Childhood Body Size Research Articles

Evaluating and implementing block jackknife resampling Mendelian randomization to mitigate bias induced by overlapping samples.

Participant overlap can induce overfitting bias into Mendelian randomization (MR) and polygenic risk score (PRS) studies. Here, we evaluated a block jackknife resampling framework for genome-wide association studies (GWAS) and PRS construction to mitigate overfitting bias in MR analyses and implemented this study design in a causal inference setting using data from the UK Biobank. We simulated PRS and MR under three scenarios: (1) using weighted SNP estimates from an external GWAS, (2) using weighted SNP estimates from an overlapping GWAS sample and (3) using a block jackknife resampling framework. Based on a P-value threshold to derive genetic instruments for MR studies (P < 5 × 10-8) and a 10% variance in the exposure explained by all SNPs, block-jackknifing PRS did not suffer from overfitting bias (mean R2 = 0.034) compared with the externally weighted PRS (mean R2 = 0.040). In contrast, genetic instruments derived from overlapping samples explained a higher variance (mean R2 = 0.048) compared with the externally derived score. Overfitting became considerably more severe when using a more liberal P-value threshold to construct PRS (e.g. P < 0.05, overlapping sample PRS mean R2 = 0.103, externally weighted PRS mean R2 = 0.086), whereas estimates using jackknife score remained robust to overfitting (mean R2 = 0.084). Using block jackknife resampling MR in an applied analysis, we examined the effects of body mass index on circulating biomarkers which provided comparable estimates to an externally weighted instrument, whereas the overfitted scores typically provided narrower confidence intervals. Furthermore, we extended this framework into sex-stratified, multivariate and bidirectional settings to investigate the effect of childhood body size on adult testosterone levels.

Separating the effects of childhood and adult body size on inflammatory arthritis: a Mendelian randomisation study

ObjectivesUsing Mendelian randomisation (MR), we examined whether childhood body size affects risk of rheumatoid arthritis (RA), ankylosing spondylitis (AS), psoriatic arthritis (PsA), gout and systemic lupus erythematosus (SLE) after accounting...

Child feeding indexes measuring adherence to New Zealand nutrition guidelines: Development and assessment.

New Zealand (NZ) lacks nationally representative or generalisable information on the dietary intakes of pre‐schoolers. We used Growing Up in New Zealand cohort data to i) develop child feeding indexes (CFIs) based on National Food and Nutrition Guidelines for 2‐ and 4.5‐year‐olds; ii) describe the cohort adherence to the guidelines at 2 (n = 6046) and 4.5 years (n = 5889) and; iii) assess the CFIs’ convergent construct validity, by exploring associations with maternal sociodemographic and health behaviours and with child body mass index for age (BMI/age) and the waist‐to‐height ratio at 4.5 years. The CFIs scores ranged from 0 to 11, with 11 representing full adherence to the guidelines. Associations were tested using multiple linear regressions and Poisson regressions with robust variance (risk ratios [RR], 95% confidence intervals, 95% CI). The CFIs mean scores (SD) at 2 and 4.5 years were, respectively, 6.13 (1.21) and 6.22 (1.26) points. Maternal characteristics explained, respectively, 27.2% and 31.9% of the variation in the CFIs scores at 2 and 4.5 years. In the adjusted model at the 4.5‐year interview, in relation to girls ranked in the 5th quintile, those in the 2nd (RR, 95% CI: 1.48; 1.03; 1.24) and 4th (1.53; 1.05; 2.23) quintiles of the CFI were more likely to have BMI/age > +2z (World Health Organization growth standards) at 4.5 years. At 2 and 4.5 years, most children fell short of meeting national guidelines. The associations between the CFIs scores at both time points with maternal characteristics and with children's body size at 4.5 years were in the expected directions, confirming the CFIs’ convergent construct validity among NZ pre‐schoolers.

Sexually antagonistic selection on educational attainment and body size in Estonian children.

