648 pubs · 68,853 cites · h-index 123
Our understanding of the genetic architecture of obesity is primarily based on studies of adults, with sparser data from childhood. Here, we conducted age-stratified genetic association studies against objectively measured ( n = 62,276) or recalled childhood adiposity-related traits ( n eff = 599,924), identifying 624 common variants associated with childhood adiposity, with one-third having no concordant association with adult body mass index. Signals linked to the leptin–melanocortin pathway ( BSX , GNAS , LEPR and PCSK1 ) and incretin signaling ( GIPR and GLP1R ) showed childhood-specific effects on adiposity. Single-nucleus RNA sequencing data identified childhood-specific adiposity-regulating cell populations in the arcuate nucleus and mammillary bodies, indicating neurocircuits that regulate adiposity specifically during childhood. Finally, sequencing in 479,615 individuals uncovered rare protein-coding variation in ADCY3 , CALCR , MC4R , MRAP2 , POMC and MYH13 , exhibiting stronger associations in childhood than in adults. Our findings suggest that childhood provides a more sensitive window for the study of key endocrine and neuropeptide pathways that regulate energy balance.
Functional and genetic association study reveals that loss-of-function GIPR coding variants lower body mass index but raise glycemia, highlighting receptor stability mechanisms for drug targeting.
Background/Objectives Childhood appetitive traits are heritable behavioural phenotypes hypothesized to link genetic susceptibility to obesity risk. Yet their genetic architecture and role in mediating polygenic adiposity risk remain poorly understood. Methods We conducted the largest survey of childhood eating behaviour to date, allowing us to perform genome-wide association studies of six appetitive domains derived from 18 items of the parent-reported Children’s Eating Behaviour Questionnaire in up to 31,018 eight-year-old children from the Norwegian Mother, Father and Child Cohort Study (MoBa). A trio-based design enabled decomposition of direct and indirect genetic effects on appetite and BMI. Results We identified ten independent genome-wide significant loci for childhood eating behaviour, primarily across Food Responsiveness , Satiety Responsiveness , and Food Fussiness , eight of which lie at established childhood or adult BMI loci. Food Responsiveness and Satiety Responsiveness showed both phenotypic and genetic correlations with BMI trajectories from early childhood through adolescence. Statistical mediation analyses indicated that 22.1% and 10.4% of the aggregated genetic association with BMI at age 8 could be decomposed through these traits, respectively. Locus-specific patterns further suggested mechanistic pathways, with the FTO locus acting predominantly via Food Responsiveness , and the ADCY3 locus via Satiety Responsiveness . Trio analyses demonstrated that both BMI and eating behaviour associations were predominantly explained by children’s inherited alleles, with minimal contribution from indirect effect from parental adiposity, although parental genetic liability influenced reporting of Satiety Responsiveness . Conclusions Childhood appetitive traits capture a substantial proportion of genetic susceptibility to adiposity through distinct eating behaviour pathways (under standard mediation assumptions). These effects are primarily driven by the child’s own genotype rather than indirect parental influences, positioning appetite as a plausible, biologically grounded target for early obesity prevention.
BACKGROUND: Eating behaviour traits (EBTs), including uncontrolled eating (UE) and emotional eating (EE), are associated with higher body weight and adiposity. However, evidence on temporal and bidirectional relationships between EBTs and adiposity in adults is limited. OBJECTIVE: This study aimed to examine longitudinal, bidirectional associations between EBTs and adiposity in a large population-based cohort of middle-aged adults. METHODS: Data were from Phase 1 (2005-2015) and 2 (2014-2020) from the Fenland cohort, a prospective study of adults living in Cambridgeshire, UK, born between 1950 and 1975. UE and EE were analysed in relation to objectively measured BMI and dual-energy X-ray absorptiometry-derived %BF . Bidirectional associations between baseline EBTs and changes in adiposity, and between baseline adiposity and changes in EBTs, were examined using bivariate latent change score models. Analyses were stratified by sex and adjusted for age, education, and household income. RESULTS: In both females and males, higher BMI at phase 1 was associated with greater increases in UE (e.g. females: γ1 = 0.13; 95% CI = 0.006, 0.25; p = 0.04) and EE (e.g. females: γ1 = 0.54; 95% CI = 0.34, 0.74; p <0.0001) from phase 1 to phase 2, while baseline UE and EE were not associated with subsequent changes in BMI. Similar patterns were observed for %BF, with higher baseline adiposity associated with increases in UE and EE over time, but not vice versa. Sensitivity analyses generally supported the primary findings, although associations between adiposity and subsequent uncontrolled eating in females were attenuated and no longer statistically significant. CONCLUSIONS: Findings challenge assumptions that UE and EE are drivers of adult weight gain and instead suggest that higher adiposity may contribute to the development or escalation of dysregulated eating behaviours. Interventions may benefit from addressing the behavioural and psychological consequences of higher body weight alongside traditional weight-focused strategies.
