Fine mapping major histocompatibility complex associations in psoriasis and its clinical subtypes.

Authors:
Yukinori Okada, Buhm Han, Lam C Tsoi, Philip E Stuart, Eva Ellinghaus, Trilokraj Tejasvi, Vinod Chandran, Fawnda Pellett, Remy Pollock, Anne M Bowcock, Gerald G Krueger, Michael Weichenthal, John J Voorhees, Proton Rahman, Peter K Gregersen, Andre Franke, Rajan P Nair, Gonçalo R Abecasis, Dafna D Gladman, James T Elder, Paul I W de Bakker, Soumya Raychaudhuri
Year of publication:
2014
Volume:
95
Issue:
2
Issn:
0002-9297
Journal title abbreviated:
AM J HUM GENET
Journal title long:
American journal of human genetics
Impact factor:
10.794
Abstract:
Psoriasis vulgaris (PsV) risk is strongly associated with variation within the major histocompatibility complex (MHC) region, but its genetic architecture has yet to be fully elucidated. Here, we conducted a large-scale fine-mapping study of PsV risk in the MHC region in 9,247 PsV-affected individuals and 13,589 controls of European descent by imputing class I and II human leukocyte antigen (HLA) genes from SNP genotype data. In addition, we imputed sequence variants for MICA, an MHC HLA-like gene that has been associated with PsV, to evaluate association at that locus as well. We observed that HLA-C(∗)06:02 demonstrated the lowest p value for overall PsV risk (p = 1.7 × 10(-364)). Stepwise analysis revealed multiple HLA-C(∗)06:02-independent risk variants in both class I and class II HLA genes for PsV susceptibility (HLA-C(∗)12:03, HLA-B amino acid positions 67 and 9, HLA-A amino acid position 95, and HLA-DQα1 amino acid position 53; p < 5.0 × 10(-8)), but no apparent risk conferred by MICA. We further evaluated risk of two major clinical subtypes of PsV, psoriatic arthritis (PsA; n = 3,038) and cutaneous psoriasis (PsC; n = 3,098). We found that risk heterogeneity between PsA and PsC might be driven by HLA-B amino acid position 45 (Pomnibus = 2.2 × 10(-11)), indicating that different genetic factors underlie the overall risk of PsV and the risk of specific PsV subphenotypes. Our study illustrates the value of high-resolution HLA and MICA imputation for fine mapping causal variants in the MHC.