Fine mapping of eight psoriasis susceptibility loci View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2015-06

AUTHORS

Sayantan Das, Philip E Stuart, Jun Ding, Trilokraj Tejasvi, Yanming Li, Lam C Tsoi, Vinod Chandran, Judith Fischer, Cynthia Helms, Kristina Callis Duffin, John J Voorhees, Anne M Bowcock, Gerald G Krueger, G Mark Lathrop, Rajan P Nair, Proton Rahman, Goncalo R Abecasis, Dafna Gladman, James T Elder

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. More... »

PAGES

844-853

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  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/ejhg.2014.172

    DOI

    http://dx.doi.org/10.1038/ejhg.2014.172

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1052748719

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/25182136


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    446 schema:name Department of Medicine, Memorial University, St John's, NL, Canada.
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    448 https://www.grid.ac/institutes/grid.418135.a schema:alternateName Centre National de Génotypage
    449 schema:name Centre National de Génotypage, Institut Génomique, Commissariat à l'Énergie Atomique, Evry, France.
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    451 https://www.grid.ac/institutes/grid.7445.2 schema:alternateName Imperial College London
    452 schema:name National Heart and Lung Institute, Imperial College London, London, UK.
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