Genetic ancestry effects on the response to viral infection are pervasive but cell type specific

Randolph, Haley E.; Fiege, Jessica K.; Thielen, Beth K; Mickelson, Clayton K.; Shiratori, Mari; Barroso-Batista, João; Langlois, Ryan A.; Barreiro, Luis B.

doi:10.1126/science.abg0928

Cited by 94 publications

(140 citation statements)

References 64 publications

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“…Generation of induced pluripotent stem cells (iPSC) may allow for the study of gene regulation across developing tissues or differentiated cells within diverse populations [68, 69], but such approaches remain technically difficult. This study is also restricted to steady state gene expression, which may miss cell-type- or dynamic, environment-specific genetic effects, which cannot be captured in bulk and/or steady-state tissues [29,70,14,13,71,72]. Despite these limitations, this study makes important contributions to our understanding of gene expression variation and the molecular basis of human adaptation in sub-Saharan Africa.…”

Section: Discussionmentioning

confidence: 99%

The Genetic and Evolutionary Basis of Gene Expression Variation in East Africans

Kelly

Ramdas

et al. 2022

Preprint

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Background: Mapping of quantitative trait loci (QTL) associated with molecular phenotypes is a powerful approach for identifying the genes and molecular mechanisms underlying human traits and diseases. How the genetic architecture of molecular traits varies across human populations, however, has been less explored. To better understand the genetics of gene regulation in East Africans, we perform expression and splicing QTL mapping in whole blood from a cohort of 162 diverse Africans from Ethiopia and Tanzania. We assess replication of these QTLs in cohorts of predominantly European ancestry and identify candidate genes under selection in human populations. Results: We find the gene regulatory architecture of African and non-African populations is broadly shared, though there is a considerable amount of variation at individual loci across populations. Comparing our analyses to an equivalently sized cohort of European Americans, we find that QTL mapping in Africans improves the detection of expression QTLs and fine mapping of causal variation. Integrating our QTL scans with signatures of selection, we find several genes related to immunity and metabolism that are highly differentiated between Africans and non-Africans, as well as a gene associated with pigmentation, TMEM216, with evidence of population-specific selection in Nilo-Saharan speaking pastoralists. Conclusion: Extending QTL-mapping studies beyond groups of European ancestry, particularly to diverse indigenous populations, is vital for a complete understanding of the genetic architecture of human traits and can reveal novel functional variation underlying human traits and disease.

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Section: Discussionmentioning

confidence: 99%

The Genetic and Evolutionary Basis of Gene Expression Variation in East Africans

Kelly

Ramdas

et al. 2022

Preprint

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“…Humans differ in their susceptibility to infectious disease due, in part, to variation in the immune response [ 81 ]. Immune pathway genes activated in response to influenza partly overlap those triggered by other single-stranded RNA viruses including COVID-19 [ 82 , 83 , 84 ]. These immune responses also vary by ancestry and stress the key role played by genetics in shaping population differences in immune responses [ 81 , 83 , 85 ].…”

Section: Discussionmentioning

confidence: 99%

“…Immune pathway genes activated in response to influenza partly overlap those triggered by other single-stranded RNA viruses including COVID-19 [ 82 , 83 , 84 ]. These immune responses also vary by ancestry and stress the key role played by genetics in shaping population differences in immune responses [ 81 , 83 , 85 ]. In the current study, we confirmed many of the previously reported COVID–SNP and pneumonia–SNP associations [ 11 , 12 , 20 , 21 , 22 , 24 , 25 ], but none of these variants modified associations between COVID/pneumonia and dietary behaviors.…”

Section: Discussionmentioning

confidence: 99%

Diet and Respiratory Infections: Specific or Generalized Associations?

