274 Phenotypic Effects of Genetic Loss of Function in Tyrosine Kinase 2 Using Large-Scale Biobanks

Abstract

We used a naturally occurring germ-line genetic variant in tyrosine kinase 2 (TYK2 [P1104A, rs34536443]), which has been shown to cause partial loss of function and protect against autoimmune disease, to survey the phenotypic consequences of reduced TYK2 function. We performed phenome-wide association studies (PheWAS) in 2 large biobanks (FinnGen and UK Biobank) and across public case-control genetic studies using Open Targets Genetics. This study found additional support for a protective effect (odds ratio [OR] ≤0.8, P < 1 x 10-4) of TYK2 partial loss of function in multiple autoimmune diseases, including rheumatoid arthritis, psoriasis, psoriatic arthritis, systemic lupus erythematosus, sarcoidosis, type 1 diabetes, inflammatory bowel disease, and hypothyroidism.