Large-scale whole-exome sequencing analyses identified protein-coding variants associated with immune-mediated diseases in 350,770 adults.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
15 Jul 2024
15 Jul 2024
Historique:
received:
16
11
2023
accepted:
18
06
2024
medline:
16
7
2024
pubmed:
16
7
2024
entrez:
15
7
2024
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 39009607
doi: 10.1038/s41467-024-49782-0
pii: 10.1038/s41467-024-49782-0
doi:
Substances chimiques
Filaggrin Proteins
0
FLG protein, human
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
5924Subventions
Organisme : National Natural Science Foundation of China (National Science Foundation of China)
ID : 82071201
Organisme : National Natural Science Foundation of China (National Science Foundation of China)
ID : 82071997
Informations de copyright
© 2024. The Author(s).
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Yang, L., Ou, Y., & Wu, B. Large-scale whole exome sequencing analyses identified protein-coding variants associated with immune-mediated diseases in 350770 adults (Version 1.0) [Data set]. https://doi.org/10.5281/zenodo.11307851 (2024).