TYK2 Protein-Coding Variants Protect against Rheumatoid Arthritis and Autoimmunity, with No Evidence of Major Pleiotropic Effects on Non-Autoimmune Complex Traits
Creators: Diogo, Dorothée
Bastarache, Lisa
Liao,  Katherine P.
Graham, Robert R.
Fulton, Robert S.
Greenberg, Jeffrey D.
Eyre, Steve
Bowes, John
Cui, Jing
Lee, Annette
Pappas, Dimitrios A.
Kremer, Joel M.
Barton, Anne
Coenen, Marieke J. H.
Franke, Barbara
Kiemeney, Lambertus A.
Mariette,  Xavier
Richard-Miceli, Corrine
Canhão, Helena
Fonseca, João E.
de Vries, Niek
P. Tak, Paul
Crusius,  J. Bart A.
Nurmohamed, Michael T.
Kurreeman, Fina
Mikuls, Ted R.
Okada, Yukinori
Stahl, Eli A.
Larson, David E.
Deluca, Tracie L.
O'Laughlin, Michelle
Fronick,  Catrina C.
Fulton, Lucinda L.
Kosoy,  Roman
Ransom, Michael
Bhangale, Tushar R.
Ortmann, Ward
Cagan, Andrew
Gainer, Vivian
Karlson, Elizabeth W.
Kohane,  Isaac
Murphy, Shawn N.
Martin, Javier
Zhernakova, Alexandra
Klareskog, Lars
Padyukov,  Leonid
Worthington, Jane
Mardis, Elaine R.
Seldin, Michael F.
Gregersen, Peter K.
Behrens, Timothy
Raychaudhuri, Soumya
Denny, Joshua C.
Plenge, Robert M.
Publisher: name: Columbia University
Year: 2015
Subjects: subject: Autoimmune diseases--Treatment
subject: Systemic lupus erythematosus
subject: Rheumatoid arthritis--Treatment
subject: Inflammatory bowel diseases
subject: Phenotype
subject: Protein-tyrosine kinase
subject: Genetics
subject: FOS: Biological sciences
subject: Immunology
subject: FOS: Clinical medicine
subject: Medicine

description: Despite the success of genome-wide association studies (GWAS) in detecting a large number of loci for complex phenotypes such as rheumatoid arthritis (RA) susceptibility, the lack of information on the causal genes leaves important challenges to interpret GWAS results in the context of the disease biology. Here, we genetically fine-map the RA risk locus at 19p13 to define causal variants, and explore the pleiotropic effects of these same variants in other complex traits. First, we combined Immunochip dense genotyping (n = 23,092 case/control samples), Exomechip genotyping (n = 18,409 case/control samples) and targeted exon-sequencing (n = 2,236 case/controls samples) to demonstrate that three protein-coding variants in TYK2 (tyrosine kinase 2) independently protect against RA: P1104A (rs34536443, OR = 0.66, P = 2.3x10-21), A928V (rs35018800, OR = 0.53, P = 1.2x10-9), and I684S (rs12720356, OR = 0.86, P = 4.6x10-7). Second, we show that the same three TYK2 variants protect against systemic lupus erythematosus (SLE, Pomnibus = 6x10-18), and provide suggestive evidence that two of the TYK2 variants (P1104A and A928V) may also protect against inflammatory bowel disease (IBD; Pomnibus = 0.005). Finally, in a phenomewide association study (PheWAS) assessing &gt;500 phenotypes using electronic medical records (EMR) in &gt;29,000 subjects, we found no convincing evidence for association of P1104A and A928V with complex phenotypes other than autoimmune diseases such as RA, SLE and IBD. Together, our results demonstrate the role of TYK2 in the pathogenesis of RA, SLE and IBD, and provide supporting evidence for TYK2 as a promising drug target for the treatment of autoimmune diseases.