Blood cell traits’ GWAS loci colocalization with variation in PU.1 genomic occupancy prioritizes causal noncoding regulatory variants

Jeong, Raehoon; Bulyk, Martha L.

doi:10.1016/j.xgen.2023.100327

Cited by 5 publications

(1 citation statement)

References 98 publications

(231 reference statements)

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“…These chromatin phenotypes may show detectable genetic effects even when an eQTL effect in the same cell type was not identified in the locus 32 . For example, only about 20% of lymphoblastoid cell lines’ (LCLs’) PU.1 binding QTLs (bQTLs) that colocalized with blood cell traits’ association showed an eQTL effect for a nearby gene in LCLs 33 .…”

Section: Introductionmentioning

confidence: 99%

Chromatin accessibility variation provides insights into missing regulation underlying immune-mediated diseases

Jeong,

Bulyk

2024

Preprint

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Most genetic loci associated with complex traits and diseases through genome-wide association studies (GWAS) are noncoding, suggesting that the causal variants likely have gene regulatory effects. However, only a small number of loci have been linked to expression quantitative trait loci (eQTLs) detected currently. To better understand the potential reasons for many trait-associated loci lacking eQTL colocalization, we investigated whether chromatin accessibility QTLs (caQTLs) in lymphoblastoid cell lines (LCLs) explain immune-mediated disease associations that eQTLs in LCLs did not. The power to detect caQTLs was greater than that of eQTLs and was less affected by the distance from the transcription start site of the associated gene. Meta-analyzing LCL eQTL data to increase the sample size to over a thousand led to additional loci with eQTL colocalization, demonstrating that insufficient statistical power is still likely to be a factor. Moreover, further eQTL colocalization loci were uncovered by surveying eQTLs of other immune cell types. Altogether, insufficient power and context-specificity of eQTLs both contribute to the 'missing regulation.'

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Section: Introductionmentioning

confidence: 99%

Chromatin accessibility variation provides insights into missing regulation underlying immune-mediated diseases

Jeong,

Bulyk

2024

Preprint

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Integration of human organoids single‐cell transcriptomic profiles and human genetics repurposes critical cell type‐specific drug targets for severe COVID‐19

Ma,

Zhou,

Jiang

et al. 2023

Cell Proliferation

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Human organoids recapitulate the cell type diversity and function of their primary organs holding tremendous potentials for basic and translational research. Advances in single‐cell RNA sequencing (scRNA‐seq) technology and genome‐wide association study (GWAS) have accelerated the biological and therapeutic interpretation of trait‐relevant cell types or states. Here, we constructed a computational framework to integrate atlas‐level organoid scRNA‐seq data, GWAS summary statistics, expression quantitative trait loci, and gene–drug interaction data for distinguishing critical cell populations and drug targets relevant to coronavirus disease 2019 (COVID‐19) severity. We found that 39 cell types across eight kinds of organoids were significantly associated with COVID‐19 outcomes. Notably, subset of lung mesenchymal stem cells increased proximity with fibroblasts predisposed to repair COVID‐19‐damaged lung tissue. Brain endothelial cell subset exhibited significant associations with severe COVID‐19, and this cell subset showed a notable increase in cell‐to‐cell interactions with other brain cell types, including microglia. We repurposed 33 druggable genes, including IFNAR2, TYK2, and VIPR2, and their interacting drugs for COVID‐19 in a cell‐type‐specific manner. Overall, our results showcase that host genetic determinants have cellular‐specific contribution to COVID‐19 severity, and identification of cell type‐specific drug targets may facilitate to develop effective therapeutics for treating severe COVID‐19 and its complications.

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Non-coding variants impact cis-regulatory coordination in a cell type-specific manner

Pushkarev,

van Mierlo,

Kribelbauer

et al. 2024

Genome Biol

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Background Interactions among cis-regulatory elements (CREs) play a crucial role in gene regulation. Various approaches have been developed to map these interactions genome-wide, including those relying on interindividual epigenomic variation to identify groups of covariable regulatory elements, referred to as chromatin modules (CMs). While CM mapping allows to investigate the relationship between chromatin modularity and gene expression, the computational principles used for CM identification vary in their application and outcomes. Results We comprehensively evaluate and streamline existing CM mapping tools and present guidelines for optimal utilization of epigenome data from a diverse population of individuals to assess regulatory coordination across the human genome. We showcase the effectiveness of our recommended practices by analyzing distinct cell types and demonstrate cell type specificity of CRE interactions in CMs and their relevance for gene expression. Integration of genotype information revealed that many non-coding disease-associated variants affect the activity of CMs in a cell type-specific manner by affecting the binding of cell type-specific transcription factors. We provide example cases that illustrate in detail how CMs can be used to deconstruct GWAS loci, assess variable expression of cell surface receptors in immune cells, and reveal how genetic variation can impact the expression of prognostic markers in chronic lymphocytic leukemia. Conclusions Our study presents an optimal strategy for CM mapping and reveals how CMs capture the coordination of CREs and its impact on gene expression. Non-coding genetic variants can disrupt this coordination, and we highlight how this may lead to disease predisposition in a cell type-specific manner.

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Blood cell traits’ GWAS loci colocalization with variation in PU.1 genomic occupancy prioritizes causal noncoding regulatory variants

Cited by 5 publications

References 98 publications

Chromatin accessibility variation provides insights into missing regulation underlying immune-mediated diseases

Chromatin accessibility variation provides insights into missing regulation underlying immune-mediated diseases

Integration of human organoids single‐cell transcriptomic profiles and human genetics repurposes critical cell type‐specific drug targets for severe COVID‐19

Non-coding variants impact cis-regulatory coordination in a cell type-specific manner

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