Horn

Achenbach

et al. 2022

Nutrients

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Background: Based on our recently reported associations between specific dietary behaviors and the risk of COVID-19 infection in the UK Biobank (UKB) cohort, we further investigate whether these associations are specific to COVID-19 or extend to other respiratory infections. Methods: Pneumonia and influenza diagnoses were retrieved from hospital and death record data linked to the UKB. Baseline, self-reported (2006–2010) dietary behaviors included being breastfed as a baby and intakes of coffee, tea, oily fish, processed meat, red meat (unprocessed), fruit, and vegetables. Logistic regression estimated the odds of pneumonia/influenza from baseline to 31 December 2019 with each dietary component, adjusting for baseline socio-demographic factors, medical history, and other lifestyle behaviors. We considered effect modification by sex and genetic factors related to pneumonia, COVID-19, and caffeine metabolism. Results: Of 470,853 UKB participants, 4.0% had pneumonia and 0.2% had influenza during follow up. Increased consumption of coffee, tea, oily fish, and fruit at baseline were significantly and independently associated with a lower risk of future pneumonia events. Increased consumption of red meat was associated with a significantly higher risk. After multivariable adjustment, the odds of pneumonia (p ≤ 0.001 for all) were lower by 6–9% when consuming 1–3 cups of coffee/day (vs. <1 cup/day), 8–11% when consuming 1+ cups of tea/day (vs. <1 cup/day), 10–12% when consuming oily fish in higher quartiles (vs. the lowest quartile—Q1), and 9–14% when consuming fruit in higher quartiles (vs. Q1); it was 9% higher when consuming red meat in the fourth quartile (vs. Q1). Similar patterns of associations were observed for influenza but only associations with tea and oily fish met statistical significance. The association between fruit and pneumonia risk was stronger in women than in men (p = 0.001 for interaction). Conclusions: In the UKB, consumption of coffee, tea, oily fish, and fruit were favorably associated with incident pneumonia/influenza and red meat was adversely associated. Findings for coffee parallel those we reported previously for COVID-19 infection, while other findings are specific to these more common respiratory infections.

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“…Recently, scRNA-seq was also used to identify the effects of genetic ancestry on susceptibility to viral infection among individuals of European and African descent [ 12 ]. The authors used PBMCs from 90 donors that were either non-infected or infected with influenza A virus (IAV).…”

Section: Literature Reviewmentioning

confidence: 99%

“…eQTL analysis using scRNA-seq is a relatively new approach and only a dozen studies are available [ 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 ]. These studies show diverse applications of scRNA-seq in identification of the quantitative effects of genetic variants or loci using purified cell types [ 4 , 5 ], induced pluripotent stem cells (iPSCs) [ 6 , 9 , 11 , 13 ] or whole organisms [ 10 ] and to study population ancestry and cell type specific response to an environmental stimulus such as viral infection [ 12 ]. In the following sections, we review the published sc-studies for of cis- eQTL analysis, and compare the results to bulk RNA-Seq based analysis ( Figure 1 ; Table 1 ).…”

Section: Introductionmentioning

confidence: 99%

The Power of Single-Cell RNA Sequencing in eQTL Discovery

Maria

Pouyanfar

Örd

2022

Genes

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Genome-wide association studies have successfully mapped thousands of loci associated with complex traits. During the last decade, functional genomics approaches combining genotype information with bulk RNA-sequencing data have identified genes regulated by GWAS loci through expression quantitative trait locus (eQTL) analysis. Single-cell RNA-Sequencing (scRNA-Seq) technologies have created new exciting opportunities for spatiotemporal assessment of changes in gene expression at the single-cell level in complex and inherited conditions. A growing number of studies have demonstrated the power of scRNA-Seq in eQTL mapping across different cell types, developmental stages and stimuli that could be obscured when using bulk RNA-Seq methods. In this review, we outline the methodological principles, advantages, limitations and the future experimental and analytical considerations of single-cell eQTL studies. We look forward to the explosion of single-cell eQTL studies applied to large-scale population genetics to take us one step closer to understanding the molecular mechanisms of disease.

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Genetic ancestry effects on the response to viral infection are pervasive but cell type specific

Cited by 94 publications

References 64 publications

The Genetic and Evolutionary Basis of Gene Expression Variation in East Africans

The Genetic and Evolutionary Basis of Gene Expression Variation in East Africans

Diet and Respiratory Infections: Specific or Generalized Associations?

The Power of Single-Cell RNA Sequencing in eQTL Discovery

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