We performed an international meta-GWAS of psoriasis, increasing effective sample size by 3.4-fold. Using COJO, we identified 191 independent psoriasis loci at genome-wide (GW) significance (179 outside the MHC). We conducted eQTL analysis of 1,195 strand-specific RNA-seq libraries passing QC (MQ30, ∼25M reads/sample) from 9 FACS-purified immune cell types (CD4/CD8, CLA-/CLA+, and 0h/24 h CD3-CD28-activated T-cells; also resting mDC) from 153 genotyped individuals, yielding 9,091 significant (p<5x10-3) cis-eQTLs mapping to the 179 non-MHC 95% Bayesian credible sets. Here we focus on TRAF3IP2 encoding Act1, an adaptor that transduces signals through IL-17R. COJO found 14 independent risk signals for this region (2 potentially protein-altering and 12 potentially regulatory). The lead protein-coding variant, rs33980500 C/T encoding Act1 D10N, is the top GWAS hit with a posterior probability of 1.00 on unconditional analysis. We have shown that rs33980500-T increases psoriasis risk and promotes Th17 expansion. We identified cis-eQTLs for the lncRNA TRAF3IP2-AS1 in activated CD8 T-cells, but not in activated CD4 or resting T-cells. In contrast, cis-eQTL signals for TRAF3IP2 itself were markedly reduced after CD8 T-cell activation. Moreover, the best cis-eQTL signal for TRAF3IP2-AS1 in activated CD8 T-cells (rs11153301, p=2.9x10-6) is a GW-significant psoriasis hit (p=3.7x10-8) after conditioning on Act1 D10N. The risk allele rs11153301-T results in reduced expression of TRAF3IP2-AS1 in activated CD8 T-cells, and a recent study (J Immunol 206:2353) describes an inhibitory effect of TRAF3IP2-AS1 on Act1 protein level and IL-17 signaling. Notably, the expanded GWAS also implicates a cluster of noncoding variants near IL17RA (p=3.9x10-9), which encodes a key subunit of IL-17R targeted by brodalumab, a highly effective psoriasis treatment. These results suggest that TRAF3IP2-AS1 acts as a brake on psoriasis via its effects on IL-17 signaling in activated CD8 T-cells.
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