Natural selection is a key mechanism of evolution, which results from the differential reproduction of phenotypes. We describe fecundity selection at different parity transitions on 15 anthropometric traits and educational attainment in Estonian children sampled in the middle of 20th century. The direction of selection on educational attainment and bodily traits was sexually antagonistic, and it occurred via different parity transitions in boys and girls. Compared to boys with primary education, obtaining tertiary education was associated with 3.5 times and secondary education two times higher odds of becoming a father. Transition to motherhood was not related to educational attainment, while education above primary was associated with lower odds (OR = 0.5-0.7) to progression to parities above one and two. Selection on anthropometric traits occurred almost exclusively via childlessness in boys, while among the girls, most of the traits that were associated with becoming a mother were additionally associated with a transition from one child to higher parities. Male (but not female) fitness was thus primarily determined by traits related to mating success. Selection favored stronger and larger boys and smaller girls. Selection on girls favored some traits that associate with perceived femininity, while other feminine traits were selected against.

Beliefs About Body Weight and Practices of Regulating Food and Physical Exercise Patterns of Children Among Parents in Southern Ethiopia.

BackgroundThe problem of childhood obesity is often associated with cultural values of body weight which includes the belief that voluptuous body size is a sign of good health status and better parental care. We examined the beliefs and behaviors of parents pertaining to preferred body weight of children, including practices of management of feeding and physical exercise patterns of children in southern Ethiopia.MethodsUsing cross-sectional survey study design, a structured questionnaire was distributed to randomly selected parents. Quantitative data were collected from 215 respondents, inserted into SPSS software, and analyzed by frequency and percentage distributions, charts, and multinomial logistic regression techniques.ResultsMost (59.1%) respondents want their child’s body weight to be normal/neither fat nor thin. In addition, 58.2% of the study participants held the opinion that average body size is an indication of good health status. Furthermore, 72.6% of respondents revealed that they control the amount of food their child consumes with the aim of preventing obesity/overweight. Moreover, 79.5% of respondents encourage their children to sometimes walk on foot, instead of always relying on vehicles while 87% of them replied that they regulate the amount of time their children spend watching TV. Above all, parents’ preference of voluptuous body size of children is significantly associated with age (OR=61.52.448, P < 0.001, 95%C.I: 57–66.14), educational status (OR = 35.605, P < 0.001; 95%C.I: 6.050–209.524), sex (OR = 0.237, P < 0.05; 95%C.I: 0.078-0.724) and grownup area (OR = 2.869, P < 0.05; 95%C.I: 1.062–7.749).ConclusionParents not only have adequate level of awareness regarding the health risks of children’s heavy body weight but also engage in the body weight management practices of their children such as by regulating the food consumption patterns of children, encouraging them to undertake physical exercises, and by being role models while doing physical exercises for themselves.

Caregiver Perception of Weight Status in 5-Year-Old Children From a Community of High Socioeconomic Deprivation in New Zealand.

BackgroundEarly childhood obesity is highly prevalent in Aotearoa New Zealand (NZ). Little is known about caregiver perception of children's weight status among those living in areas of high socioeconomic deprivation, particularly Māori and Pacific children.AimsTo explore caregiver perception of weight status among children starting school in areas of high socioeconomic deprivation and examine potential associations between the child's body mass index (BMI) z-score and their caregiver's perception of their child's body size or health.MethodsParticipants were 5-year-old children living in a community of high socioeconomic deprivation and their caregivers. Children had their weight and height measured. BMI z-scores were calculated according to World Health Organization standards. Caregivers were asked to assess their child's BMI and health status, and choose a silhouette that best represented their child's body size.ResultsOne hundred and six children (>75% Māori or Pacific) were included. Over half (58%) had overweight or obesity, with only 16% correctly perceived by their caregiver as overweight. These children tended to have higher BMI z-scores than those not correctly perceived as overweight. Caregivers chose larger silhouettes to represent children's body sizes as children's BMI z-scores increased. There was no discernible association between children's BMI z-scores and caregiver perception of children's health.ConclusionsCaregivers appeared to judge their child's body size in comparison to other children. The normalization of childhood obesity and infrequent caregiver recognition of this condition in children in communities with a high prevalence may impact the uptake and efficacy of intervention initiatives.

A lifecourse mendelian randomization study highlights the long-term influence of childhood body size on later life heart structure.

