Uncovering the role of admixture in disease and drug response: Association of hepatocyte gene expression and DNA methylation with African Ancestry in African Americans

Park, C. S.; De, Tanima; Xu, Yuchen; Zhong, Yi; Gamazon, Eric R.; Smithberger, Erin; Alarcón, Cristina; Perera, Minoli A.

doi:10.1101/491225

Cited by 3 publications

(4 citation statements)

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“…We excluded any livers with active cancer or with a history of hepatocarcinoma. Primary hepatocytes were isolated and cultured as previously described in Park et al [54]. The workflow of genotyping QC and RNA sequencing QC is in Fig 1A. Genotyping and imputation DNA was extracted from each hepatocyte line using Gentra Puregene Blood kit (Qiagen).…”

Section: Cohortmentioning

confidence: 99%

Discovery of novel hepatocyte eQTLs in African Americans

Zhong

Alarcón

et al. 2020

PLoS Genet

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African Americans (AAs) are disproportionately affected by metabolic diseases and adverse drug events, with limited publicly available genomic and transcriptomic data to advance the knowledge of the molecular underpinnings or genetic associations to these diseases or drug response phenotypes. To fill this gap, we obtained 60 primary hepatocyte cultures from AA liver donors for genome-wide mapping of expression quantitative trait loci (eQTL) using LAMatrix. We identified 277 eGenes and 19,770 eQTLs, of which 67 eGenes and 7,415 eQTLs are not observed in the Genotype-Tissue Expression Project (GTEx) liver eQTL analysis. Of the eGenes found in GTEx only 25 share the same lead eQTL. These AA-specific eQTLs are less correlated to GTEx eQTLs. in effect sizes and have larger Fst values compared to eQTLs found in both cohorts (overlapping eQTLs). We assessed the overlap between GWAS variants and their tagging variants with AA hepatocyte eQTLs and demonstrated that AA hepatocyte eQTLs can decrease the number of potential causal variants at GWAS loci. Additionally, we identified 75,002 exon QTLs of which 48.8% are not eQTLs in AA hepatocytes. Our analysis provides the first comprehensive characterization of AA hepatocyte eQTLs and highlights the unique discoveries that are made possible due to the increased genetic diversity within the African ancestry genome.

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Section: Cohortmentioning

confidence: 99%

Discovery of novel hepatocyte eQTLs in African Americans

Zhong

Alarcón

et al. 2020

PLoS Genet

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“…The CYP2C19*17 allele, which is found in African ancestry populations (24%), was associated with an increased 1‐year mortality rate and an increased risk of bleeding in African Americans . A recent study has shown that the proportion of African ancestry may be associated with the hepatic expression on CYP2C19 . Even in genes as important as these, most GWAS of drug response have been conducted in European and Asian populations, leaving the effect of population‐specific variants unknown.…”

Section: Pharmacogenomics and Minority Populationsmentioning

confidence: 99%

“…53 A recent study has shown that the proportion of African ancestry may be associated with the hepatic expression on CYP2C19. 54 Even in genes as important as these, most GWAS of drug response have been conducted in European and Asian populations, leaving the effect of population-specific variants unknown.…”

Section: Cross-population Differences In Drug Responsementioning

confidence: 99%

The Advantages and Challenges of Diversity in Pharmacogenomics: Can Minority Populations Bring Us Closer to Implementation?

Zhang

Zhong

et al. 2019

Clin Pharma and Therapeutics

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Health disparities exist among minorities in the United States, with differences seen in disease prevalence, mortality, and responses to medications. These differences are multifactorial with genetic variation explaining a portion of this variability. Pharmacogenomics aims to find the effect of genetic variations on drug response, with the goal of optimizing drug therapy and development. Although genome‐wide association studies have been useful in unbiasedly surveying the genome for genetic drivers of clinically relevant phenotypes, most of these studies have been conducted in mainly participants of European and Asian descent, contributing to a growing health disparity in precision medicine. Diversity is important to pharmacogenomic studies, and there may be real advantages to the use of these complex genomes in pharmacogenomics. In this review we will outline some of the advantages and confounders of pharmacogenomics in minorities, describe the role of genetic variation in pharmacologic pathways, and highlight a number of population‐specific findings.

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“…COVID-19 cases and deaths are disproportionately higher among African Americans; this is often attributed to a complex combination of socio-economic factors 15,36,37 . However, a number of studies have shown differences in genes expression among races [38][39][40][41] . Gene expression reflects the interaction between environmental/physiological and genetic influences.…”

Section: Introductionmentioning

confidence: 99%

Differential expression of COVID-19-related genes in European Americans and African Americans

Singh

Wurtele

2020

Preprint

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The Coronavirus disease 2019 (COVID-19) pandemic has affected African American populations disproportionately in regards to both morbidity and mortality. A multitude of factors likely account for this discrepancy. Gene expression represents the interaction of genetics and environment. To elucidate whether levels of expression of genes implicated in COVID-19 vary in African Americans as compared to European Americans, we re-mine The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) RNA-Seq data. Multiple genes integral to infection, inflammation and immunity are differentially regulated across the two populations. Most notably, F8A2 and F8A3, which encode the HAP40 protein that mediates early endosome movement in Huntington’s Disease, are more highly expressed by up to 24-fold in African Americans. Such differences in gene expression can establish prognostic signatures and have critical implications for precision treatment of diseases such as COVID-19. We advocate routine inclusion of information such as postal code, education level, and profession (as a proxies for socioeconomic condition) and race in the metadata about each individual sampled for sequencing studies. This relatively simple change would enable large-scale data-driven approaches to dissect relationships among race, socio-economic factors, and disease.

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Uncovering the role of admixture in disease and drug response: Association of hepatocyte gene expression and DNA methylation with African Ancestry in African Americans

Cited by 3 publications

References 101 publications

Discovery of novel hepatocyte eQTLs in African Americans

Discovery of novel hepatocyte eQTLs in African Americans

The Advantages and Challenges of Diversity in Pharmacogenomics: Can Minority Populations Bring Us Closer to Implementation?

Differential expression of COVID-19-related genes in European Americans and African Americans

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