ArticleGenome biology2021
The impact of cell type and context-dependent regulatory variants on human immune traits.
Article in Genome biology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 53 papers, 1 of them a synthesis that pooled it.
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53 citing papers in PubMed, 1 synthesis or guideline pooled it, 75 citations in OpenAlex.
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- Beyond the baseline: mapping the context-specific regulatory landscape of disease.Trends in genetics : TIG · 2026Review
- Impact of disease-associated chromatin accessibility QTLs across immune cell types and contexts.Cell genomics · 2026Article
- Circulating chromatin reveals the effects of disease-associated variants on gene regulation.bioRxiv : the preprint server for biology · 2025Article
- Splicing QTL mapping in stimulated macrophages associates low-usage splice junctions with immune-mediated disease risk.Nature communications · 2025Article
- A multi-omics resource of B cell activation reveals genetic mechanisms for immune-mediated diseases.medRxiv : the preprint server for health sciences · 2025Article
- Article
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- Polymorphic tandem repeats influence cell type-specific gene expression across the human immune landscape.bioRxiv : the preprint server for biology · 2025Article
- The identification of blood-derived response eQTLs reveals complex effects of regulatory variants on inflammatory and infectious disease risk.PLoS genetics · 2025Article
- Efficient count-based models improve power and robustness for large-scale single-cell eQTL mapping.medRxiv : the preprint server for health sciences · 2025Article
- Implications of gene × environment interactions in post-traumatic stress disorder risk and treatment.The Journal of clinical investigation · 2025Review
- Long-read RNA sequencing atlas of human microglia isoforms elucidates disease-associated genetic regulation of splicing.Nature genetics · 2025Article
- Single-cell RNA sequencing of peripheral blood links cell-type-specific regulation of splicing to autoimmune and inflammatory diseases.Nature genetics · 2024Article
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Authors and funding
6 authors at 3 institutions in 3 countries.
Funding
Abstract
backgroundThe vast majority of trait-associated variants identified using genome-wide association studies (GWAS) are noncoding, and therefore assumed to impact gene regulation. However, the majority of trait-associated loci are unexplained by regulatory quantitative trait loci (QTLs).
resultsWe perform a comprehensive characterization of the putative mechanisms by which GWAS loci impact human immune traits. By harmonizing four major immune QTL studies, we identify 26,271 expression QTLs (eQTLs) and 23,121 splicing QTLs (sQTLs) spanning 18 immune cell types. Our colocalization analyses between QTLs and trait-associated loci from 72 GWAS reveals that genetic effects on RNA expression and splicing in immune cells colocalize with 40.4% of GWAS loci for immune-related traits, in many cases increasing the fraction of colocalized loci by two fold compared to previous studies. Notably, we find that the largest contributors of this increase are splicing QTLs, which colocalize on average with 14% of all GWAS loci that do not colocalize with eQTLs. By contrast, we find that cell type-specific eQTLs, and eQTLs with small effect sizes contribute very few new colocalizations. To investigate the 60% of GWAS loci that remain unexplained, we collect H3K27ac CUT&Tag data from rheumatoid arthritis and healthy controls, and find large-scale differences between immune cells from the different disease contexts, including at regions overlapping unexplained GWAS loci.
conclusionAltogether, our work supports RNA splicing as an important mediator of genetic effects on immune traits, and suggests that we must expand our study of regulatory processes in disease contexts to improve functional interpretation of as yet unexplained GWAS loci.
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