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

    Research output: Contribution to journalArticle

    52 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

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    Atopic Dermatitis
    Psoriasis
    Genome
    Chromosomes
    Alleles
    Locus Control Region
    Chromosomes, Human, Pair 22
    Inborn Genetic Diseases
    Genome-Wide Association Study
    Major Histocompatibility Complex
    Meta-Analysis
    Phenotype
    Skin

    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

    Cite this

    Baurecht, Hansjörg ; Hotze, Melanie ; Brand, Stephan ; Büning, Carsten ; Cormican, Paul ; Corvin, Aiden ; Ellinghaus, David ; Ellinghaus, Eva ; Esparza-Gordillo, Jorge ; Fölster-Holst, Regina ; Franke, Andre ; Gieger, Christian ; Hubner, Norbert ; Illig, Thomas ; Irvine, Alan D. ; Kabesch, Michael ; Lee, Young A. E. ; Lieb, Wolfgang ; Marenholz, Ingo ; McLean, W. H. Irwin ; Morris, Derek W. ; Mrowietz, Ulrich ; Nair, Rajan ; Nöthen, Markus M. ; Novak, Natalija ; O'Regan, Grainne M. ; PAGE Consortium ; Schreiber, Stefan ; Smith, Catherine ; Strauch, Konstantin ; Stuart, Philip E. ; Trembath, Richard ; Tsoi, Lam C. ; Weichenthal, Michael ; Barker, Jonathan ; Elder, James T. ; Weidinger, Stephan ; Cordell, Heather J. ; Brown, Sara J. / Genome-wide comparative analysis of atopic dermatitis and psoriasis gives insight into opposing genetic mechanisms. In: American Journal of Human Genetics. 2015 ; Vol. 96, No. 1. pp. 104-120.
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    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.",
    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",
    author = "Hansj{\"o}rg Baurecht and Melanie Hotze and Stephan Brand and Carsten B{\"u}ning and Paul Cormican and Aiden Corvin and David Ellinghaus and Eva Ellinghaus and Jorge Esparza-Gordillo and Regina F{\"o}lster-Holst and Andre Franke and Christian Gieger and Norbert Hubner and Thomas Illig and Irvine, {Alan D.} and Michael Kabesch and Lee, {Young A. E.} and Wolfgang Lieb and Ingo Marenholz and McLean, {W. H. Irwin} and Morris, {Derek W.} and Ulrich Mrowietz and Rajan Nair and N{\"o}then, {Markus M.} and Natalija Novak and O'Regan, {Grainne M.} and {PAGE Consortium} and Stefan Schreiber and Catherine Smith and Konstantin Strauch and Stuart, {Philip E.} and Richard Trembath and Tsoi, {Lam C.} and Michael Weichenthal and Jonathan Barker and Elder, {James T.} and Stephan Weidinger and Cordell, {Heather J.} and Brown, {Sara J.}",
    note = "Copyright {\circledC} 2015 The Authors. Published by Elsevier Inc. All rights reserved.",
    year = "2015",
    month = "1",
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    doi = "10.1016/j.ajhg.2014.12.004",
    language = "English",
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    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, AD, Kabesch, M, Lee, YAE, Lieb, W, Marenholz, I, McLean, WHI, Morris, DW, Mrowietz, U, Nair, R, Nöthen, MM, Novak, N, O'Regan, GM, PAGE Consortium, Schreiber, S, Smith, C, Strauch, K, Stuart, PE, Trembath, R, Tsoi, LC, Weichenthal, M, Barker, J, Elder, JT, Weidinger, S, Cordell, HJ & Brown, SJ 2015, 'Genome-wide comparative analysis of atopic dermatitis and psoriasis gives insight into opposing genetic mechanisms', American Journal of Human Genetics, vol. 96, no. 1, pp. 104-120. https://doi.org/10.1016/j.ajhg.2014.12.004

