Abstract Objective We estimated the effect of body mass index (BMI) on circulating metabolites in young adults using a recall-by-genotype (RbG) study design. Methods An RbG study was implemented in the Avon Longitudinal Study of Parents and Children. Samples from 756 participants were selected for untargeted metabolomics analysis based on low/high genetic liability for higher BMI defined by a genetic score (GS). Regression analyses were performed to investigate the association between BMI GS groups and relative abundance of 973 metabolites. Results After correction for multiple testing, 29 metabolites were associated with BMI GS group. Bilirubin was amongst the most strongly associated metabolites with reduced levels measured in individuals with the highest BMI GS (beta=-0.32, 95% confidence interval (CI): -0.46, -0.18, Benjamini-Hochberg (BH) adjusted p =0.005). We observed associations between BMI GS group and levels of several potentially diet-related metabolites including hippurate which had lower mean abundance in individuals in the high BMI GS group (beta=-0.29, 95% CI: -0.44, -0.15, BH adjusted p =0.008). Conclusions Together with existing literature our results suggest a genetic predisposition to higher BMI captures differences in metabolism leading to adiposity gain. In the absence of prospective data, separating these effects from the downstream consequences of weight gain is challenging. Study Importance questions What is already known about this subject? Metabolomics, defined as the measurement and study of circulating small molecules that are the substrates and products of cellular metabolism, is increasingly used by epidemiologists to provide a functional read-out of bulk cellular activity and a proxy to individual current health. This approach also provides insight into biological pathways linking exposures and disease. In observational studies, elevated body mass index (BMI) has been associated with a wide range of circulating metabolites. Researchers are now looking to genetic epidemiological methods, such as Mendelian randomization, to offer insight into potential causal relationships. What are the new findings in your manuscript? We identified 29 metabolites whose relative abundance varies with a genetic predisposition to higher BMI. Bilirubin, a key component of the heme catabolic pathway and a potent antioxidant, showed the strongest association with BMI score group. How might your results change the direction of research or the focus of clinical practice? Results of both Mendelian randomization and recall-by-genotype studies need to be combined with alternative study designs to distinguish between biomarkers that are intermediates on the pathway to BMI from those reflective of metabolic changes that result from increased adiposity. Separating causal biomarkers from non-causative biomarkers of adiposity is important since only the former are relevant to treatment and prevention, whilst both could be informative with respect to prediction and the downstream consequences of high BMI.
