ArticlePLoS genetics2021
An autoimmune disease risk variant: A trans master regulatory effect mediated by IRF1 under immune stimulation?
Article in PLoS genetics, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers, 1 of them a synthesis that pooled it.
What it found
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
21 citing papers in PubMed, 1 synthesis or guideline pooled it, 35 citations in OpenAlex.
- Trans-eQTL mapping prioritises USP18 as a negative regulator of interferon response at a lupus risk locus.Nature communications · 2025Pooled it
- IFNγ-induced IRF1 synergizes with TLR7 signals to tune the IRF4-IRF8 axis and drive pathogenic effector B cell fate.bioRxiv : the preprint server for biology · 2026Article
- Review
- Trans-eQTL hotspots shape complex traits by modulating cellular states.Cell genomics · 2025Article
- Lack of evidence for GWAS signals of exfoliation glaucoma working via monogenic loss-of-function mutation in the nearest gene.Human molecular genetics · 2024Article
- The relationship between extreme inter-individual variation in macrophage gene expression and genetic susceptibility to inflammatory bowel disease.Human genetics · 2024Article
- Article
- Haplotype-aware modeling of cis-regulatory effects highlights the gaps remaining in eQTL data.Nature communications · 2024Article
- multi-GPA-Tree: Statistical approach for pleiotropy informed and functional annotation tree guided prioritization of GWAS results.PLoS computational biology · 2023Article
- Inferring cell-type-specific causal gene regulatory networks during human neurogenesis.Genome biology · 2023Article
- A lncRNA from an inflammatory bowel disease risk locus maintains intestinal host-commensal homeostasis.Cell research · 2023Article
- Integrated analysis of Mendelian Randomization and Bayesian colocalization reveals bidirectional causal association between inflammatory bowel disease and psoriasis.Annals of medicine · 2023Article
- GREEN-DB: a framework for the annotation and prioritization of non-coding regulatory variants from whole-genome sequencing data.Nucleic acids research · 2022Article
- Article
- Transcription factor regulation of eQTL activity across individuals and tissues.PLoS genetics · 2022Article
- TF-RBP-AS Triplet Analysis Reveals the Mechanisms of Aberrant Alternative Splicing Events in Kidney Cancer: Implications for Their Possible Clinical Use as Prognostic and Therapeutic Biomarkers.International journal of molecular sciences · 2021Article
- Genome editing to define the function of risk loci and variants in rheumatic disease.Nature reviews. Rheumatology · 2021Review
- A trans locus causes a ribosomopathy in hypertrophic hearts that affects mRNA translation in a protein length-dependent fashion.Genome biology · 2021Article
- Interferon Lambda in the Pathogenesis of Inflammatory Bowel Diseases.Frontiers in immunology · 2021Review
- Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
12 authors at 4 institutions in 2 countries.
Funding
Abstract
Functional mechanisms remain unknown for most genetic loci associated to complex human traits and diseases. In this study, we first mapped trans-eQTLs in a data set of primary monocytes stimulated with LPS, and discovered that a risk variant for autoimmune disease, rs17622517 in an intron of C5ORF56, affects the expression of the transcription factor IRF1 20 kb away. The cis-regulatory effect specific to IRF1 is active under early immune stimulus, with a large number of trans-eQTL effects across the genome under late LPS response. Using CRISPRi silencing, we showed that perturbation of the SNP locus downregulates IRF1 and causes widespread transcriptional effects. Genome editing by CRISPR had suggestive recapitulation of the LPS-specific trans-eQTL signal and lent support for the rs17622517 site being functional. Our results suggest that this common genetic variant affects inter-individual response to immune stimuli via regulation of IRF1. For this autoimmune GWAS locus, our work provides evidence of the functional variant, demonstrates a condition-specific enhancer effect, identifies IRF1 as the likely causal gene in cis, and indicates that overactivation of the downstream immune-related pathway may be the cellular mechanism increasing disease risk. This work not only provides rare experimental validation of a master-regulatory trans-eQTL, but also demonstrates the power of eQTL mapping to build mechanistic hypotheses amenable for experimental follow-up using the CRISPR toolkit.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.