Enhanced meta-analysis and replication studies identify five new psoriasis susceptibility loci

Psoriasis is a chronic autoimmune disease with complex genetic architecture. Previous genome-wide association studies (GWAS) and a recent meta-analysis using Immunochip data have uncovered 36 susceptibility loci. Here, we extend our previous meta-analysis of European ancestry by refined genotype calling and imputation and by the addition of 5,033 cases and 5,707 controls. The combined analysis, consisting of over 15,000 cases and 27,000 controls, identifies five new psoriasis susceptibility loci at genome-wide significance (Pless than5 x 10(-8)). The newly identified signals include two that reside in intergenic regions (1q31.1 and 5p13.1) and three residing near PLCL2 (3p24.3), NFKBIZ (3q12.3) and CAMK2G (10q22.2). We further demonstrate that NFKBIZ is a TRAF3IP2-dependent target of IL-17 signalling in human skin keratinocytes, thereby functionally linking two strong candidate genes. These results further integrate the genetics and immunology of psoriasis, suggesting new avenues for functional analysis and improved therapies.
Funding Agencies|National Institutes of Health [R01AR042742, R01AR050511, R01AR054966, R01AR062382, R01AR065183]; Wellcome Trust; German Research Foundation; Medical Research Council [G0000934]; Wellcome Trust [068545/Z/02]; Medical Research Council Stratified Medicine award [MR/L011808/1]; German Ministry of Education and Research (BMBF) through the e:Med sysINFLAME grant; Doris Duke Foundation; Department of Health via the NIHR comprehensive Biomedical Research Center award; Kings College London; KCH NHS Foundation Trust; Heinz Nixdorf Foundation; Estonian Ministry of Education and Research [IUT20-46]; Centre of Translational Genomics of University of Tartu (SP1GVARENG); European Regional Development Fund (Centre of Translational Medicine, University of Tartu); German Federal Ministry of Education and Research (BMBF); Ann Arbor Veterans Affairs Hospital