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Splicing QTL mapping in stimulated macrophages associates low-usage splice junctions with immune-mediated disease risk

Author

Listed:
  • Omar El Garwany

    (Wellcome Genome Campus)

  • Nikolaos I. Panousis

    (Wellcome Genome Campus)

  • Andrew Knights

    (Wellcome Genome Campus)

  • Natsuhiko Kumasaka

    (Wellcome Genome Campus)

  • Maria Imaz

    (Wellcome Genome Campus)

  • Lorena Boquete Vilarino

    (Wellcome Genome Campus
    Campus Vida 15782 Santiago de Compostela)

  • Anthi Tsingene

    (Wellcome Genome Campus)

  • Alex Tokolyi

    (Wellcome Genome Campus)

  • Cristina Cotobal Martin

    (Wellcome Genome Campus)

  • Tobi Alegbe

    (Wellcome Genome Campus)

  • Monika Krzak

    (Wellcome Genome Campus)

  • Tim Raine

    (Cambridge University Teaching Hospitals)

  • Alice Barnett

    (Wellcome Genome Campus)

  • Celine Gomez

    (Wellcome Genome Campus)

  • Daniel J. Gaffney

    (Wellcome Genome Campus)

  • Carl A. Anderson

    (Wellcome Genome Campus)

Abstract

The majority of immune-mediated disease (IMD) risk loci are located in non-coding regions of the genome, making it difficult to decipher their functional effects in relevant physiological contexts. To assess the extent to which alternative splicing contributes to IMD risk, we mapped genetic variants associated with alternative splicing (splicing quantitative trait loci or sQTL) in macrophages exposed to a wide range of environmental stimuli. We found that genes involved in innate immune response pathways undergo extensive differential splicing in response to stimulation and detected significant sQTL effects for over 5734 genes across all stimulation conditions. We colocalised sQTL signals for over 700 genes with IMD-associated risk loci from 22 IMDs with high confidence (PP4 ≥ 0.75). Approximately half of the colocalisations implicate lowly-used splice junctions (mean usage ratio

Suggested Citation

  • Omar El Garwany & Nikolaos I. Panousis & Andrew Knights & Natsuhiko Kumasaka & Maria Imaz & Lorena Boquete Vilarino & Anthi Tsingene & Alex Tokolyi & Cristina Cotobal Martin & Tobi Alegbe & Monika Krz, 2025. "Splicing QTL mapping in stimulated macrophages associates low-usage splice junctions with immune-mediated disease risk," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-61669-2
    DOI: 10.1038/s41467-025-61669-2
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