Associations of body mass and fat indexes with cardiometabolic traits

Background Body mass index (BMI) is criticized for not distinguishing fat from lean mass and ignoring fat distribution, leaving its ability to detect health effects unclear. Objectives The aim of this study was to compare BMI with total and regional fat indexes from dual-energy x-ray absorptiometry in their associations with cardiometabolic traits. Duration of exposure to and change in each index across adolescence were examined in relation to detailed traits in young adulthood. Methods BMI was examined alongside total, trunk, arm, and leg fat indexes (each in kilograms per square meter) from dual-energy x-ray absorptiometry at ages 10 and 18 years in relation to 230 traits from targeted metabolomics at age 18 years in 2,840 offspring from the Avon Longitudinal Study of Parents and Children. Results Higher total fat mass index and BMI at age 10 years were similarly associated with cardiometabolic traits at age 18 years, including higher systolic and diastolic blood pressure, higher very low-density lipoprotein and low-density lipoprotein cholesterol, lower high-density lipoprotein cholesterol, higher triglycerides, and higher insulin and glycoprotein acetyls. Associations were stronger for both indexes measured at age 18 years and for gains in each index from age 10 to 18 years (e.g., 0.45 SDs [95% confidence interval: 0.38 to 0.53] in glycoprotein acetyls per SD unit gain in fat mass index vs. 0.38 SDs [95% confidence interval: 0.27 to 0.48] per SD unit gain in BMI). Associations resembled those for trunk fat index. Higher lean mass index was weakly associated with traits and was not protective against higher fat mass index. Conclusions The results of this study support abdominal fatness as a primary driver of cardiometabolic dysfunction and BMI as a useful tool for detecting its effects

Additional file 2 of Establishing the relationships between adiposity and reproductive factors: a multivariable Mendelian randomization analysis

Additional file 2: Table S1. Relationships explored in the univariable analysis. Table S2. Relationships explored in the multivariable analysis with adjustments. Table S3. Replication consortia and information. Table S4. Multivariable mendelian randomization instrument strength and SNP overlap. Table S5. Univariable mendelian randomization findings – IVW method. Table S6. Multivariable mendelian randomization findings - IVW method. Table S7. Steiger filtering. Table S8. Univariable mendelian randomization analyses – heterogeneity test. Table S9. Univariable mendelian randomization analyses - additional MR methods. Table S10. Univariable mendelian randomization analyses – Egger intercept test. Table S11. Univariable mendelian randomization analyses- MR PRESSO. Table S12. Univariable mendelian randomization analyses- MRlap. Table S13. Multivariable mendelian randomization analyses – heterogeneity test. Table S14. Multivariable mendelian randomization with minimised Q statistic findings. Table S15. Multivariable mendelian randomization analysis of childhood body size on reproductive factors - steiger filtered SNPs removed. Table S16. Replication multivariable mendelian randomization instrument strength. Table S17. Replication univariable mendelian randomization findings - IVW method. Table S18. Replication multivariable mendelian randomization findings - IVW method

Additional file 1 of Establishing the relationships between adiposity and reproductive factors: a multivariable Mendelian randomization analysis

Additional file 1. Further details

S1 File -

BackgroundMitochondria are organelles responsible for converting glucose into energy. Mitochondrial DNA is exclusively maternally inherited. The role of mitochondrial DNA haplogroups in the aetiology of cardiometabolic disease risk is not well understood.MethodsSex-specific associations between common European mitochondrial DNA haplogroups (H, U, J, T, K, V, W, I and X) and trajectories of cardiometabolic risk factors from birth to 18 years were examined in a prospective cohort. Cardiometabolic risk factors measured from birth/mid-childhood to 18 years included body mass index (BMI), fat and lean mass, systolic and diastolic blood pressure, pulse rate, high-density lipoprotein cholesterol (HDL-c), non-HDL-c and triglycerides. Fractional polynomial and linear spline multilevel models explored the sex-specific association between haplogroups and risk factor trajectories.ResultsAmong a total of 7,954 participants with 79,178 repeated measures per outcome, we found no evidence that haplogroups U, T, J, K and W were associated with cardiometabolic risk factors compared to haplogroup H. In females, haplogroup V was associated with 4.0% (99% CI: -7.5, -0.6) lower BMI at age one but associations did not persist at age 18. Haplogroup X was associated with 1.3kg (99% CI: -2.5, -0.2) lower lean mass at age 9 which persisted at 18. Haplogroup V and X were associated with 9.3% (99% CI: -0.4, 19.0) and 16.4% (99% CI: -0.5,33.3) lower fat mass at age 9, respectively, although confidence intervals spanned the null and associations did not persist at 18. In males, haplogroup I was associated with 2.4% (99% CI: -0.5, 5.3) higher BMI at age 7; widening to 5.1% (99% CI: -0.5, 10.6) at 18 with confidence intervals spanning the null.ConclusionsOur study demonstrated little evidence of sex-specific associations between mitochondrial DNA haplogroups and cardiometabolic risk factors.</div

Mean trajectories of HDL-c, Non-HDL-c and log triglycerides in females and males, by haplogroup.

