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

Abstract

AbstractBackgroundFindings 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.MethodGenetic instruments for childhood and adult adiposity were used to estimate lifestage specific effects on leptin levels measured during early life (mean age:10 years) in the Avon Longitudinal Study of Parents and Children (ALSPAC) and in adulthood (mean age:55 years) 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 MR to simultaneously estimate their separate effects on childhood and adult leptin levels.ResultsThere was strong evidence that childhood adiposity has a direct effect on leptin levels at age 10 years in the lifecourse (Beta=1.10, 95% CI=0.90 to 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 (Beta=0.74, 95% CI=0.62 to 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 (Beta=0.79, 95% CI=0.22 to 1.36, P=6×10−3& Beta=0.51, 95% CI=0.32 to 0.69, P=1×10−7respectively).ConclusionsOur 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 aetiological importance of appetite regulation in the effect of adiposity on leptin levels, as well as raising implications for the gene-environment equivalence assumption in MR.FundingThis 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).