Body mass index and adipose distribution have opposing genetic impacts on human blood traits
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Curated by eLife
Evaluation Summary:
The study investigates obesity and adipose distribution on hematopoiesis. It shows that genetically determined adiposity plays a previously underappreciated role in determining blood cell formation and function. The authors performed all the relevant and available MR analyses in the "toolbox". The results support the conclusions. The study will help understand the pathogenesis for clonal hematopoiesis.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)
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Abstract
Body mass index (BMI), hyperlipidemia, and truncal adipose distribution concordantly elevate cardiovascular disease risks, but have unknown genetic effects on blood trait variation. Using Mendelian randomization, we define unexpectedly opposing roles for increased BMI and truncal adipose distribution on blood traits. Elevated genetically determined BMI and lipid levels decreased hemoglobin and hematocrit levels, consistent with clinical observations associating obesity and anemia. We found that lipid-related effects were confined to erythroid traits. In contrast, BMI affected multiple blood lineages, indicating broad effects on hematopoiesis. Increased truncal adipose distribution opposed BMI effects, increasing hemoglobin and blood cell counts across lineages. Conditional analyses indicated genes, pathways, and cell types responsible for these effects, including Leptin Receptor and other blood cell-extrinsic factors in adipocytes and endothelium that regulate hematopoietic stem and progenitor cell biology. Our findings identify novel roles for obesity on hematopoiesis, including a previously underappreciated role for genetically determined adipose distribution in determining blood cell formation and function.
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Evaluation Summary:
The study investigates obesity and adipose distribution on hematopoiesis. It shows that genetically determined adiposity plays a previously underappreciated role in determining blood cell formation and function. The authors performed all the relevant and available MR analyses in the "toolbox". The results support the conclusions. The study will help understand the pathogenesis for clonal hematopoiesis.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)
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Reviewer #1 (Public Review):
The paper by Thom et al investigates genetic associations between adiposity and human blood traits. They use the Mendelian Randomization framework and conclude that BMI may be causally linked to low hemoglobin levels. Strengths of the study are the different methods used that put higher confidence to the results and several exposures/outcomes. Limitations may be that the paper is better for a more specialized audience as it is a bit difficult to follow all the exposure/outcome variables used and why and how some analyses were done.
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Reviewer #2 (Public Review):
The study investigates obesity and adipose distribution on hematopoiesis. It shows that genetically determined adiposity plays a previously underappreciated role in determining blood cell formation and function.
The authors performed all the relevant and available MR analyses in the "toolbox". The results support the conclusions. The study will help understand the pathogenesis for clonal hematopoiesis.
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Reviewer #3 (Public Review):
The authors, using Mendelian Randomisation, showed that obesity (overall weight) and truncal adiposity (weight distribution) have opposite effects on blood traits. They show that the effect of BMI is not restricted to the erythroid lineage, but it also has an effect on other blood cell types. These findings explain some observation previously made in obese individuals. Moreover, using their conditional analysis they were able to show that there are loci that lose their association with blood traits and other that do become associated to a particular trait.
While the analyses are convincing, the manuscript would benefit from a better introduction of the key concepts, which in the current version are just considered a given, especially for a journal with a wide audience such as this.
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