Trans-eQTL mapping prioritises USP18 as a negative regulator of interferon response at a lupus risk locus

Krista Freimann, Anneke Brümmer, Robert Warmerdam, Tarran S. Rupall, Ana Laura Hernández-Ledesma, Joshua Chiou, Emily R. Holzinger, Joseph C. Maranville, Nikolina Nakic, Halit Ongen, Luca Stefanucci, Michael C. Turchin, Lude Franke, Urmo Võsa, Carla P. Jones, Alejandra Medina-Rivera, Gosia Trynka, Kai Kisand, Sven Bergmann and Kaur Alasoo ()
Additional contact information
Krista Freimann: University of Tartu
Anneke Brümmer: University of Lausanne
Robert Warmerdam: University Medical Center Groningen
Tarran S. Rupall: Hinxton
Ana Laura Hernández-Ledesma: Universidad Nacional Autónoma de
Joshua Chiou: Pfizer
Emily R. Holzinger: Bristol Myers Squibb
Joseph C. Maranville: Bristol Myers Squibb
Nikolina Nakic: GSK
Halit Ongen: GSK
Luca Stefanucci: Hinxton
Michael C. Turchin: Bristol Myers Squibb
Lude Franke: University Medical Center Groningen
Urmo Võsa: University of Tartu
Carla P. Jones: Hinxton
Alejandra Medina-Rivera: Universidad Nacional Autónoma de
Gosia Trynka: Hinxton
Kai Kisand: University of Tartu
Sven Bergmann: University of Lausanne
Kaur Alasoo: University of Tartu

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract Although genome-wide association studies have provided valuable insights into the genetic basis of complex traits and diseases, translating these findings to causal genes and their downstream mechanisms remains challenging. We performed trans expression quantitative trait locus (trans-eQTL) meta-analysis in 3734 lymphoblastoid cell line samples, identifying four robust loci that replicated in an independent multi-ethnic dataset of 682 individuals. The trans-eQTL signal at the ubiquitin specific peptidase 18 (USP18) locus colocalised with a GWAS signal for systemic lupus erythematosus (SLE). USP18 is a known negative regulator of interferon signalling and the SLE risk allele increased the expression of 50 interferon-inducible genes, suggesting that the risk allele impairs USP18’s ability to effectively limit the interferon response. Intriguingly, the USP18 trans-eQTL signal would not have been discovered in a meta-analysis of up to 43,301 whole blood samples, reaffirming the importance of capturing context-specific genetic effects for GWAS interpretation.

Date: 2025
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-025-63856-7 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-63856-7

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-025-63856-7

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().