Children with obesity typically have larger left ventricular heart dimensions during adulthood. However, whether this is due to a persistent effect of adiposity extending into adulthood is challenging to disentangle due to confounding factors throughout the lifecourse. We conducted a multivariable mendelian randomization (MR) study to separate the independent effects of childhood and adult body size on 4 magnetic resonance imaging (MRI) measures of heart structure and function in the UK Biobank (UKB) study. Strong evidence of a genetically predicted effect of childhood body size on all measures of adulthood heart structure was identified, which remained robust upon accounting for adult body size using a multivariable MR framework (e.g., left ventricular end-diastolic volume (LVEDV), Beta = 0.33, 95% confidence interval (CI) = 0.23 to 0.43, P = 4.6 × 10-10). Sensitivity analyses did not suggest that other lifecourse measures of body composition were responsible for these effects. Conversely, evidence of a genetically predicted effect of childhood body size on various other MRI-based measures, such as fat percentage in the liver (Beta = 0.14, 95% CI = 0.05 to 0.23, P = 0.002) and pancreas (Beta = 0.21, 95% CI = 0.10 to 0.33, P = 3.9 × 10-4), attenuated upon accounting for adult body size. Our findings suggest that childhood body size has a long-term (and potentially immutable) influence on heart structure in later life. In contrast, effects of childhood body size on other measures of adulthood organ size and fat percentage evaluated in this study are likely explained by the long-term consequence of remaining overweight throughout the lifecourse.

Food Creatine and Head Circumference Among Children Aged 0–2 Years

ObjectivesSeveral small-scalle studies demonstrated an association between dietary creatine intake and body size in school-aged children and adolescents, yet no such connection has been evaluated in very young children at the populational level. We conducted a secondary analysis of previously completed cross-sectional study, and determined an association between food creatine and body measures in 597 U.S children aged 0 to 2 years, using the 2017–2018 National Health and Nutrition Examination Survey database.MethodsTotal grams of creatine consumed per day were computed using the average amount of creatine (e.g., 0.20 g/kg for milk-based foods and 3.88 g/kg for meat-based sources) across all creatine-containing food sources.ResultsDietary creatine intake was positively correlated with head circumference (r = 0.184; P = 0.031) when controlled for age at screening, while no link was found between creatine consumption and recumbent length (r = - 0.003; P = 0.955) or body weight (r = 0.048; P = 0.317). A multiple regression analysis revealed a significant relationship between food creatine and head circumference (P < 0.001) when adjusted for the effects of selected dietary variables (e.g., weight of food consumed, total caloric content, protein intake).ConclusionsOur findings indicate a relationship between food creatine and head circumference as a surrogate marker of brain size in early childhood; further pediatric studies should appraise the role of dietary creatine in neurodevelopment.Funding SourcesN/A.

Association of life course adiposity with risk of incident dementia: a prospective cohort study of 322,336 participants.

Cohort studies report inconsistent associations between body mass index (BMI) and all-cause incident dementia. Furthermore, evidence on fat distribution and body composition measures are scarce and few studies estimated the association between early life adiposity and dementia risk. Here, we included 322,336 participants from UK biobank to investigate the longitudinal association between life course adiposity and risk of all-cause incident dementia and to explore the underlying mechanisms driven by metabolites, inflammatory cells and brain structures. Among the 322,336 individuals (mean (SD) age, 62.24 (5.41) years; 53.9% women) in the study, during a median 8.74 years of follow-up, 5083 all-cause incident dementia events occurred. The risk of dementia was 22% higher with plumper childhood body size (p < 0.001). A strong U-shaped association was observed between adult BMI and dementia. More fat and less fat-free mass distribution on arms were associated with a higher risk of dementia. Interestingly, similar U-shaped associations were found between BMI and four metabolites (i.e., 3-hydroxybutrate, acetone, citrate and polyunsaturated fatty acids), four inflammatory cells (i.e., neutrophil, lymphocyte, monocyte and leukocyte) and abnormalities in brain structure that were also related to dementia. The findings that adiposity is associated with metabolites, inflammatory cells and abnormalities in brain structure that were related to dementia risk might provide clues to underlying biological mechanisms. Interventions to prevent dementia should begin early in life and include not only BMI control but fat distribution and body composition.

Childhood body size directly increases type 1 diabetes risk based on a lifecourse Mendelian randomization approach

The rising prevalence of childhood obesity has been postulated as an explanation for the increasing rate of individuals diagnosed with type 1 diabetes (T1D). In this study, we use Mendelian randomization (MR) to provide evidence that childhood body size has an effect on T1D risk (OR = 2.05 per change in body size category, 95% CI = 1.20 to 3.50, P = 0.008), which remains after accounting for body size at birth and during adulthood using multivariable MR (OR = 2.32, 95% CI = 1.21 to 4.42, P = 0.013). We validate this direct effect of childhood body size using data from a large-scale T1D meta-analysis based on n = 15,573 cases and n = 158,408 controls (OR = 1.94, 95% CI = 1.21 to 3.12, P = 0.006). We also provide evidence that childhood body size influences risk of asthma, eczema and hypothyroidism, although multivariable MR suggested that these effects are mediated by body size in later life. Our findings support a causal role for higher childhood body size on risk of being diagnosed with T1D, whereas its influence on the other immune-associated diseases is likely explained by a long-term effect of remaining overweight for many years over the lifecourse.

