Family-Based Analysis Using a Dense Single-Nucleotide Polymorphism–Based Map Defines Genetic Variation at PSORS1, the Major Psoriasis-Susceptibility Locus

Abstract

Psoriasis is a common skin disorder of multifactorial origin. Genomewide scans for disease susceptibility have repeatedly demonstrated the existence of a major locus, PSORS1 (psoriasis susceptibility 1), contained within the major histocompatibility complex (MHC), on chromosome 6p21. Subsequent refinement studies have highlighted linkage disequilibrium (LD) with psoriasis, along a 150-kb segment that includes at least three candidate genes (encoding human leukocyte antigen-C [HLA-C], alpha-helix-coiled-coil-rod homologue, and corneodesmosin), each of which has been shown to harbor disease-associated alleles. However, the boundaries of the minimal PSORS1 region remain poorly defined. Moreover, interpretations of allelic association with psoriasis are compounded by limited insight of LD conservation within MHC class I interval. To address these issues, we have pursued a high-resolution genetic characterization of the PSORS1 locus. We resequenced genomic segments along a 220-kb region at chromosome 6p21 and identified a total of 119 high-frequency SNPs. Using 59 SNPs (18 coding and 41 noncoding SNPs) whose position was representative of the overall marker distribution, we genotyped a data set of 171 independently ascertained parent-affected offspring trios. Family-based association analysis of this cohort highlighted two SNPs (n.7 and n.9) respectively lying 7 and 4 kb proximal to HLA-C. These markers generated highly significant evidence of disease association (P<10-9), several orders of magnitude greater than the observed significance displayed by any other SNP that has previously been associated with disease susceptibility. This observation was replicated in a Gujarati Indian case/control data set. Haplotype-based analysis detected overtransmission of a cluster of chromosomes, which probably originated by ancestral mutation of a common disease-bearing haplotype. The only markers exclusive to the overtransmitted chromosomes are SNPs n.7 and n.9, which define a 10-kb PSORS1 core risk haplotype. These data demonstrate the power of SNP haplotype-based association analyses and provide high-resolution dissection of genetic variation across the PSORS1 interval, the major susceptibility locus for psoriasis.

Psoriasis: genetic associations and immune system changes

“…49 A study from our group looking at both SNPs and classical HLA alleles revealed that haplotypes harboring HLACw*0602 and HLACw*1203 were over-transmitted to affecteds, suggesting that a variant or combination of variants exclusive to these haplotypes were predisposing. 50 Interestingly, one of these variants leads to acquisition of an additional site for the transcription factor RUNX, within intron 7.…”

Corneodesmosin gene ablation induces lethal skin-barrier disruption and hair-follicle degeneration related to desmosome dysfunction

“…Some CDSN single nucleotide polymorphisms (SNPs) have been associated with psoriasis in many genetic studies (reviewed by Capon et al, 2002), and a recent study revealed that only two genes from PSORS1, HLAC and CDSN, yield protein alleles that are unique to risk haplotypes (Nair et al, 2006). However, according to the latter study and others, the exact identity of the PSORS1 gene remains controversial (Veal et al, 2002;Capon et al, 2003;Helms et al, 2005;Orrù et al, 2005;Nair et al, 2006). Intriguingly, the only monogenic disease identified so far to be associated with mutations in CDSN revealed a hair phenotype and did not affect the epidermis (Levy-Nissenbaum et al, 2003); hypotrichosis simplex of the scalp (HSS; OMIM 146520) is a rare autosomal-dominant disease characterized by progressive loss of scalp hair resulting in almost complete baldness by the third decade.…”

Differential contribution of CDKAL1 variants to psoriasis, Crohn's disease and type II diabetes

“…2 Genome-wide linkage scans have unambiguously mapped a primary disease susceptibility locus (PSORS1) to the major histocompatibility complex (MHC), 3 where refinement studies and resequencing efforts point to HLA-C as the most likely PSORS1 candidate. 4,5 More recently, the advent of genome-wide association scans has allowed the identification of several non-MHC susceptibility genes, including IL12B, IL23R, RNF114, TNFAIP3, TNIP1, IL4/IL13 and LCE3B/3C [6][7][8][9][10][11] Of these, IL12B and IL23R harbour variants that also confer susceptibility to Crohn's disease (CD) 12 and ankylosing spondylitis. 13 Similarly, TNFAIP3 alleles have been associated with rheumatoid arthritis, 14 systemic lupus erythematosus 15 and type I diabetes.…”