Objective:

Our objectives are: (1) identify putative variants across 40 autoimmune diseases, including Guillain-Barre syndrome, myasthenia gravis, multiple sclerosis, narcolepsy, at an exome-wide level; (2) elucidate clinical impacts, and underlying biological pathways of these variants and to identify potential therapeutic targets.

Background:

Immune-mediated diseases (IMDs) pose a huge challenge to human health, yet a significant proportion lacked effective treatments. Since they exhibit substantial heritability (around 50%), unraveling the genetic architecture of IMDs might illuminate potential therapeutic strategies. However, current genome-wide association studies focused on common variants only, among which many fall outside protein-coding regions. Compared to GWAS, whole-exome sequencing (WES) focused on protein-coding regions, potentially unmasking variants directly associated with IMDs

Design/Methods:

We conducted a comprehensive WES study for 40 IMDs from 350,770 UKB individuals. We adopted collapse analysis for rare variants and logistic analysis for common variants. We further performed time-to-event analysis to reveal the longitudinal clinical impact. Mendelian randomization (MR) analysis was adopted to identify whether the relationships were causal. To unravel the biological insights, we conducted several functional annotations. Finally, we looked up the druggability of identified genes.

Results:

We identified 162 unique genes in 35 IMDs, among which 124 were novel genes. Several genes, including FLG, 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).MR identified five causal genes, of which four were approved drug targets (CDSN, DDR1, LTA, andIL18BP). Proteomic analysis indicated that mutations associated with specific IMDs might also affect protein expression in other IMDs. Identified genes predominantly impact immune and biochemical processes, and can be clustered into pathways of immune-related, urate metabolism, and antigen processing.

Conclusions:

Our findings identified protein-coding variants which are the key to IMDs pathogenesis and provided new insights into tailored innovative therapies.