Deciphering how early life adiposity influences breast cancer risk using Mendelian randomization

Studies suggest that adiposity in childhood may reduce the risk of breast cancer in later life. The biological mechanism underlying this effect is unclear but is likely to be independent of body size in adulthood. Using a Mendelian randomization framework, we investigate 18 hypothesised mediators of the protective effect of childhood adiposity on later-life breast cancer, including hormonal, reproductive, physical, and glycaemic traits. Our results indicate that, while most of the hypothesised mediators are affected by childhood adiposity, only IGF-1 (OR: 1.08 [1.03: 1.15]), testosterone (total/free/bioavailable ~ OR: 1.12 [1.05: 1.20]), age at menopause (OR: 1.05 [1.03: 1.07]), and age at menarche (OR: 0.92 [0.86: 0.99], direct effect) influence breast cancer risk. However, multivariable Mendelian randomization analysis shows that the protective effect of childhood body size remains unaffected when accounting for these traits (ORs: 0.59–0.67). This suggests that none of the investigated potential mediators strongly contribute to the protective effect of childhood adiposity on breast cancer risk individually. It is plausible, however, that several related traits could collectively mediate the effect when analysed together, and this work provides a compelling foundation for investigating other mediating pathways in future studies.

Association Between Childhood Body Size and Premenstrual Disorders in Young Adulthood

Emerging data suggest that more than two-thirds of premenstrual disorders (PMDs), including premenstrual syndrome and premenstrual dysphoric disorder, have symptom onset during the teen years. Adulthood adiposity has been associated with PMDs; however, the association with childhood and adolescent body size is unknown. To examine the association between childhood and adolescent body size and risk of PMDs in young adulthood. This prospective cohort study included 6524 US female participants from the Growing Up Today Study (1996-2013). Data were analyzed from February 26, 2020, to June 23, 2021. Body mass index (BMI) was estimated using self-reported height and weight through adolescence and converted to BMI for age (z score). In 2013, premenstrual symptoms and identified PMDs were assessed with a validated scale based on the Calendar of Premenstrual Experiences. The associations of BMI for age with PMDs and premenstrual symptoms were examined using log-binomial and linear regressions, respectively. Among 6524 participants (mean [SD] age, 26 [3.5] years; 6108 [93.6%] White), 1004 (15.4%) met the criteria for a PMD. Baseline BMI for age reported at a mean (SD) age of 12.7 (1.1) years was associated with increased risk of PMDs (confounding-adjusted relative risk, 1.09 per unit of z score; 95% CI, 1.03-1.15) and higher burden of premenstrual symptoms (β = 0.06; 95% CI, 0.04-0.08). Associations were particularly pronounced for premenstrual dysphoric disorder and for PMDs with symptom onset before 20 years of age and remained in the absence of psychiatric comorbidities, including depression, anxiety, and disordered eating behavior. When analyzing BMI change over time, individuals with high BMI throughout adolescence had a higher burden of premenstrual symptoms (β = 0.17; 95% CI, 0.08-0.27) compared with those with normal BMI throughout adolescence. Individuals with high BMI early followed by a mild decrease later did not report higher premenstrual symptoms (β = 0.06; 95% CI, 0.00-0.12). In this cohort study, childhood body size was associated with PMD risk and premenstrual symptoms in young adulthood. These findings suggest that maintaining a normal body mass in childhood may be considered for lowering the burden of PMDs in adulthood.

Childhood Body Size and Premenstrual Disorders—Is There an Association?

Childhood Body Size and Premenstrual Disorders—Is There an Association?

