Cell Press, American Journal of Human Genetics, 2(95), p. 162-172, 2014
DOI: 10.1016/j.ajhg.2014.07.002
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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 x 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-DQalpha1 amino acid position 53; p < 5.0 x 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 x 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.