Body mass index and adipose distribution have opposing genetic impacts on human blood traits
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.
Data availability
The current manuscript is a computational study based on publicly available data sets, so no primary data were generated for this manuscript. All relevant coding scripts and data sets can be found on GitHub (https://github.com/thomchr/ObesityAdiposityBloodMR) or by request.
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Blood Trait Summary Statistics (UKBB)GWAS Catalog: GCST90002379-GCST90002407.
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Blood Trait Summary Statistics (Meta-analysis)http://www.mhi-humangenetics.org/en/resources.
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Obesity and Adiposity Summary Statisticshttps://doi.org/10.5281/zenodo.1251813.
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CAD Summary StatisticsMendeley Data: doi:10.17632/2zdd47c94h.1; doi:10.17632/gbbsrpx6bs.1.
Article and author information
Author details
Funding
Eunice Kennedy Shriver National Institute of Child Health and Human Development (T32HD043021)
- Christopher S Thom
National Heart, Lung, and Blood Institute (K99HL156052)
- Christopher S Thom
National Heart, Lung, and Blood Institute (U01HL124696)
- Stella T Chou
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK101478)
- Ben Voight
National Institute of Diabetes and Digestive and Kidney Diseases (UM1DK126194)
- Ben Voight
Linda Pechenik Montague (Investigator Award)
- Ben Voight
Children's Hospital of Philadelphia (K-readiness award)
- Christopher S Thom
National Heart, Lung, and Blood Institute (U24HL134763)
- Christopher S Thom
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2022, Thom et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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