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Genetics and Epigenetics

DNA methylation and adiposity phenotypes: an epigenome-wide association study among adults in the Strong Heart Study

Subjects

Abstract

Background

Elevated adiposity is often posited by medical and public health researchers to be a risk factor associated with cardiovascular disease, diabetes, and other diseases. These health challenges are now thought to be reflected in epigenetic modifications to DNA molecules, such as DNA methylation, which can alter gene expression.

Methods

Here we report the results of three Epigenome Wide Association Studies (EWAS) in which we assessed the differential methylation of DNA (obtained from peripheral blood) associated with three adiposity phenotypes (BMI, waist circumference, and impedance-measured percent body fat) among American Indian adult participants in the Strong Heart Study.

Results

We found differential methylation at 8264 CpG sites associated with at least one of our three response variables. Of the three adiposity proxies we measured, waist circumference had the highest number of associated differentially methylated CpGs, while percent body fat was associated with the lowest. Because both waist circumference and percent body fat relate to physiology, we focused interpretations on these variables. We found a low degree of overlap between these two variables in our gene ontology enrichment and Differentially Methylated Region analyses, supporting that waist circumference and percent body fat measurements represent biologically distinct concepts.

Conclusions

We interpret these general findings to indicate that highly significant regions of the genome (DMR) and synthesis pathways (GO) in waist circumference analyses are more likely to be associated with the presence of visceral/abdominal fat than more general measures of adiposity. Our findings confirmed numerous CpG sites previously found to be differentially methylated in association with adiposity phenotypes, while we also found new differentially methylated CpG sites and regions not previously identified.

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Fig. 1: Diagram illustrating data processing procedure used for this study.
Fig. 2: Venn Diagram of results of three EWAS studies (BMI, waist circumference, and percent body fat).
Fig. 3: Manhattan plot of three EWAS studies (BMI, waist circumference, and percent body fat).
Fig. 4: Venn diagram of differentially methylated CpG sites.
Fig. 5: Venn diagram of differentially methylated CpG regions.
Fig. 6: Graphical representation of selected results from DMR analyses.
Fig. 7: Venn diagram of Gene Ontology Enrichment Association results.

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Data availability

Access to Strong Heart Study raw data is subject to approval by participating tribes following the procedures established by the Strong Heart Study in agreement with the tribes. Detailed information is available in the Strong Heart Study website https://strongheartstudy.org/.

Code availability

Code used to analyze data in this paper is available from the senior author and the corresponding author.

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Acknowledgements

This work was supported by grants for the National Heart, Lung, and Blood Institute (NHLBI) (under contract numbers 75N92019D00027, 75N92019D00028, 75N92019D00029, and 75N92019D00030) and previous grants (R01HL090863, R01HL109315, R01HL109301, R01HL109284, R01HL109282, and R01HL109319 and cooperative agreements: U01HL41642, U01HL41652, U01HL41654, U01HL65520, and U01HL65521) and by the National Institutes of Health Sciences (R01ES021367, R01ES025216, P42ES010349, P30ES009089). Thanks to Dr. Pascale R Leroueil for computational expertise and Ali Thompson for illuminating discussions. All analyses and writing of this manuscript were done on the occupied territory of the Lenape and Wappinger Nations.

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Correspondence to Katherine C. Crocker.

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Crocker, K.C., Domingo-Relloso, A., Haack, K. et al. DNA methylation and adiposity phenotypes: an epigenome-wide association study among adults in the Strong Heart Study. Int J Obes 44, 2313–2322 (2020). https://doi.org/10.1038/s41366-020-0646-z

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