Body mass index and adipose distribution have opposing genetic impacts on human blood traits

Abstract
Data availability
Article and author information
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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.

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.

The following previously published data sets were used

1. Vuckovic et al
(2020) Blood Trait Summary Statistics (UKBB)
GWAS Catalog: GCST90002379-GCST90002407.

ftp://ftp.sanger.ac.uk/pub/project/humgen/summary_statistics/UKBB_blood_cell_traits/
1. Vuckovic et al
(2020) Blood Trait Summary Statistics (Meta-analysis)
http://www.mhi-humangenetics.org/en/resources.

http://www.mhi-humangenetics.org/en/resources
1. Pulit et al
(2019) Obesity and Adiposity Summary Statistics
https://doi.org/10.5281/zenodo.1251813.

https://doi.org/10.5281/zenodo.1251813
1. van der Harst and Verweij
(2018) CAD Summary Statistics
Mendeley Data: doi:10.17632/2zdd47c94h.1; doi:10.17632/gbbsrpx6bs.1.

https://data.mendeley.com/datasets/2zdd47c94h/1
1. Klarin et al
(2018) Lipid Trait Summary Statistics
dbGap: phs001672.v6.p1.

https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs001672.v6.p1

Article and author information

Author details

Christopher S Thom

Division of Neonatology, Children's Hospital of Philadelphia, Philadelphia, United States

For correspondence
thomc@chop.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-1830-9922
Madison B Wilken

Division of Neonatology, Children's Hospital of Philadelphia, Philadelphia, United States

Competing interests
The authors declare that no competing interests exist.
Stella T Chou

Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, United States

Competing interests
The authors declare that no competing interests exist.
Ben Voight

Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, United States

For correspondence
bvoight@pennmedicine.upenn.edu

Competing interests
The authors declare that no competing interests exist.

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

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.