TY - JOUR
T1 - Hepatocyte gene expression and DNA methylation as ancestry-dependent mechanisms in African Americans
AU - Park, C. S.
AU - De, T.
AU - Xu, Y.
AU - Zhong, Y.
AU - Smithberger, E.
AU - Alarcon, C.
AU - Gamazon, E. R.
AU - Perera, M. A.
N1 - Funding Information:
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).
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - 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).
AB - 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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U2 - 10.1038/s41525-019-0102-y
DO - 10.1038/s41525-019-0102-y
M3 - Article
C2 - 31798965
AN - SCOPUS:85075584516
SN - 2056-7944
VL - 4
JO - npj Genomic Medicine
JF - npj Genomic Medicine
IS - 1
M1 - 29
ER -