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

Author

Listed:
  • Krista Freimann

    (University of Tartu
    Hinxton)

  • Anneke Brümmer

    (University of Lausanne
    Swiss Institute of Bioinformatics)

  • Robert Warmerdam

    (University Medical Center Groningen
    Oncode Institute)

  • Tarran S. Rupall

    (Hinxton
    Wellcome Genome Campus)

  • 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
    Wellcome Genome Campus)

  • Michael C. Turchin

    (Bristol Myers Squibb)

  • Lude Franke

    (University Medical Center Groningen
    Oncode Institute)

  • Urmo Võsa

    (University of Tartu)

  • Carla P. Jones

    (Hinxton
    Wellcome Genome Campus)

  • Alejandra Medina-Rivera

    (Universidad Nacional Autónoma de)

  • Gosia Trynka

    (Hinxton
    Wellcome Genome Campus)

  • Kai Kisand

    (University of Tartu)

  • Sven Bergmann

    (University of Lausanne
    Swiss Institute of Bioinformatics
    University of Cape Town)

  • Kaur Alasoo

    (University of Tartu
    Hinxton)

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.

Suggested Citation

  • 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 St, 2025. "Trans-eQTL mapping prioritises USP18 as a negative regulator of interferon response at a lupus risk locus," Nature Communications, Nature, vol. 16(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-63856-7
    DOI: 10.1038/s41467-025-63856-7
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