99% confidence intervals for all haplogroups are displayed in grey. Detailed results with confidence intervals are provided in S16 & S17 Tables in S1 File. Note the different age range on the X axis for each outcome. HDL-c, high density lipoprotein cholesterol.</p

Mean trajectories of SBP, DBP and pulse in females and males, by haplogroup.

99% confidence intervals for all haplogroups are displayed in grey. Detailed results with confidence intervals are provided in S15 Table in S1 File. SBP, systolic blood pressure; DBP, diastolic blood pressure.</p

Using Super-Imposition by Translation And Rotation (SITAR) to relate pubertal growth to bone health in later life: the Medical Research Council (MRC) National Survey of Health and Development

Background: To explore associations between pubertal growth and later bone health in a cohort with infrequent measurements, using another cohort with more frequent measurements to support the modelling, data from the MRC National Survey of Health and Development (2-26 years, 4901/30 004 subjects/measurements) and the Avon Longitudinal Study of Parents and Children (5-20 years) (10 896/74 120) were related to NSHD bone health outcomes at 60-64 years. Methods: NSHD data were analysed using SITAR growth curve analysis, either alone or jointly with ALSPAC data. Improved estimation of pubertal growth parameters of size, tempo and velocity was assessed by changes in model fit and correlations with contemporary measures of pubertal timing. Bone outcomes of radius (trabecular volumetric bone mineral density (vBMD) and diaphysis cross-sectional area (CSA)) were regressed on the SITAR parameters, adjusted for current body size. Results: The NSHD SITAR parameters were better estimated in conjunction with ALSPAC, i.e. more strongly correlated with pubertal timing. Trabecular vBMD was associated with early height tempo, while diaphysis CSA was related to weight size, early tempo and slow velocity, the bone outcomes being around 15% higher for the better versus worse growth pattern. Conclusions: By pooling NSHD and ALSPAC data, SITAR more accurately summarised pubertal growth and weight gain in NSHD, and in turn demonstrated notable associations between pubertal timing and later bone outcomes. These associations give insight into the importance of the pubertal period for future skeletal health and osteoporosis risk

DataSheet1_Molecular mediators of the association between child obesity and mental health.docx

Biological mechanisms underlying the association between obesity and depression remain unclear. We investigated the role of metabolites and DNA methylation as mediators of the relationship between childhood obesity and subsequent poor mental health in the English Avon Longitudinal Study of Parents and Children. Obesity was defined according to United Kingdom Growth charts at age 7 years and mental health through the Short Mood and Feelings Questionnaire (SMFQ) completed at age 11 years. Metabolites and DNA methylation were measured by nuclear magnetic resonance spectroscopy and Illumina array in blood at the age of 7 years. The associations between obesity and SMFQ score, as continuous count data or using cut-offs to define depressive symptoms (SMFQ >7) or depression (SMFQ >11), were tested using adjusted Poisson and logistic regression. Candidate metabolite mediators were identified through metabolome-wide association scans for obesity and SMFQ score, correcting for false-discovery rate. Candidate DNA methylation mediators were identified through testing the association of putative BMI-associated CpG sites with SMFQ scores, correcting for look-up false-discovery rate. Mediation by candidate molecular markers was tested. Two-sample Mendelian randomization (MR) analyses were additionally applied to test causal associations of metabolites with depression in independent adult samples. 4,018 and 768 children were included for metabolomics and epigenetics analyses, respectively. Obesity at 7 years was associated with a 14% increase in SMFQ score (95% CI: 1.04, 1.25) and greater odds of depression (OR: 1.46 (95% CI: 0.78, 2.38) at 11 years. Natural indirect effects (mediating pathways) between obesity and depression for tyrosine, leucine and conjugated linoleic acid were 1.06 (95% CI: 1.00, 1.13, proportion mediated (PM): 15%), 1.04 (95% CI: 0.99, 1.10, PM: 9.6%) and 1.06 (95% CI: 1.00, 1.12, PM: 13.9%) respectively. In MR analysis, one unit increase in tyrosine was associated with 0.13 higher log odds of depression (p = 0.1). Methylation at cg17128312, located in the FBXW9 gene, had a natural indirect effect of 1.05 (95% CI: 1.01,1.13, PM: 27%) as a mediator of obesity and SMFQ score. Potential biologically plausible mechanisms involving these identified molecular features include neurotransmitter regulation, inflammation, and gut microbiome modulation. These results require replication in further observational and mechanistic studies.</p

