Time-varying and tissue-dependent effects of adiposity on leptin levels: A Mendelian randomization study

BACKGROUND: Findings from Mendelian randomization (MR) studies are conventionally interpreted as lifelong effects, which typically do not provide insight into the molecular mechanisms underlying the effect of an exposure on an outcome. In this study, we apply two recently developed MR approaches (known as ‘lifecourse’ and ‘tissue-partitioned’ MR) to investigate lifestage-specific effects and tissues of action in the relationship between adiposity and circulating leptin levels. METHODS: Genetic instruments for childhood and adult adiposity were incorporated into a multivariable MR (MVMR) framework to estimate lifestage-specific effects on leptin levels measured during early life (mean age: 10 y) in the Avon Longitudinal Study of Parents and Children and in adulthood (mean age: 55 y) using summary-level data from the deCODE Health study. This was followed by partitioning body mass index (BMI) instruments into those whose effects are putatively mediated by gene expression in either subcutaneous adipose or brain tissues, followed by using MVMR to simultaneously estimate their separate effects on childhood and adult leptin levels. RESULTS: There was strong evidence that childhood adiposity has a direct effect on leptin levels at age 10 y in the lifecourse (β = 1.10 SD change in leptin levels, 95% CI = 0.90–1.30, p=6 × 10(-28)), whereas evidence of an indirect effect was found on adulthood leptin along the causal pathway involving adulthood body size (β = 0.74, 95% CI = 0.62–0.86, p=1 × 10(-33)). Tissue-partitioned MR analyses provided evidence to suggest that BMI exerts its effect on leptin levels during both childhood and adulthood via brain tissue-mediated pathways (β = 0.79, 95% CI = 0.22–1.36, p=6 × 10(-3) and β = 0.51, 95% CI = 0.32–0.69, p=1 × 10(-7), respectively). CONCLUSIONS: Our findings demonstrate the use of lifecourse MR to disentangle direct and indirect effects of early-life exposures on time-varying complex outcomes. Furthermore, by integrating tissue-specific data, we highlight the etiological importance of appetite regulation in the effect of adiposity on leptin levels. FUNDING: This work was supported by the Integrative Epidemiology Unit, which receives funding from the UK Medical Research Council and the University of Bristol (MC_UU_00011/1).