Large-scale whole-exome sequencing analyses identified protein-coding variants associated with immune-mediated diseases in 350,770 adults.
Liu YangYa-Nan OuBang-Sheng WuWei-Shi LiuYue-Ting DengXiao-Yu HeYi-Lin ChenJu-Jiao KangChen-Jie FeiYing ZhuLan TanQiang DongJian-Feng FengWei ChengJin-Tai YuPublished in: Nature communications (2024)
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.
Keyphrases
- genome wide
- copy number
- genome wide identification
- dna methylation
- gene expression
- bioinformatics analysis
- genome wide analysis
- chronic obstructive pulmonary disease
- atopic dermatitis
- transcription factor
- multiple sclerosis
- protein protein
- lung function
- metabolic syndrome
- type diabetes
- amino acid
- small molecule
- cystic fibrosis
- air pollution
- adverse drug