Objectives To describe the triple burden of malnutrition among a large, school-going sample of adolescents in rural Agincourt and urban Soweto, South Africa.Design Cross-sectional study.Setting Schools and community centres across rural Agincourt and urban Soweto, South Africa.Subjects 12 644 adolescents (mean age 15.5 years; 62% girls; 70.7% rural).Measures International Obesity Task Force cut-offs were used to calculate the prevalence of underweight, healthy weight, overweight, and obesity. Haemoglobin levels were measured in Soweto to assess the prevalence of anaemia.Results This large, population-based study reveals a high burden of malnutrition, with 34.9% of adolescents either underweight, overweight, or obese. Underweight prevalence was 14.3%, with relatively uniform distribution across sex and setting. Overweight and obesity were notably more prevalent in urban girls (32.3% and 7.0%, respectively), nearly doubling the rates observed in their rural peers (17.4% and 5.8%), and substantially higher than urban and rural boys (all < 6%). Boys consistently exhibited lower body fat percentage and fat mass index compared with girls across both settings. In a subsample of urban adolescents with haemoglobin data, anaemia was common, particularly in girls (31.6% vs. 10.2% in boys).Conclusions These findings highlight the complexity of the burden of malnutrition in adolescence, including both under- and over-nutrition with overlapping micronutrient deficiencies.
Background Puberty in girls is occurring earlier worldwide with a declining trend over the recent decades, resulting in increased attention on the accompanying risks of psychosocial challenges and adverse health outcomes for the affected girls. Diverse mechanisms have been proposed as mediators of the tendency for earlier pubertal maturation, including a shift toward a more sedentary lifestyle and changes in dietary habits leading to childhood obesity. Several studies have demonstrated a potential association between the rise in childhood obesity prevalence and the decline in the age at which puberty begins. Increased insulin resistance is thought to play a role in this connection, and previous studies indicated that improved insulin sensitivity following either treatment with metformin or weight loss could delay pubertal progression in girls with overweight. Methods LIFE-MET is a randomized, placebo-controlled, four-arm, multicenter trial of girls ( n = 80) with overweight and early puberty. Allocation to metformin or placebo will be double-blinded. Eligible girls will be randomly assigned to one of the four study arms: Metformin + lifestyle intervention ( N = 20), Metformin alone ( N = 20), Placebo + lifestyle intervention ( N = 20), Placebo alone ( N = 20). The intervention period is 6 months with a follow-up after an additional 6 months. The primary outcome is the change in bone age from baseline to 12 months, as a marker of pubertal progression. Secondary outcomes include changes in body composition, Tanner stage, fitness level, sex hormones, insulin resistance, and age at menarche. Discussion New strategies not only for the treatment but also for the prevention of both overweight and early puberty are needed. The LIFE-MET trial is a randomized controlled trial with a combination of lifestyle intervention including online, virtual reality training and a pharmacological intervention consisting of metformin and/or placebo, to our knowledge the first of its kind. We expect that this intervention will have a beneficial effect on both pubertal progression, daily physical activity level, and body composition. Additionally, a healthier body composition may have beneficial effects on long-term co-morbidities related to early puberty. Trial registration Clinical Trial Information System (CTIS): 2024-511009-50-00. Approved 04/30/2024. https://euclinicaltrials.eu/search-for-clinical-trials/?lang=en&EUCT=2024-511009-50-00 .
Identification of rare variants in HTRA1, SGTB, and RBM12 provides novel genetic insights into the pathophysiology of atherosclerotic cardiovascular disease across multiple vascular beds.
Genetically predicted higher circulating testosterone is associated with an increased risk of coronary artery disease in men, a relationship that appears to be mediated by higher blood pressure.
Analysis establishes research priorities in reproductive disorders and developmental endocrinology, highlighting critical areas for future funding.
Population-scale cohort study uncovers rare protein-coding variants linked to obesity and diabetes across two biobanks, highlighting novel therapeutic targets for metabolic disease.
Observational and Mendelian randomization study reveals IGF-1 influences height in childhood and adulthood.
Population-based analysis shows GIPR coding variants influence BMI and glycaemia, indicating metabolic disease insights.
Bidirectional Mendelian randomization reveals links between branched-chain amino acids and insulin sensitivity, suggesting implications for metabolic health.
