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

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.

Figure 1

Plots of Nominal Association between the MHC Variants and PsV and Its Subphenotypes of PsA and PsC Each diamond represents the –log₁₀(p) of the variants, including SNPs, classical HLA or MICA alleles, and amino acid polymorphisms encoded by the HLA genes or MICA. The dotted horizontal line represents the significance threshold of p = 5.0 × 10⁻⁸. The bottom panel shows the physical positions of the HLA genes, MICA, and PSORS1 on chromosome 6 (UCSC Genome Browser hg18). We tested four binary phenotypes: (A) PsV-affected versus control individuals, (B) PsA-affected versus control individuals, (C) PsC-affected versus control individuals, and (D) PsA-affected versus PsC-affected individuals.

Figure 2

Plots of Stepwise Conditional Association of the Variants in the MHC Region (A–E) Stepwise analysis of HLA-C, HLA-B, HLA-A, and HLA-DQA1 in PsV-affected versus control individuals. (F and G) Stepwise analysis of HLA-B in PsA versus PsC individuals. Each diamond represents the –log₁₀(p) of the variants, including SNPs, classical HLA or MICA alleles, and amino acid polymorphisms encoded by the HLA genes or MICA. The dotted horizontal line represents the significance threshold of p = 5.0 × 10⁻⁸. The most strongly associated amino acid polymorphisms and HLA classical alleles are labeled when their associations satisfied p < 5.0 × 10⁻⁸.

Figure 3

Plots of Stepwise Conditional Association of the HLA Amino Acid Polymorphisms and Classical HLA Alleles (A–D) Stepwise analysis of HLA-C, HLA-B, HLA-A, and HLA-DQA1 in PsV-affected versus control individuals. (E) Stepwise analysis of HLA-B in PsA-affected versus PsC-affected individuals. Each diamond represents the –log₁₀(p_omnibus) of the amino acid polymorphism encoded by the HLA gene. The colored horizontal line represents the –log₁₀(p_omnibus) of the most strongly associated classical allele of the HLA gene. The dotted horizontal line represents the significance threshold of p = 5.0 × 10⁻⁸. The most strongly associated amino acid polymorphisms and HLA classical alleles are labeled when their associations satisfied p < 5.0 × 10⁻⁸.

Figure 4

Associations of Classical HLA-B Alleles and HLA-B Amino Acid Position 45 for PsA versus PsC Individuals The –log₁₀(p) of HLA-B classical two- and four-digit HLA-B alleles and HLA-B amino acid residues at position 45 in PsA versus PsC individuals. HLA-B Glu45 demonstrated the strongest association (p = 2.9 × 10⁻¹²; highlighted with a red circle), whereas the HLA-B classical alleles showed much smaller effects (p > 1.0 × 10⁻⁴).

Figure 5

3D Ribbon Models for HLA-B HLA-B structures are based on Protein Data Bank entry 2bvp and were prepared with UCSF Chimera version 1.7. Amino acid position 67 and 9 residues associated with overall PsV risk are highlighted as red and pink spheres, respectively. An amino acid position 45 residue associated with subphenotype risk heterogeneity (PsA versus PsC) is highlighted as a green sphere.