    Genome-wide comparative analysis of atopic dermatitis and psoriasis gives insight into opposing genetic mechanisms. / Baurecht, Hansjörg; Hotze, Melanie; Brand, Stephan; Büning, Carsten; Cormican, Paul; Corvin, Aiden; Ellinghaus, David; Ellinghaus, Eva; Esparza-Gordillo, Jorge; Fölster-Holst, Regina; Franke, Andre; Gieger, Christian; Hubner, Norbert; Illig, Thomas; Irvine, Alan D.; Kabesch, Michael; Lee, Young A. E.; Lieb, Wolfgang; Marenholz, Ingo; McLean, W. H. Irwin; Morris, Derek W.; Mrowietz, Ulrich; Nair, Rajan; Nöthen, Markus M.; Novak, Natalija; O'Regan, Grainne M.; PAGE Consortium; Schreiber, Stefan; Smith, Catherine; Strauch, Konstantin; Stuart, Philip E.; Trembath, Richard; Tsoi, Lam C.; Weichenthal, Michael; Barker, Jonathan; Elder, James T.; Weidinger, Stephan (Lead / Corresponding author); Cordell, Heather J.; Brown, Sara J. (Lead / Corresponding author).

    In: American Journal of Human Genetics, Vol. 96, No. 1, 08.01.2015, p. 104-120.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Genome-wide comparative analysis of atopic dermatitis and psoriasis gives insight into opposing genetic mechanisms

    AU - Baurecht, Hansjörg

    AU - Hotze, Melanie

    AU - Brand, Stephan

    AU - Büning, Carsten

    AU - Cormican, Paul

    AU - Corvin, Aiden

    AU - Ellinghaus, David

    AU - Ellinghaus, Eva

    AU - Esparza-Gordillo, Jorge

    AU - Fölster-Holst, Regina

    AU - Franke, Andre

    AU - Gieger, Christian

    AU - Hubner, Norbert

    AU - Illig, Thomas

    AU - Irvine, Alan D.

    AU - Kabesch, Michael

    AU - Lee, Young A. E.

    AU - Lieb, Wolfgang

    AU - Marenholz, Ingo

    AU - McLean, W. H. Irwin

    AU - Morris, Derek W.

    AU - Mrowietz, Ulrich

    AU - Nair, Rajan

    AU - Nöthen, Markus M.

    AU - Novak, Natalija

    AU - O'Regan, Grainne M.

    AU - PAGE Consortium

    AU - Schreiber, Stefan

    AU - Smith, Catherine

    AU - Strauch, Konstantin

    AU - Stuart, Philip E.

    AU - Trembath, Richard

    AU - Tsoi, Lam C.

    AU - Weichenthal, Michael

    AU - Barker, Jonathan

    AU - Elder, James T.

    AU - Weidinger, Stephan

    AU - Cordell, Heather J.

    AU - Brown, Sara J.

    N1 - Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

    PY - 2015/1/8

    Y1 - 2015/1/8

    N2 - 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.

    AB - 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.

    KW - Alleles

    KW - Case-Control Studies

    KW - Chromosomes, Human, Pair 1

    KW - Chromosomes, Human, Pair 5

    KW - Chromosomes, Human, Pair 6

    KW - Cohort Studies

    KW - Comparative Genomic Hybridization

    KW - Dermatitis, Atopic

    KW - Genetic Loci

    KW - Genome-Wide Association Study

    KW - Humans

    KW - Logistic Models

    KW - Major Histocompatibility Complex

    KW - Polymorphism, Single Nucleotide

    KW - Psoriasis

    KW - Quality Control

    KW - Reproducibility of Results

    U2 - 10.1016/j.ajhg.2014.12.004

    DO - 10.1016/j.ajhg.2014.12.004

    M3 - Article

    C2 - 25574825

    VL - 96

    SP - 104

    EP - 120

    JO - American Journal of Human Genetics

    JF - American Journal of Human Genetics

    SN - 0002-9297

    IS - 1

    ER -