Dietary Fiber, Insulin and Breast Tissue Composition at Age 15–18: A Cross-Sectional Study

Background Risk of breast cancer in adult life is influenced by body size and height in childhood, but the mechanisms responsible for these associations are currently unknown. We carried out research to determine if, at age 15–18, measures of dietary intake were associated with body size, hormones, and with variations in breast tissue composition that in adult life are associated with risk of breast cancer. Methods In a cross-sectional study of 766 healthy Caucasian women aged 15–18, we measured percent breast water (PBW), total breast water and fat by magnetic resonance (MR), and assessed dietary intake using a validated food frequency questionnaire. We also measured height, weight, skin-fold thicknesses and waist-to-hip ratio, and in fasting blood assayed glucose and insulin. Results After adjustment for age, measures of body size, and energy intake, dietary fiber (insoluble and total fiber) and insulin were associated positively and significantly with PBW. Conclusions Dietary fiber and fasting insulin were associated with breast tissue measures. These data suggest a potential approach to breast cancer prevention.

Babies of South Asian and European Ancestry Show Similar Associations With Genetic Risk Score for Birth Weight Despite the Smaller Size of South Asian Newborns.

Size at birth is known to be influenced by various fetal and maternal factors, including genetic effects. South Asians have a high burden of low birth weight and cardiometabolic diseases, yet studies of common genetic variations underpinning these phenotypes are lacking. We generated independent, weighted fetal genetic scores (fGSs) and maternal genetic scores (mGSs) from 196 birth weight-associated variants identified in Europeans and conducted an association analysis with various fetal birth parameters and anthropometric and cardiometabolic traits measured at different follow-up stages (5-6-year intervals) from seven Indian and Bangladeshi cohorts of South Asian ancestry. The results from these cohorts were compared with South Asians in UK Biobank and the Exeter Family Study of Childhood Health, a European ancestry cohort. Birth weight increased by 50.7 g and 33.6 g per SD of fGS (P = 9.1 × 10-11) and mGS (P = 0.003), respectively, in South Asians. A relatively weaker mGS effect compared with Europeans indicates possible different intrauterine exposures between Europeans and South Asians. Birth weight was strongly associated with body size in both childhood and adolescence (P = 3 × 10-5 to 1.9 × 10-51); however, fGS was associated with body size in childhood only (P < 0.01) and with head circumference, fasting glucose, and triglycerides in adults (P < 0.01). The substantially smaller newborn size in South Asians with comparable fetal genetic effect to Europeans on birth weight suggests a significant role of factors related to fetal growth that were not captured by the present genetic scores. These factors may include different environmental exposures, maternal body size, health and nutritional status, etc. Persistent influence of genetic loci on size at birth and adult metabolic syndrome in our study supports a common genetic mechanism that partly explains associations between early development and later cardiometabolic health in various populations, despite marked differences in phenotypic and environmental factors in South Asians.

Anthropometric parameters to estimate body frame size in children and adolescents: A systematic review.

To determine the most frequently body frame size (BFS) measurement and to compare the cut-off values used for classifying body size in children and adolescents. This systematic review focused on primary studies and scientific reports published in Medline Ovid, EMBASE, Web of Science, or Scopus between January 1, 2007 and March 31, 2021. Eligible studies must have included at least one BFS parameter measured in healthy children or adolescents. A descriptive analysis and graphic comparison were performed when values of the body frame were available. A total of 26 studies involving 317 202 children and adolescents from all over the world were included. The report of Frame index predominated (46%). It was followed by the biacromial diameter single or combined with the bitrochanteric and biiliocristal diameter (27%), the wrist circumference (19%), and the grant index (12%). Fourteen studies reported percentile values of the BFS measurement, but only four presented cut-off values. There was no unified BFS measurement in children and adolescents neither reference cut-off values for categorization. The Frame index was the most frequently used. It is difficult to compare BFS statistics due to the diversity of measurements. It is necessary to standardize the use of the methods for measuring BFS.

Striking a balance in sports: the interrelation between children's sports experience, body size, and posture.

This study investigated the relation between sports participation, body size, and postural control in children between 3 and 11 years of age. To explore this question, children's body sway was measured across multisensory conditions manipulating visual input (the presence versus absence of visual information) and proprioceptive input (varying stance widths), with postural sway in these conditions then related to reports of children's sports participation, and anthropometric measures. Corroborating well-known findings, postural sway was systematically influenced by multisensory factors, with the removal of visual information and narrower stance widths decreasing postural stability. Of more novelty, postural sway in the most stable stance, but without vision, was significantly predicted by measures of sports participation and body size variables, with these factors contributing independently to this prediction. Moreover, the impact on postural sway of having visual input, relative to removing visual input in unstable stances, was significantly predicted by sports participation in activities stressing changing stances and bases of support (e.g., dance, martial arts). Generally, these findings support multisensory and dynamic systems theories of perceptual-motor behavior, and also support sports specificity effects in assessments of the relation between posture and sports.

