Document Type
Article
Publication Date
10-1-2025
Original Citation
Ho C,
Dippel M,
McQuade M,
Nguyen L,
Mishra A,
Pribitzer S,
Hardy S,
Chandok H,
Chardon F,
McDiarmid T,
DeBerg H,
Buckner J,
Shendure J,
de Boer C,
Guo M,
Tewhey R,
Ray J.
Genetic and epigenetic screens in primary human T cells link candidate causal autoimmune variants to T cell networks. Nat Genet. 2025;57(10):2536–45.
Keywords
JMG, Humans, Autoimmune Diseases, CD4-Positive T-Lymphocytes, Epigenesis, Genetic, Genetic Predisposition to Disease, T-Lymphocytes, Alleles, Lymphocyte Activation, Polymorphism, Single Nucleotide, Gene Expression Regulation, Genetic Variation, Gene Regulatory Networks, Single-Cell Analysis
JAX Source
Nat Genet. 2025;57(10):2536–45.
ISSN
1546-1718
PMID
40968290
DOI
https://doi.org/10.1038/s41588-025-02301-3
Grant
; National Institutes of Health grant R01AI151051 (R.T.); National Institutes of Health grant R35HG011329 (R.T.)
Abstract
Genetic variants associated with autoimmune diseases are highly enriched within putative cis-regulatory regions of CD4+ T cells, suggesting that they could alter disease risk through changes in gene regulation. However, very few genetic variants have been shown to affect T cell gene expression or function. Here we tested >18,000 autoimmune disease-associated variants for allele-specific effects on expression using massively parallel reporter assays in primary human CD4+ T cells. We find 545 variants that modulate expression in an allele-specific manner (emVars). Primary T cell emVars greatly enrich for likely causal variants, are mediated by common upstream pathways and their putative target genes are highly enriched within a lymphocyte activation network. Using bulk and single-cell CRISPR-interference screens, we confirm that emVar-containing T cell cis-regulatory elements modulate both known and previously unappreciated target genes that regulate T cell proliferation, providing plausible mechanisms by which these variants alter autoimmune disease risk.
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.