Meta-Analysis of the TNFAIP3 Region in Psoriasis Reveals a Risk Haplotype that is Distinct from Other Autoimmune Diseases

TNFAIP3 encodes aubiquitin-modifying protein, A20, that is a critical regulator of inflammatory responses. TNFAIP3 polymorphisms are associated with susceptibility to multiple autoimmune diseases including psoriasis, systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis, and celiac disease. In order to refine the TNFAIP3 association signal in psoriasis and identify candidate causal variants, we performed imputation and meta-analysis of the TNFAIP3 region in five European ancestry cohorts totaling 4,704 psoriasis cases and 7,805 controls. We identified 49 variants whose significance exceeded a corrected Bonferroni threshold, with the top variant being rs582757 (P = 6.07 × 10(−12), OR = 1.23). Conditional analysis revealed a suggestive independent association at rs6918329 (P(cond) = 7.22 × 10(−5), OR=1.15). Functional annotation of the top variants identified several with strong evidence of regulatory potential and several within long non-coding RNAs. Analysis of TNFAIP3 haplotypes revealed that the psoriasis risk haplotype is distinct from other autoimmune diseases. Overall, our findings identify novel candidate causal variants of TNFAIP3 in psoriasis and highlight the complex genetic architecture of this locus in autoimmune susceptibility.