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Large-scale whole-exome sequencing analyses identified protein-coding variants associated with immune-mediated diseases in 350,770 adults

Author

Listed:
  • Liu Yang

    (Fudan University)

  • Ya-Nan Ou

    (Qingdao University)

  • Bang-Sheng Wu

    (Fudan University)

  • Wei-Shi Liu

    (Fudan University)

  • Yue-Ting Deng

    (Fudan University)

  • Xiao-Yu He

    (Fudan University)

  • Yi-Lin Chen

    (Fudan University)

  • Jujiao Kang

    (Fudan University
    Fudan University, Ministry of Education)

  • Chen-Jie Fei

    (Fudan University)

  • Ying Zhu

    (Fudan University)

  • Lan Tan

    (Qingdao University)

  • Qiang Dong

    (Fudan University)

  • Jianfeng Feng

    (Fudan University
    Fudan University, Ministry of Education)

  • Wei Cheng

    (Fudan University
    Fudan University
    Fudan University, Ministry of Education)

  • Jin-Tai Yu

    (Fudan University)

Abstract

The genetic contribution of protein-coding variants to immune-mediated diseases (IMDs) remains underexplored. Through whole exome sequencing of 40 IMDs in 350,770 UK Biobank participants, we identified 162 unique genes in 35 IMDs, among which 124 were novel genes. Several genes, including FLG which is associated with atopic dermatitis and asthma, showed converging evidence from both rare and common variants. 91 genes exerted significant effects on longitudinal outcomes (interquartile range of Hazard Ratio: 1.12-5.89). Mendelian randomization identified five causal genes, of which four were approved drug targets (CDSN, DDR1, LTA, and IL18BP). Proteomic analysis indicated that mutations associated with specific IMDs might also affect protein expression in other IMDs. For example, DXO (celiac disease-related gene) and PSMB9 (alopecia areata-related gene) could modulate CDSN (autoimmune hypothyroidism-, psoriasis-, asthma-, and Graves’ disease-related gene) expression. Identified genes predominantly impact immune and biochemical processes, and can be clustered into pathways of immune-related, urate metabolism, and antigen processing. Our findings identified protein-coding variants which are the key to IMDs pathogenesis and provided new insights into tailored innovative therapies.

Suggested Citation

  • Liu Yang & Ya-Nan Ou & Bang-Sheng Wu & Wei-Shi Liu & Yue-Ting Deng & Xiao-Yu He & Yi-Lin Chen & Jujiao Kang & Chen-Jie Fei & Ying Zhu & Lan Tan & Qiang Dong & Jianfeng Feng & Wei Cheng & Jin-Tai Yu, 2024. "Large-scale whole-exome sequencing analyses identified protein-coding variants associated with immune-mediated diseases in 350,770 adults," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-49782-0
    DOI: 10.1038/s41467-024-49782-0
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