In this issue of Cell Genomics, Garcia-Perez et al.1 report a comprehensive and careful association analysis between gene expression and splicing measured by the GTEx Consortium2 in 46 human tissues ...and 21 demographic and clinical traits.
In this issue of Cell Genomics, Garcia-Perez et al.1 report a comprehensive and careful association analysis between gene expression and splicing measured by the GTEx Consortium2 in 46 human tissues and 21 demographic and clinical traits.
Many gene expression quantitative trait locus (eQTL) studies have published their summary statistics, which can be used to gain insight into complex human traits by downstream analyses, such as fine ...mapping and co-localization. However, technical differences between these datasets are a barrier to their widespread use. Consequently, target genes for most genome-wide association study (GWAS) signals have still not been identified. In the present study, we present the eQTL Catalogue ( https://www.ebi.ac.uk/eqtl ), a resource of quality-controlled, uniformly re-computed gene expression and splicing QTLs from 21 studies. We find that, for matching cell types and tissues, the eQTL effect sizes are highly reproducible between studies. Although most QTLs were shared between most bulk tissues, we identified a greater diversity of cell-type-specific QTLs from purified cell types, a subset of which also manifested as new disease co-localizations. Our summary statistics are freely available to enable the systematic interpretation of human GWAS associations across many cell types and tissues.
Regulatory variants are often context specific, modulating gene expression in a subset of possible cellular states. Although these genetic effects can play important roles in disease, the molecular ...mechanisms underlying context specificity are poorly understood. Here, we identified shared quantitative trait loci (QTLs) for chromatin accessibility and gene expression in human macrophages exposed to IFNγ, Salmonella and IFNγ plus Salmonella. We observed that ~60% of stimulus-specific expression QTLs with a detectable effect on chromatin altered the chromatin accessibility in naive cells, thus suggesting that they perturb enhancer priming. Such variants probably influence binding of cell-type-specific transcription factors, such as PU.1, which can then indirectly alter the binding of stimulus-specific transcription factors, such as NF-κB or STAT2. Thus, although chromatin accessibility assays are powerful for fine-mapping causal regulatory variants, detecting their downstream effects on gene expression will be challenging, requiring profiling of large numbers of stimulated cellular states and time points.
Understanding the causal processes that contribute to disease onset and progression is essential for developing novel therapies. Although
-acting expression quantitative trait loci (
-eQTLs) can ...directly reveal cellular processes modulated by disease variants, detecting
-eQTLs remains challenging due to their small effect sizes. Here, we analysed gene expression and genotype data from six blood cell types from 226 to 710 individuals. We used co-expression modules inferred from gene expression data with five methods as traits in
-eQTL analysis to limit multiple testing and improve interpretability. In addition to replicating three established associations, we discovered a novel
-eQTL near
regulating a module of metallothionein genes in LPS-stimulated monocytes. Interestingly, this effect was mediated by a transient
-eQTL present only in early LPS response and lost before the
effect appeared. Our analyses highlight how co-expression combined with functional enrichment analysis improves the identification and prioritisation of
-eQTLs when applied to emerging cell-type-specific datasets.
Genetic variants regulating RNA splicing and transcript usage have been implicated in both common and rare diseases. Although transcript usage quantitative trait loci (tuQTLs) have been mapped across ...multiple cell types and contexts, it is challenging to distinguish between the main molecular mechanisms controlling transcript usage: promoter choice, splicing and 3' end choice. Here, we analysed RNA-seq data from human macrophages exposed to three inflammatory and one metabolic stimulus. In addition to conventional gene-level and transcript-level analyses, we also directly quantified promoter usage, splicing and 3' end usage. We found that promoters, splicing and 3' ends were predominantly controlled by independent genetic variants enriched in distinct genomic features. Promoter usage QTLs were also 50% more likely to be context-specific than other tuQTLs and constituted 25% of the transcript-level colocalisations with complex traits. Thus, promoter usage might be an underappreciated molecular mechanism mediating complex trait associations in a context-specific manner.
...variants can influence whether RNA molecules undergo A-to-I RNA editing1 - a process in which a subunit of RNA is changed from adenosine (A) to inosine (I). ...the authors zoomed in to identify ...specific edQTLs that bring about disease-associated changes in editing, and found that 33% of these genomic regions encode proteins. ...variants that seem to be specifically associated with RNA editing in the GTEx data set might turn out to control gene expression or splicing in cell types not included in GTEx, such as immune cells. Because Li and colleagues focused on cis variants, a key next question is whether trans variants, which have broad effects on RNA editing across the genome, might also have a part to play in the risk of autoimmune disease.
The proteome holds great potential as an intermediate layer between the genome and phenome. Previous protein quantitative trait locus studies have focused mainly on describing the effects of common ...genetic variations on the proteome. Here, we assessed the impact of the common and rare genetic variations as well as the copy number variants (CNVs) on 326 plasma proteins measured in up to 500 individuals. We identified 184 cis and 94 trans signals for 157 protein traits, which were further fine-mapped to credible sets for 101 cis and 87 trans signals for 151 proteins. Rare genetic variation contributed to the levels of 7 proteins, with 5 cis and 14 trans associations. CNVs were associated with the levels of 11 proteins (7 cis and 5 trans), examples including a 3q12.1 deletion acting as a hub for multiple trans associations; and a CNV overlapping NAIP, a sensor component of the NAIP-NLRC4 inflammasome which is affecting pro-inflammatory cytokine interleukin 18 levels. In summary, this work presents a comprehensive resource of genetic variation affecting the plasma protein levels and provides the interpretation of identified effects.
A number of pathogens, including several human-restricted organisms, persist and replicate within macrophages (Mφs) as a key step in pathogenesis. The mechanisms underpinning such host-restricted ...intracellular adaptations are poorly understood, in part, due to a lack of appropriate model systems. Here we explore the potential of human induced pluripotent stem cell derived macrophages (iPSDMs) to study such pathogen interactions. We show iPSDMs express a panel of established Mφ-specific markers, produce cytokines, and polarise into classical and alternative activation states in response to IFN-γ and IL-4 stimulation, respectively. iPSDMs also efficiently phagocytosed inactivated bacterial particles as well as live Salmonella Typhi and S. Typhimurium and were able to kill these pathogens. We conclude that iPSDMs can support productive Salmonella infection and propose this as a flexible system to study host/pathogen interactions. Furthermore, iPSDMs can provide a flexible and practical cellular platform for assessing host responses in multiple genetic backgrounds.
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