Discovery of novel hepatocyte eQTLs in African Americans

Zhong, Yi; De, Tanima; Alarcón, Cristina; Park, C. Sehwan; Lec, Bianca; Perera, Minoli

doi:10.1371/journal.pgen.1008662

Cited by 27 publications

(54 citation statements)

References 76 publications

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“…Re-mining existing RNA-Seq data and metadata has several caveats. Because race assignments are self-reported, many of the individuals sampled will be from admixed populations 41,44 . We are terming those self-reporting as "black or African American" as "African Americans" and "white" as "European Americans".…”

Section: Resultsmentioning

confidence: 99%

“…Genetics of human populations contribute to the propensity and severity of diseases 37,39,41,41,45,[60][61][62][63][64][65] . Sometimes the contribution is straightforward; a single allele variation found in Ashkenazi Jews, causes the vast majority of Tay-Sachs disease 66 .…”

Section: Discussionmentioning

confidence: 99%

“…Sometimes it is more complex; for example, hypertension, which more prevalent in African American than European American populations 60 in part due to detrimental APOL1 mutations that are more frequent in West African populations 62 . Despite the paucity of studies focused on Western African populations, the propensity and severity of several other diseases among this population have been attributed to genetics 41,62,67 .…”

Section: Discussionmentioning

confidence: 99%

“…Despite the paucity of studies focused on Western African populations, the propensity and severity of several other diseases among this population have been attributed to genetics 41,95,101 . Here, by revealing differential expression of genes that may be key players in COVID-19 between African Americans and European Americans, we emphasize the importance of integrating gene expression into the mix of factors considered in studying this pandemic.…”

Section: Discussionmentioning

confidence: 99%

“…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%

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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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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Singh

Wurtele

2020

Preprint

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Differences in the Platelet mRNA Landscape Portend Racial Disparities in Platelet Function and Suggest Novel Therapeutic Targets

Garofano

Park

Alarcón

et al. 2021

Clin Pharma and Therapeutics

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The African American (AA) population displays a 1.6 to 3‐fold higher incidence of thrombosis and stroke mortality compared with European Americans (EAs). Current antiplatelet therapies target the ADP‐mediated signaling pathway, which displays significant pharmacogenetic variation for platelet reactivity. The focus of this study was to define underlying population differences in platelet function in an effort to identify novel molecular targets for future antiplatelet therapy. We performed deep coverage RNA‐Seq to compare gene expression levels in platelets derived from a cohort of healthy volunteers defined by ancestry determination. We identified > 13,000 expressed platelet genes of which 480 were significantly differentially expressed genes (DEGs) between AAs and EAs. DEGs encoding proteins known or predicted to modulate platelet aggregation, morphology, or platelet count were upregulated in AA platelets. Numerous G‐protein coupled receptors, ion channels, and pro‐inflammatory cytokines not previously associated with platelet function were likewise differentially expressed. Many of the signaling proteins represent potential pharmacologic targets of intervention. Notably, we confirmed the differential expression of cytokines IL32 and PROK2 in an independent cohort by quantitative real‐time polymerase chain reaction, and provide functional validation of the opposing actions of these two cytokines on collagen‐induced AA platelet aggregation. Using Genotype‐Tissue Expression whole blood data, we identified 516 expression quantitative trait locuses with Fst values > 0.25, suggesting that population‐differentiated alleles may contribute to differences in gene expression. This study identifies gene expression differences at the population level that may affect platelet function and serve as potential biomarkers to identify cardiovascular disease risk. Additionally, our analysis uncovers candidate novel druggable targets for future antiplatelet therapies.

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Multi‐Omics Studies in Historically Excluded Populations: The Road to Equity

Yang

Mishra

Perera

2023

Clin Pharma and Therapeutics

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Over the past few decades, genomewide association studies (GWASs) have identified the specific genetics variants contributing to many complex diseases by testing millions of genetic variations across the human genome against a variety of phenotypes. However, GWASs are limited in their ability to uncover mechanistic insight given that most significant associations are found in non‐coding region of the genome. Furthermore, the lack of diversity in studies has stymied the advance of precision medicine for many historically excluded populations. In this review, we summarize most popular multi‐omics approaches (genomics, transcriptomics, proteomics, and metabolomics) related to precision medicine and highlight if diverse populations have been included and how their findings have advance biological understanding of disease and drug response. New methods that incorporate local ancestry have been to improve the power of GWASs for admixed populations (such as African Americans and Latinx). Because most signals from GWAS are in the non‐coding region, other machine learning and omics approaches have been developed to identify the potential causative single‐nucleotide polymorphisms and genes that explain these phenotypes. These include polygenic risk scores, expression quantitative trait locus mapping, and transcriptome‐wide association studies. Analogous protein methods, such as proteins quantitative trait locus mapping, proteome‐wide association studies, and metabolomic approaches provide insight into the consequences of genetic variation on protein abundance. Whereas, integrated multi‐omics studies have improved our understanding of the mechanisms for genetic association, we still lack the datasets and cohorts for historically excluded populations to provide equity in precision medicine and pharmacogenomics.

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Discovery of novel hepatocyte eQTLs in African Americans

Cited by 27 publications

References 76 publications

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

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

Differences in the Platelet mRNA Landscape Portend Racial Disparities in Platelet Function and Suggest Novel Therapeutic Targets

Multi‐Omics Studies in Historically Excluded Populations: The Road to Equity

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