DataSheet2_Molecular mediators of the association between child obesity and mental health.xlsx

Biological mechanisms underlying the association between obesity and depression remain unclear. We investigated the role of metabolites and DNA methylation as mediators of the relationship between childhood obesity and subsequent poor mental health in the English Avon Longitudinal Study of Parents and Children. Obesity was defined according to United Kingdom Growth charts at age 7 years and mental health through the Short Mood and Feelings Questionnaire (SMFQ) completed at age 11 years. Metabolites and DNA methylation were measured by nuclear magnetic resonance spectroscopy and Illumina array in blood at the age of 7 years. The associations between obesity and SMFQ score, as continuous count data or using cut-offs to define depressive symptoms (SMFQ >7) or depression (SMFQ >11), were tested using adjusted Poisson and logistic regression. Candidate metabolite mediators were identified through metabolome-wide association scans for obesity and SMFQ score, correcting for false-discovery rate. Candidate DNA methylation mediators were identified through testing the association of putative BMI-associated CpG sites with SMFQ scores, correcting for look-up false-discovery rate. Mediation by candidate molecular markers was tested. Two-sample Mendelian randomization (MR) analyses were additionally applied to test causal associations of metabolites with depression in independent adult samples. 4,018 and 768 children were included for metabolomics and epigenetics analyses, respectively. Obesity at 7 years was associated with a 14% increase in SMFQ score (95% CI: 1.04, 1.25) and greater odds of depression (OR: 1.46 (95% CI: 0.78, 2.38) at 11 years. Natural indirect effects (mediating pathways) between obesity and depression for tyrosine, leucine and conjugated linoleic acid were 1.06 (95% CI: 1.00, 1.13, proportion mediated (PM): 15%), 1.04 (95% CI: 0.99, 1.10, PM: 9.6%) and 1.06 (95% CI: 1.00, 1.12, PM: 13.9%) respectively. In MR analysis, one unit increase in tyrosine was associated with 0.13 higher log odds of depression (p = 0.1). Methylation at cg17128312, located in the FBXW9 gene, had a natural indirect effect of 1.05 (95% CI: 1.01,1.13, PM: 27%) as a mediator of obesity and SMFQ score. Potential biologically plausible mechanisms involving these identified molecular features include neurotransmitter regulation, inflammation, and gut microbiome modulation. These results require replication in further observational and mechanistic studies.</p

Supplementary Information Files for Early childhood weight gain: latent patterns and body composition outcomes

Supplementary Information Files for Early childhood weight gain: latent patterns and body composition outcomesBackground: Despite early childhood weight gain being a key indicator of obesity risk, we do not have a good understanding of the different patterns that exist. Objectives: To identify and characterise distinct groups of children displaying similar early life weight trajectories. Methods: A growth mixture model captured heterogeneity in weight trajectories between 0-60 months in 1,390 children in the Avon Longitudinal Study of Parents and Children. Differences between the classes in characteristics and body size/composition at 9 years were investigated. Results: The best model had five classes. The “Normal” (45%) and “Normal after initial catch-down” (24%) classes were close to the 50th centile of a growth standard between 24-60 months. The “High-decreasing” (21%) and “Stable-high” (7%) classes peaked at the ~91st centile at 12-18 months, but while the former declined to the ~75th centile and comprised constitutionally big children, the latter did not. The “Rapidlyincreasing” (3%) class gained weight from below the 50th centile at 4 months to above the 91st centile at 60 months. By 9 years, their mean body mass index (BMI) placed them at the 98th centile. This class was characterised by the highest maternal BMI; highest parity; highest levels of gestational hypertension and diabetes; and the lowest socio-economic position. At 9 years, the “Rapidly-increasing” class was estimated to have 68.2% (48.3,88.1) more fat mass than the “Normal” class, but only 14.0% (9.1,18.9) more lean mass. Conclusions: Criteria used in growth monitoring practice are unlikely to consistently distinguish between the different patterns of weight gain reported here.<br