Mendelian Randomization Analyses Suggest Childhood Body Size Indirectly Influences End Points From Across the Cardiovascular Disease Spectrum Through Adult Body Size.

BackgroundObesity is associated with long‐term health consequences including cardiovascular disease. Separating the independent effects of childhood and adulthood obesity on cardiovascular disease risk is challenging as children with obesity typically remain overweight throughout the lifecourse.Methods and ResultsThis study used 2‐sample univariable and multivariable Mendelian randomization to estimate the effect of childhood body size both independently and after accounting for adult body size on 12 endpoints across the cardiovascular disease disease spectrum. Univariable analyses identified strong evidence of a total effect between genetically predicted childhood body size and increased risk of atherosclerosis, atrial fibrillation, coronary artery disease, heart failure, hypertension, myocardial infarction, peripheral artery disease, and varicose veins. However, evidence of a direct effect was weak after accounting for adult body size using multivariable Mendelian randomization, suggesting that childhood body size indirectly increases risk of these 8 disease outcomes via the pathway involving adult body size.ConclusionsThese findings suggest that the effect of genetically predicted childhood body size on the cardiovascular disease outcomes analyzed in this study are a result of larger body size persisting into adulthood. Further research is necessary to ascertain the critical timepoints where, if ever, the detrimental impact of obesity initiated in early life begins to become immutable.

Breast Tissue Composition-Why It Matters and How Can We Measure It More Accurately in Epidemiology Studies.

Early-life body size has been consistently associated with breast cancer risk. The direction of the association changes over time, with high birth weight, smaller adolescent body size, and adult weight gain all increasing breast cancer risk. There is also a clear positive association between larger body size and increased breast adipose tissue measured by mammograms, but less is known about how body size changes across life stages affect stromal and epithelial breast tissue. Using breast tissue slides from women with benign breast disease, Oh and colleagues applied machine learning methods to evaluate body size across the life course and adipose, epithelial, and stromal tissue concentrations in adulthood. They found consistent patterns for higher adipose and lower stromal tissue concentrations with larger childhood and adult body size at age 18 years. They reported lower levels of epithelial tissue with larger body size at 18 years, but not at other time periods. Additional studies examining how body size at different life stages may affect breast tissue composition will be important. Noninvasive methods that can provide measures of breast tissue composition may offer potential ways forward to ensure generalizability, and repeated measurements by life stage.See related article by Oh et al., p. 608.

Evaluating the direct effects of childhood adiposity on adult systemic metabolism: a multivariable Mendelian randomization analysis.

BackgroundIndividuals who are obese in childhood have an elevated risk of disease in adulthood. However, whether childhood adiposity directly impacts intermediate markers of this risk, independently of adult adiposity, is unclear. In this study, we have simultaneously evaluated the effects of childhood and adulthood body size on 123 systemic molecular biomarkers representing multiple metabolic pathways.MethodsTwo-sample Mendelian randomization (MR) was conducted to estimate the causal effect of childhood body size on a total of 123 nuclear magnetic resonance-based metabolic markers using summary genome-wide association study (GWAS) data from up to 24 925 adults. Multivariable MR was then applied to evaluate the direct effects of childhood body size on these metabolic markers whilst accounting for adult body size. Further MR analyses were undertaken to estimate the potential mediating effects of these circulating metabolites on the risk of coronary artery disease (CAD) in adulthood using a sample of 60 801 cases and 123 504 controls.ResultsUnivariable analyses provided evidence that childhood body size has an effect on 42 of the 123 metabolic markers assessed (based on P < 4.07 × 10−4). However, the majority of these effects (35/42) substantially attenuated when accounting for adult body size using multivariable MR. We found little evidence that the biomarkers that were potentially influenced directly by childhood body size (leucine, isoleucine and tyrosine) mediate this effect onto adult disease risk. Very-low-density lipoprotein markers provided the strongest evidence of mediating the long-term effect of adiposity on CAD risk.ConclusionsOur findings suggest that childhood adiposity predominantly exerts its detrimental effect on adult systemic metabolism along a pathway that involves adulthood body size.