Genome-wide comparative analysis of atopic dermatitis and psoriasis gives insight into opposing genetic mechanisms

Hansjörg Baurecht, Melanie Hotze, Stephan Brand, Carsten Büning, Paul Cormican, Aiden Corvin, David Ellinghaus, Eva Ellinghaus, Jorge Esparza-Gordillo, Regina Fölster-Holst, Andre Franke, Christian Gieger, Norbert Hubner, Thomas Illig, Alan D. Irvine, Michael Kabesch, Young A. E. Lee, Wolfgang Lieb, Ingo Marenholz, W. H. Irwin McLeanDerek W. Morris, Ulrich Mrowietz, Rajan Nair, Markus M. Nöthen, Natalija Novak, Grainne M. O'Regan, PAGE Consortium, Stefan Schreiber, Catherine Smith, Konstantin Strauch, Philip E. Stuart, Richard Trembath, Lam C. Tsoi, Michael Weichenthal, Jonathan Barker, James T. Elder, Stephan Weidinger, Heather J. Cordell, Sara J. Brown

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    67 Citations (Scopus)

    Abstract

    Atopic dermatitis and psoriasis are the two most common immune-mediated inflammatory disorders affecting the skin. Genome-wide studies demonstrate a high degree of genetic overlap, but these diseases have mutually exclusive clinical phenotypes and opposing immune mechanisms. Despite their prevalence, atopic dermatitis and psoriasis very rarely co-occur within one individual. By utilizing genome-wide association study and ImmunoChip data from >19,000 individuals and methodologies developed from meta-analysis, we have identified opposing risk alleles at shared loci as well as independent disease-specific loci within the epidermal differentiation complex (chromosome 1q21.3), the Th2 locus control region (chromosome 5q31.1), and the major histocompatibility complex (chromosome 6p21-22). We further identified previously unreported pleiotropic alleles with opposing effects on atopic dermatitis and psoriasis risk in PRKRA and ANXA6/TNIP1. In contrast, there was no evidence for shared loci with effects operating in the same direction on both diseases. Our results show that atopic dermatitis and psoriasis have distinct genetic mechanisms with opposing effects in shared pathways influencing epidermal differentiation and immune response. The statistical analysis methods developed in the conduct of this study have produced additional insight from previously published data sets. The approach is likely to be applicable to the investigation of the genetic basis of other complex traits with overlapping and distinct clinical features.

    Original languageEnglish
    Pages (from-to)104-120
    Number of pages17
    JournalAmerican Journal of Human Genetics
    Volume96
    Issue number1
    DOIs
    Publication statusPublished - 8 Jan 2015

    Keywords

    • Alleles
    • Case-Control Studies
    • Chromosomes, Human, Pair 1
    • Chromosomes, Human, Pair 5
    • Chromosomes, Human, Pair 6
    • Cohort Studies
    • Comparative Genomic Hybridization
    • Dermatitis, Atopic
    • Genetic Loci
    • Genome-Wide Association Study
    • Humans
    • Logistic Models
    • Major Histocompatibility Complex
    • Polymorphism, Single Nucleotide
    • Psoriasis
    • Quality Control
    • Reproducibility of Results

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    Cite this

    Baurecht, H., Hotze, M., Brand, S., Büning, C., Cormican, P., Corvin, A., Ellinghaus, D., Ellinghaus, E., Esparza-Gordillo, J., Fölster-Holst, R., Franke, A., Gieger, C., Hubner, N., Illig, T., Irvine, A. D., Kabesch, M., Lee, Y. A. E., Lieb, W., Marenholz, I., ... Brown, S. J. (2015). Genome-wide comparative analysis of atopic dermatitis and psoriasis gives insight into opposing genetic mechanisms. American Journal of Human Genetics, 96(1), 104-120. https://doi.org/10.1016/j.ajhg.2014.12.004