Time-varying and tissue-dependent effects of adiposity on leptin levels: A Mendelian randomization study
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eLife assessment
The authors have combined their two recently developed novel approaches to Mendelian randomization studies (1) Lifecourse mendelian randomization which relates genes to the outcome, eg obesity, at different stages of life, and (2) Tissue partitioned mendelian randomization to determine if there are different genetic effects in different tissues. They have successfully combined these two approaches to investigate the influence of adiposity on circulating leptin in childhood and adulthood to demonstrate the value/proof of concept of combining these two techniques. This is very clearly presented and well-conducted work showing both new methodology and compelling results and will be important to both those who use Mendelian randomization and those who are interested in obesity.
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Abstract
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).
Article activity feed
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eLife assessment
The authors have combined their two recently developed novel approaches to Mendelian randomization studies (1) Lifecourse mendelian randomization which relates genes to the outcome, eg obesity, at different stages of life, and (2) Tissue partitioned mendelian randomization to determine if there are different genetic effects in different tissues. They have successfully combined these two approaches to investigate the influence of adiposity on circulating leptin in childhood and adulthood to demonstrate the value/proof of concept of combining these two techniques. This is very clearly presented and well-conducted work showing both new methodology and compelling results and will be important to both those who use Mendelian randomization and those who are interested in obesity.
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Reviewer #1 (Public Review):
The authors have succeeded in demonstrating that they can further extend the methodology and value of Mendelian randomization by combining their two recently developed novel approaches to Mendelian randomization studies (1) Lifecourse MR which relates the genetic instruments to the outcome, eg obesity, at different stages of life eg childhood and adulthood and (2) Tissue partitioned MR to determine if the genetic instruments have different effects on different tissues such as the brain and adipose tissue. They have successfully combined these two to investigate the influence of adiposity on circulating leptin to demonstrate the value/proof of concept of these techniques in extending the use of MR.
This is a very clearly presented and well-conducted work showing both new methodology and clear-cut results on …
Reviewer #1 (Public Review):
The authors have succeeded in demonstrating that they can further extend the methodology and value of Mendelian randomization by combining their two recently developed novel approaches to Mendelian randomization studies (1) Lifecourse MR which relates the genetic instruments to the outcome, eg obesity, at different stages of life eg childhood and adulthood and (2) Tissue partitioned MR to determine if the genetic instruments have different effects on different tissues such as the brain and adipose tissue. They have successfully combined these two to investigate the influence of adiposity on circulating leptin to demonstrate the value/proof of concept of these techniques in extending the use of MR.
This is a very clearly presented and well-conducted work showing both new methodology and clear-cut results on the impact of adiposity at age 10 and in middle life and the weight gain in between on leptin levels and that the effect is mediated via the brain. They show that childhood obesity has a direct effect on leptin levels at age 10 years and an indirect effect on adult leptin along a causal pathway involving adulthood body size. They also show that BMI exerts its effect on leptin levels at both life stages via brain-tissue-mediated pathways.
Major strengths are the well-characterized data sets used and in particular, having a comprehensive data set for children and the successful use of a new approach to address a complex issue. There are no major weaknesses
The authors have achieved their two aims - the use of the new methodology and its application to the specific issue to demonstrate how it works ie proof of concept. Their results support their conclusions.
The main advance here is a demonstration of a new further enhanced approach to Mendelian randomization. This is likely to end up being used by other researchers to address complex questions.
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Reviewer #2 (Public Review):
In this proof-of-concept study, Richardson et al explore lifecourse effects of adiposity on leptin levels using life course Mendelian randomization and perform a tissue-partitioned MR to study the effects of tissue-specific BMI genetic instruments on leptin levels. The methods are solid and they have been nicely applied in the context of the present study. The results are important, revealing differences in the impact of adiposity on leptin levels in childhood vs adulthood, and highlighting the importance of the adipose-brain pathway in leptin homeostasis.
Additional MR analyses are suggested to explore bidirectional associations between leptin levels and adiposity, due to the interrelation of these two markers. Also, the fact that the MR instruments for childhood adiposity are based on self-reported body …
Reviewer #2 (Public Review):
In this proof-of-concept study, Richardson et al explore lifecourse effects of adiposity on leptin levels using life course Mendelian randomization and perform a tissue-partitioned MR to study the effects of tissue-specific BMI genetic instruments on leptin levels. The methods are solid and they have been nicely applied in the context of the present study. The results are important, revealing differences in the impact of adiposity on leptin levels in childhood vs adulthood, and highlighting the importance of the adipose-brain pathway in leptin homeostasis.
Additional MR analyses are suggested to explore bidirectional associations between leptin levels and adiposity, due to the interrelation of these two markers. Also, the fact that the MR instruments for childhood adiposity are based on self-reported body size, while the MR instruments for adult adiposity are based on measured adult BMI should be highlighted in the manuscript, and the possible impact of this in the findings should be discussed.
In summary, this important study is a proof of concept of life course and tissue-partitioned MR, while providing interesting insights into the regulation of leptin homeostasis by adiposity in different life stages.
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