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

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 and Jin-Tai Yu ()
Additional contact information
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
Chen-Jie Fei: Fudan University
Ying Zhu: Fudan University
Lan Tan: Qingdao University
Qiang Dong: Fudan University
Jianfeng Feng: Fudan University
Wei Cheng: Fudan University
Jin-Tai Yu: Fudan University

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-49782-0

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