title: Fine mapping of eight psoriasis susceptibility loci.
abstract: Previous studies have identified 41 independent genome-wide significant psoriasis susceptibility loci. After our first psoriasis genome-wide association study, we designed a custom genotyping array to fine-map eight genome-wide significant susceptibility loci known at that time (IL23R, IL13, IL12B, TNIP1, MHC, TNFAIP3, IL23A and RNF114) enabling genotyping of 2269 single-nucleotide polymorphisms (SNPs) in the eight loci for 2699 psoriasis cases and 2107 unaffected controls of European ancestry. We imputed these data using the latest 1000 Genome reference haplotypes, which included both indels and SNPs, to increase the marker density of the eight loci to 49 239 genetic variants. Using stepwise conditional association analysis, we identified nine independent signals distributed across six of the eight loci. In the major histocompatibility complex (MHC) region, we detected three independent signals at rs114255771 (P = 2.94 × 10(-74)), rs6924962 (P = 3.21 × 10(-19)) and rs892666 (P = 1.11 × 10(-10)). Near IL12B we detected two independent signals at rs62377586 (P = 7.42 × 10(-16)) and rs918518 (P = 3.22 × 10(-11)). Only one signal was observed in each of the TNIP1 (rs17728338; P = 4.15 × 10(-13)), IL13 (rs1295685; P = 1.65 × 10(-7)), IL23A (rs61937678; P = 1.82 × 10(-7)) and TNFAIP3 (rs642627; P = 5.90 × 10(-7)) regions. We also imputed variants for eight HLA genes and found that SNP rs114255771 yielded a more significant association than any HLA allele or amino-acid residue. Further analysis revealed that the HLA-C*06-B*57 haplotype tagged by this SNP had a significantly higher odds ratio than other HLA-C*06-bearing haplotypes. The results demonstrate allelic heterogeneity at IL12B and identify a high-risk MHC class I haplotype, consistent with the existence of multiple psoriasis effectors in the MHC.
authors.affiliation: Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Sayantan
authors.initials: S
authors.lastname: Das
authors.affiliation: Department of Dermatology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Philip E
authors.initials: PE
authors.lastname: Stuart
authors.affiliation: 1] Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA [2] Laboratory of Genetics, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Ding
authors.affiliation: Department of Dermatology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Trilokraj
authors.initials: T
authors.lastname: Tejasvi
authors.affiliation: Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Yanming
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Lam C
authors.initials: LC
authors.lastname: Tsoi
authors.affiliation: Division of Rheumatology, Department of Medicine, University of Toronto, Toronto, ON, Canada.
authors.forename: Vinod
authors.initials: V
authors.lastname: Chandran
authors.affiliation: Centre National de Génotypage, Institut Génomique, Commissariat à l'Énergie Atomique, Evry, France.
authors.forename: Judith
authors.initials: J
authors.lastname: Fischer
authors.affiliation: National Heart and Lung Institute, Imperial College London, London, UK.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Helms
authors.affiliation: Department of Dermatology, University of Utah, Salt Lake City, UT, USA.
authors.forename: Kristina Callis
authors.initials: KC
authors.lastname: Duffin
authors.affiliation: Department of Dermatology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: Voorhees
authors.affiliation: National Heart and Lung Institute, Imperial College London, London, UK.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Bowcock
authors.affiliation: Department of Dermatology, University of Utah, Salt Lake City, UT, USA.
authors.forename: Gerald G
authors.initials: GG
authors.lastname: Krueger
authors.affiliation: Centre National de Génotypage, Institut Génomique, Commissariat à l'Énergie Atomique, Evry, France.
authors.forename: G Mark
authors.initials: GM
authors.lastname: Lathrop
authors.affiliation: Department of Dermatology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Rajan P
authors.initials: RP
authors.lastname: Nair
authors.affiliation: Department of Medicine, Memorial University, St John's, NL, Canada.
authors.forename: Proton
authors.initials: P
authors.lastname: Rahman
authors.affiliation: Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Goncalo R
authors.initials: GR
authors.lastname: Abecasis
authors.affiliation: 1] Division of Rheumatology, Department of Medicine, University of Toronto, Toronto, ON, Canada [2] Psoriatic Arthritis Program, Centre for Prognosis Studies in the Rheumatic Diseases, Toronto Western Research Institute, Toronto, ON, Canada.
authors.forename: Dafna
authors.initials: D
authors.lastname: Gladman
authors.affiliation: 1] Department of Dermatology, University of Michigan, Ann Arbor, MI, USA [2] Ann-Arbor Veteran Affairs Hospital, Ann Arbor, MI, USA.
authors.forename: James T
authors.initials: JT
authors.lastname: Elder
mesh_terms: D002352:Carrier Proteins / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D006680:HLA Antigens / Q000235:genetics; D006801:Humans; D007378:Interleukins / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011565:Psoriasis / Q000235:genetics*; D018123:Receptors, Interleukin / Q000235:genetics; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D044767:Ubiquitin-Protein Ligases
chemical_list: D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D006680:HLA Antigens; C515500:IL23R protein, human; D007378:Interleukins; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D018123:Receptors, Interleukin; C117046:TNIP1 protein, human; C477146:RNF114 protein, human; D044767:Ubiquitin-Protein Ligases; C076529:TNFAIP3 protein, human; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3