Molecular mediators of the association between child obesity and mental health

Abstract

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.

Keywords: ALSPAC; child; depression; multiomics; obesity.

FIGURE 1

Overview of the analysis and methodological workflow. Mediation analysis is a directed acyclic graph analytical framework of the hypothetical causal relationship between an exposure (X) and an outcome (Y) through a mediator (M). The blue rectangles are the statical analysis steps.

FIGURE 2

(A) Histogram of SMFQ score at 11 years. The vertical orange and red lines are the cut-offs of depressive symptoms (SMFQ>7) and depression (SMFQ>11), respectively. (B) Rate ratio per standard deviation (95% CI) of obesity at 7 years (exposure variable) for SMFQ score (outcome), and odds ratio of obesity at 7 years (exposure variable) for depressive symptoms (SMFQ>7) (outcome), and depression (SMFQ>11) at 11 years (outcome). The model is adjusted for sex and age, physical activity at age 5, mother’s age at birth, birthweight, mother’s pre-pregnancy BMI, average weekly family income at age 7, and mother’s highest education qualification. The error Bars show 95% confidence intervals (calculated through parametric methods).

FIGURE 3

Associations of metabolic measures at 7 years SMFQ score at 11 years (outcome). Bars show strength of association (-log10 p-value), colored by direction of effect. Model is adjusted for sex and age of child, physical activity at age 5, mother’s age at birth, birthweight, mother’s pre-pregnancy BMI, average weekly family income at 7, mother’s highest education qualification. FDR at 5%. The abbreviation of the metabolites is available in the Codebook (Supporting Information S2).

FIGURE 4

Forest plot of mediation analysis for mood related outcomes, (A) SMFQ score and (B) depressive symptoms (SMFQ score> 7), across 11 metabolic compounds. Models are adjusted for sex and age of child, physical activity at the age of 5 years, age of mother at birth, birthweight, mother’s pre-pregnancy BMI, average weekly family income at 7, mother’s highest education qualification. The rate and odds ratio are presented as dots. Bars show 95%CI calculated based on a bootstrapping approach (1,000 replications).

FIGURE 5

Volcano plot of the p-value and β coefficient for the association between 483 putative BMI-associated CpGs and the SMFQ score. The linear mixed-effect model is adjusted for sex and age of child, physical activity at the age of 5 years, age of mother at birth, birthweight, mother’s pre-pregnancy BMI, average weekly family income at 7, mother’s highest education qualification, CD4T, Bcell, CD8T, Gran, Mono, NK as fixed effect and chip and position bead array as random effects. The red dots are the CpGs with FDR<0.05. The vertical black dashed line indicates the rate ratio at 1. The vertical axis is the significance (p-value) on a log10 scale, and the horizontal axis is the beta estimate.

FIGURE 6

Forest plot of the natural indirect effect of the mediation analysis for the relation between obesity at 7 years and SMFQ score at 11 years as mediated by 10 CpGs simultaneously associated (p < 0.05) with BMI and (FDR 5%) SQFM at 11 years. Red dots and bars show rate ratio and 95% CI for natural directed effect, respectively. The model is adjusted for sex, age of mother at birth, birthweight, mother’s pre-pregnancy BMI, average weekly family income at 7, mother’s highest education qualification. 95% CI was calculated by bootstrapping with 1,000 replications.

FIGURE 7

Forest plot of the mediation analysis by methylation risk scores at age 7 years of obesity at 7 years and SMFQ score at 11 years, follow-up. Rate ratio and 95% CI(bars) for natural direct effect (red line), natural indirect effect (green line) and total effect (blue line) from single mediation analysis of obesity at 7 years on SMFQ through MRS. Rate ratio refers to MRS 1) based on Wahl et al. (2017) study (Supporting Information S1, Supplementary Table S1) and 2) based on 275 CpGs associated with child adiposity (Alfano et al., 2021) (Supporting Information S1, Supplementary Table S2).