Investigating the functional basis of shared genetic etiology across autoimmune diseases (360G-Wellcome-204290_Z_16_Z)

Autoimmune diseases are a diverse set of conditions afflicting ~10% of the population worldwide, they pose a substantial personal and socioeconomic burden, and they have no cure. Currently prescribed treatments have variable efficacies and can be associated with severe side effects such as malignancies and even fatal opportunistic infections. Designing improved therapeutic strategies requires a better understanding of the pathways that drive these conditions to achieve an optimal modulation of the immune system. Investigating the biological consequences of disease-associated genetic variants provides an avenue for delineating critical pathophysiological mechanisms. However, for each of these conditions, tens to > 100 different loci have been found to influence disease risk. Therefore, prioritization is required, and the approach taken in this proposal is to focus on genetic variation shared across multiple autoimmune diseases, including a polymorphism in the tyrosine kinase 2 (TYK2) gene that protects against no fewer than 11 such conditions. The key goals of this research are to (i) investigate the molecular basis of shared genetic risk across autoimmune diseases; (ii) elucidate the downstream signatures and impact of shared genetic risk to help define key disease pathways; and (iii) investigate how key disease pathways can be fine-tuned for maximal benefit.