Branched-chain amino acids (BCAAs) are essential nutrients for humans. An elevated circulating BCAA level has been associated with obesity and type 2 diabetes (T2D), but the causal role of BCAAs in metabolic health remains unclear. Using a two-sample bidirectional Mendelian randomization (MR) approach, we assessed the bidirectional causal effects of circulating BCAAs on body composition, lipids, glucose metabolism, and insulin sensitivity in ∼250,000 UK Biobank participants. In MR models, a higher circulating level of BCAAs seemed to be the outcome of poor metabolic health, including higher BMI, more circulating triglycerides (TGs), lower HDL cholesterol (HDL-C), greater insulin resistance, and higher T2D risk (all P < 6 × 10-4). Conversely, a higher level of BCAAs as the exposure seemed causally associated with more TGs and lower HDL-C (indicating dyslipidemia), independent of BMI and T2D risk. Our bioinformatic and functional analyses further identified PDE3B as a potential regulator of BCAAs and lipid metabolism in adipocytes. These findings confirm the role of circulating BCAAs as a biomarker reflecting metabolic health and identify a potential bidirectional causal link with lipid dysregulation. Additional studies should explore how BCAAs affect lipid metabolism in both insulin-resistant and metabolically healthy individuals. ARTICLE HIGHLIGHTS: We undertook this study to estimate the causal role of circulating branched-chain amino acids (BCAAs) in metabolic health using genetics. Are circulating BCAAs a cause or consequence of metabolic health? We found that a higher circulating level of BCAAs likely reflects poorer metabolic health. There is a potential bidirectional causal link between BCAAs and dyslipidemia that warrants further tissue-specific functional studies. Our findings suggest that BCAAs may causally affect lipid metabolism, with adipocytes as a key site. Understanding tissue-specific pathways of BCAA-induced lipid dysregulation could guide BCAAs' potential as a clinical intervention target.
Background Genetic variants that are associated with phenotypic variability, or variance quantitative trait loci (vQTLs), have been detected for multiple human traits. Gene-environment interactions can lead to differential phenotypic variability across genotype groups, therefore, genetic variants that interact with environmental exposures can manifest as vQTLs. Although changes in DNA methylation variability have been observed in several diseases, vQTLs for methylation levels (vmeQTL) have not yet been explored in depth. Results We optimize the value of monozygotic (MZ) twin studies to identify and replicate vmeQTLs for blood DNA methylation variance at 358 CpGs in 988 adult MZ twin pairs from two European twin registries. Over a third of vmeQTLs captured identical vmeQTL-environmental factor interactions in both datasets, and the majority of interactions were observed with blood cell counts. Correspondingly, over 60% of CpGs affected by genotype-monocyte and genotype-T cell interactions replicated as CpGs affected by genetic effects in the relevant cell type in an independent dataset. Most vmeQTLs also replicated in 1,348 UK non-twin adults and showed longitudinal stability in a sample subset. Integrating gene expression and phenotype association results identified multiple vmeQTLs that capture GxE effects relevant to human health. Examples include vmeQTLs interacting with blood cell type to influence DNA methylation in FAM65A, NAPRT, and CSGALNACT1 underlying immune disease susceptibility and progression. Conclusion Our findings identify novel genetic effects on human DNA methylation variability within a unique MZ twin study design. The results show the potential of vmeQTLs to identify gene-environment interactions and provide novel insights into complex traits.
Objectives Endocrine disrupting chemicals (EDCs) interfere with hormonal homeostasis, and have been observationally linked to altered pubertal timing, defined by the age of menarche (AAM) in girls and the age at voice change (AVC) in boys. However, the causality of these associations remains unclear. We used Mendelian randomization (MR) to investigate if genetically altered serum EDC levels affect pubertal timing. Methods We performed univariate MR to assess the effects of 22 EDCs on AAM and AVC, using the largest GWAS for EDCs as well as European and multi-ethnic GWAS on AAM and AVC. Multivariate MR (MVMR) and two-step MR were conducted to examine mediating effects of body mass index (BMI). Results We found causal MR associations with AAM for three polychlorinated biphenyls (PCBs): PCB 74 (βIVW: −0.015, 95 % CI [−0.028, −0.003], p=0.014), PCB 194 (βIVW: −0.015, 95 % CI [−0.024, −0.007], p=3.27×10−4), and PCB 206 (βIVW: −0.024, 95 % CI [−0.041, −0.006], p=0.0068) and for dibutyl phthalate (DBP, βIVW: 0.006, 95 % CI [0.001, 0.010], p=0.013). One MR association was found with AVC for bisphenol A (BPA, βWald ratio= −0.032, 95 % CI [−0.044, −0.019], p=2.62×10−7). Mediation analyses by MVMR or Two-Step MR suggested BMI’s mediating role in the associations of EDCs with AAM and AVC. Conclusions Our findings indicate that exposure to specific PCBs leads to earlier AAM whereas exposure to DBP delays AAM. Exposure to BPA leads to earlier AVC, with BMI potentially acting as a mediator.
