure, and pulse pressure) across five ancestry groups in two stages using 2 degree of freedom (df) joint test followed by 1df test of interaction effects. Primary multi-ancestry analysis in 62,969 individuals in stage 1 identified three novel gene by sleep interactions that were replicated in an additional 59,296 individuals in stage 2 (stage 1 + 2 P-joint < 5 x 10(-8)), including rs7955964 (FIGNL2/ANKRD33) that increases BP among long sleepers, and rs73493041 (SNORA26/C9orf170) and rs10406644 (KCTD15/LSM14A) that increase BP among short sleepers (P-int < 5 x 10(-8)). Secondary ancestry-specific analysis identified another novel gene by long sleep interaction at rs111887471 (TRPC3/KIAA1109) in individuals of African ancestry (P-int = 2 x 10(-6)). Combined stage 1 and 2 analyses additionally identified significant gene by long sleep interactions at 10 loci including MKLN1 and RGL3/ELAVL3 previously associated with BP, and significant gene by short sleep interactions at 10 loci including C2orf43 previously associated with BP (P-int < 10(-3)). 2df test also identified novel loci for BP after modeling sleep that has known functions in sleep-wake regulation, nervous and cardiometabolic systems. This study indicates that sleep and primary mechanisms regulating BP may interact to elevate BP level, suggesting novel insights into sleep-related BP regulation.

Dietary Mediators of the Genetic Susceptibility to Obesity - Results from the Quebec Family Study.

Abstract: BACKGROUND Recent studies showed that eating behaviors such as disinhibition, emotional and external eating, and snacking mediate genetic susceptibility to obesity. It remains unknown if diet quality and intake of specific food groups also mediate the genetic susceptibility to obesity. OBJECTIVE This study aimed to assess if diet quality and intakes of specific food groups mediate the association between a polygenic risk score (PRS) for body mass index (BMI) and BMI and waist circumference (WC). We hypothesized that poor diet quality, high intakes of energy-dense food groups and low intakes of nutrient-dense food groups mediate the genetic susceptibility to obesity. METHODS This cross-sectional study included 750 participants (56.3% women, age 41.5 ± 14.9 years, BMI 27.8 ± 7.5 kg/m2) from the Quebec Family Study. A PRSBMI based on > 500,000 genetic variants was calculated using LDpred2. Dietary intakes were assessed with a 3-day food record from which a diet quality score (i.e., Nutrient Rich Food Index 6.3) and food groups were derived. Mediation analyses were conducted using a regression-based and bootstrapping approach. RESULTS : The PRSBMI explained 25.7% and 19.8% of the variance in BMI and WC, respectively. The association between PRSBMI and BMI was partly mediated by poor diet quality (β = 0.33 ± 0.12; 95% CI: 0.13, 0.60), high intakes of fat and high-fat foods (β = 0.46 ± 0.16; 95% CI: 0.19, 0.79) and sugar-sweetened beverages (β = 0.25 ± 0.14; 95% CI: 0.05, 0.60), and low intakes of vegetables (β = 0.15 ± 0.08; 95% CI: 0.03, 0.32), fruits (β = 0.37 ± 0.12; 95% CI: 0.17, 0.64) and dairy products (β = 0.17 ± 0.09; 95% CI: 0.02, 0.37). The same trends were observed for WC. CONCLUSIONS The genetic susceptibility to obesity was partly mediated by poor diet quality and intakes of specific food groups. These results suggest that improvement in diet quality may reduce obesity risk among individuals with high genetic susceptibility and emphasize the need to intervene on diet quality among these individuals.

Regular exercise and patterns of response across multiple cardiometabolic traits: the HERITAGE family study.

Abstract: Objectives We investigated whether high responsiveness or low responsiveness to exercise training aggregates in the same individuals across seven cardiometabolic traits. Methods A total of 564 adults (29.2% black, 53.7% female) from the HERITAGE family study completed a 20-week endurance training programme (at 55%–75% of participants’ maximal oxygen uptake (VO2max)) with VO2max, per cent body fat, visceral adipose tissue, fasting levels of insulin, high-density lipoprotein cholesterol, small low-density lipoprotein particles and inflammatory marker GlycA measured before and after training. For each exercise response trait, we created ethnicity-specific, sex-specific and generation-specific quintiles. High responses were defined as those within the 20th percentile representing the favourable end of the response trait distribution, low responses were defined as the 20th percentile from the least favourable end, and the remaining were labelled as average responses. Results Only one individual had universally high or low responses for all seven cardiometabolic traits. Almost half (49%) of the cohort had at least one high response and one low response across the seven traits. About 24% had at least one high response but no low responses, 24% had one or more low responses but no high responses, and 2.5% had average responses across all traits. Conclusions Interindividual variation in exercise responses was evident in all the traits we investigated, and responsiveness did not aggregate consistently in the same individuals. While adherence to an exercise prescription is known to produce health benefits, targeted risk factors may not improve.

Genomics and transcriptomics landscapes associated to changes in insulin sensitivity in response to endurance exercise training.

Abstract: Despite good adherence to supervised endurance exercise training (EET), some individuals experience no or little improvement in peripheral insulin sensitivity. The genetic and molecular mechanisms underlying this phenomenon are currently not understood. By investigating genome-wide variants associated with baseline and exercise-induced changes (∆) in insulin sensitivity index (Si) in healthy volunteers, we have identified novel candidate genes whose mouse knockouts phenotypes were consistent with a causative effect on Si. An integrative analysis of functional genomic and transcriptomic profiles suggests genetic variants have an aggregate effect on baseline Si and ∆Si, focused around cholinergic signalling, including downstream calcium and chemokine signalling. The identification of calcium regulated MEF2A transcription factor as the most statistically significant candidate driving the transcriptional signature associated to ∆Si further strengthens the relevance of calcium signalling in EET mediated Si response.