Hepatocyte gene expression and DNA methylation as ancestry-dependent mechanisms in African Americans

C. S. Park; T. De; Y. Xu; Y. Zhong; E. Smithberger; C. Alarcon; E. R. Gamazon; M. A. Perera

doi:10.1038/s41525-019-0102-y

Hepatocyte gene expression and DNA methylation as ancestry-dependent mechanisms in African Americans

C. S. Park, T. De, Y. Xu, Y. Zhong, E. Smithberger, C. Alarcon, E. R. Gamazon, M. A. Perera^*

^*Corresponding author for this work

Pharmacology

Research output: Contribution to journal › Article › peer-review

11 Scopus citations

Abstract

African Americans (AAs) are an admixed population with widely varying proportion of West African ancestry (WAA). Here we report the correlation of WAA to gene expression and DNA methylation in AA-derived hepatocytes, a cell type important in disease and drug response. We perform mediation analysis to test whether methylation is a mediator of the effect of ancestry on expression. GTEx samples and a second cohort are used as validation. One hundred and thirty-one genes are associated with WAA (FDR < 0.10), 28 of which replicate and represent 220 GWAS phenotypes. Among PharmGKB pharmacogenes, VDR, PTGIS, ALDH1A1, CYP2C19, and P2RY1 nominally associate with WAA (p < 0.05). We find 1037 WAA-associated, differentially methylated regions (FDR < 0.05), with hypomethylated genes enriched in drug-response pathways. In conclusion, WAA contributes to variability in hepatocyte expression and DNA methylation with identified genes previously implicated for diseases disproportionately affecting AAs, including cardiovascular (PTGIS, PLAT) and renal (APOL1) disease, and drug response (CYP2C19).

Original language	English (US)
Article number	29
Journal	npj Genomic Medicine
Volume	4
Issue number	1
DOIs	https://doi.org/10.1038/s41525-019-0102-y
State	Published - Dec 1 2019

Funding

We would like to acknowledge Dr. Heather Wheeler for her invaluable scientific input. E.R.G. wishes to thank the President and Fellows of Clare Hall, University of Cambridge for providing a stimulating intellectual home and for the generous support during the Academic Terms of Cambridge University. E.R.G. is supported by the National Human Genome Research Institute of the National Institutes of Health under Award Number R35HG010718. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This work was supported by NIH National Institute on Minority Health and Health Disparities (NIMHD) Research Project 1R01MD009217-01 (R01).

ASJC Scopus subject areas

Molecular Biology
Genetics
Genetics(clinical)

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abstract = "African Americans (AAs) are an admixed population with widely varying proportion of West African ancestry (WAA). Here we report the correlation of WAA to gene expression and DNA methylation in AA-derived hepatocytes, a cell type important in disease and drug response. We perform mediation analysis to test whether methylation is a mediator of the effect of ancestry on expression. GTEx samples and a second cohort are used as validation. One hundred and thirty-one genes are associated with WAA (FDR < 0.10), 28 of which replicate and represent 220 GWAS phenotypes. Among PharmGKB pharmacogenes, VDR, PTGIS, ALDH1A1, CYP2C19, and P2RY1 nominally associate with WAA (p < 0.05). We find 1037 WAA-associated, differentially methylated regions (FDR < 0.05), with hypomethylated genes enriched in drug-response pathways. In conclusion, WAA contributes to variability in hepatocyte expression and DNA methylation with identified genes previously implicated for diseases disproportionately affecting AAs, including cardiovascular (PTGIS, PLAT) and renal (APOL1) disease, and drug response (CYP2C19).",

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AU - Alarcon, C.

AU - Gamazon, E. R.

AU - Perera, M. A.

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Hepatocyte gene expression and DNA methylation as ancestry-dependent mechanisms in African Americans

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