Our understanding of the genetic architecture of obesity has primarily been shaped by observations from adult populations with relatively few studies on childhood obesity. To address this gap, we conduct a longitudinal genetic association study in up to ∼600,000 individuals with objectively measured or recalled childhood adiposity-related traits. We identify 624 common variant signals (only 7% are previously reported) associated with childhood adiposity, of which one third have no concordant association with adult BMI. Signals linked to the leptin-melanocortin pathway ( BSX, GNAS , LEPR and PCSK1 ) and incretin-signalling genes ( GIPR and GLP1R ) show stronger associations in childhood than in adults, suggesting that childhood provides a more sensitive window for detecting variation in key endocrine and neuropeptide pathways regulating energy balance. This observation is further supported by integrating single-nucleus RNA sequencing data from the human hypothalamus, identifying childhood-specific adiposity-regulating cell populations in the arcuate nucleus and mammillary bodies, indicating distinct neuro-circuits that regulate adiposity only during childhood. Three signals showed parent-of-origin specific associations with childhood BMI, at KLF14 (maternal-specific), GNAS (parental-discordant) and ZDBF2 (paternal-specific). Finally, we complement these common variant analyses with DNA sequence data in 479,615 individuals, identifying rare protein-coding variation in ADCY3 , CALCR , MC4R , MRAP2 , POMC and MYH13, all of which demonstrate stronger adiposity associations in childhood than in adults. Collectively, our findings emphasize the value of expanding research on childhood adiposity alongside studies focused on adult obesity measures.
Changes in the proteome and its dysregulation have long been known to be a hallmark of aging. We derived a proteomic aging trait using data on 1459 plasma proteins from 44,435 UK Biobank individuals measured using an antibody-based assay. This metric is strongly associated with four age-related disease outcomes, even after adjusting for chronological age. Survival analysis showed that one-year older proteomic age, relative to chronological age, increases all-cause mortality hazard by 13 percent. We performed a genome-wide association analysis of proteomic age acceleration (proteomic aging trait minus chronological age) to identify its biological determinants. Proteomic age acceleration showed modest genetic correlations with four epigenetic clocks ( R g = 0.17 to 0.19) and telomere length ( R g = −0.2). Once we removed associations that were explained by a single pQTL, we were left with three signals mapping to BRCA1 , POLR2A and TET2 with apparent widespread effects on plasma proteomic aging. Genetic variation at these three loci has been shown to affect other omics-related aging measures. Mendelian randomisation analyses showed causal effects of higher BMI and type 2 diabetes on faster proteomic age acceleration. This supports the idea that obesity and other features of metabolic syndrome have an adverse effect on the processes of human aging.
PURPOSE: Physical activity (PA) is recommended for the management of women with polycystic ovary syndrome (PCOS). However, it is not known whether PA modulates the risk of components of PCOS diagnostic criteria during adolescence. METHODS: We included participants from the Avon Longitudinal Study of Parents and Children prospective cohort with objective measurement of PA and sedentary behavior using accelerometry between ages 11 and 15 years, biochemical and clinical measures of hyperandrogenism (serum total testosterone level at 15 years and self-reported hirsutism at 19 years), and self-reported menstrual regularity at 17 years. Two-stage regression models evaluated the association of repeated measures of PA and sedentary behavior with components of PCOS diagnostic criteria. RESULTS: Among 1,526 singleton girls with accelerometer data and testosterone samples, time spent in light PA was inversely associated with total testosterone (ß = -0.070, 95% CI -0.114, -0.025; nmol/L, per 60 minutes) and continuous hirsutism score (ß = -0.756, 95% CI -1.41, -0.103; per 60 minutes). Conversely, time spent sedentary was associated with higher total testosterone level (ß = 0.052, 95% CI 0.013, 0.090; per 60 minutes) and hirsutism score (ß = 0.668, 95% CI 0.103, 1.23; per 60 minutes). Associations were independent of adiposity, but results for hirsutism were attenuated following adjustment for age at menarche and after stratification by hormonal contraceptive use. No associations were observed with menstrual irregularity, for other PA intensity components, or among users of hormonal contraceptives. DISCUSSION: More time spent in light intensity physical activity and less time spent sedentary during early adolescence is associated with lower testosterone concentrations and lower hirsutism scores in late adolescence.
Review highlights barriers in evaluating early-life cancer risk in aging populations, suggesting mature birth cohorts provide critical lifecourse insights.