title: Genome-wide comparative analysis of atopic dermatitis and psoriasis gives insight into opposing genetic mechanisms.
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.
authors.affiliation: Department of Dermatology, Allergology, and Venereology, University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany.
authors.forename: Hansjörg
authors.initials: H
authors.lastname: Baurecht
authors.affiliation: Department of Dermatology, Allergology, and Venereology, University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Hotze
authors.affiliation: Department of Medicine II - Grosshadern, Ludwig-Maximilians-University (LMU), 81377 Munich, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Brand
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Charité, Campus Mitte, 10117 Berlin, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Büning
authors.affiliation: Neuropsychiatric Genetics Research Group, Department of Psychiatry and Institute of Molecular Medicine, Trinity College Dublin, Dublin 2, Ireland.
authors.forename: Paul
authors.initials: P
authors.lastname: Cormican
authors.affiliation: Neuropsychiatric Genetics Research Group, Department of Psychiatry and Institute of Molecular Medicine, Trinity College Dublin, Dublin 2, Ireland.
authors.forename: Aiden
authors.initials: A
authors.lastname: Corvin
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, 24105 Kiel, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Ellinghaus
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, 24105 Kiel, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Ellinghaus
authors.affiliation: Max-Delbrück-Centrum (MDC) for Molecular Medicine, Berlin-Buch, 13092 Berlin, Germany; Pediatric Allergy, Experimental and Clinical Research Center, Charité Universitätsmedizin Berlin, 10117 Berlin, Germany.
authors.forename: Jorge
authors.initials: J
authors.lastname: Esparza-Gordillo
authors.affiliation: Department of Dermatology, Allergology, and Venereology, University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany.
authors.forename: Regina
authors.initials: R
authors.lastname: Fölster-Holst
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, 24105 Kiel, Germany.
authors.forename: Andre
authors.initials: A
authors.lastname: Franke
authors.affiliation: Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany; Research Unit of Molecular Epidemiology, German Research Center for Environmental Health, 85764 Neuherberg, Germany; Institute of Epidemiology II, Helmholtz Zentrum München - German Research Center for Environmental Health, 85764 Neuherberg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Gieger
authors.affiliation: Max-Delbrück-Centrum (MDC) for Molecular Medicine, Berlin-Buch, 13092 Berlin, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Hubner
authors.affiliation: Research Unit of Molecular Epidemiology, German Research Center for Environmental Health, 85764 Neuherberg, Germany; Hannover Unified Biobank, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Illig
authors.affiliation: Department of Paediatric Dermatology, Our Lady's Children's Hospital, Crumlin, Dublin 12, Ireland; National Children's Research Centre, Dublin 12, Ireland; Department of Clinical Medicine, Trinity College Dublin, Dublin 2, Ireland.
authors.forename: Alan D
authors.initials: AD
authors.lastname: Irvine
authors.affiliation: Department of Pediatric Pneumology and Allergy, University Children's Hospital Regensburg (KUNO), 93042 Regensburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Kabesch
authors.affiliation: Max-Delbrück-Centrum (MDC) for Molecular Medicine, Berlin-Buch, 13092 Berlin, Germany; Pediatric Allergy, Experimental and Clinical Research Center, Charité Universitätsmedizin Berlin, 10117 Berlin, Germany.
authors.forename: Young A E
authors.initials: YA
authors.lastname: Lee
authors.affiliation: Institute of Epidemiology and PopGen Biobank, University Hospital Schleswig-Holstein, 24105 Kiel, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Lieb
authors.affiliation: Max-Delbrück-Centrum (MDC) for Molecular Medicine, Berlin-Buch, 13092 Berlin, Germany; Pediatric Allergy, Experimental and Clinical Research Center, Charité Universitätsmedizin Berlin, 10117 Berlin, Germany.
authors.forename: Ingo
authors.initials: I
authors.lastname: Marenholz
authors.affiliation: Dermatology and Genetic Medicine, College of Life Sciences and College of Medicine, Dentistry & Nursing, University of Dundee, Dundee DD1 5EH, UK.
authors.forename: W H Irwin
authors.initials: WH
authors.lastname: McLean
authors.affiliation: Neuropsychiatric Genetics Research Group, Department of Psychiatry and Institute of Molecular Medicine, Trinity College Dublin, Dublin 2, Ireland; Cognitive Genetics and Therapy Group, School of Psychology and Discipline of Biochemistry, National University of Ireland, Galway, Ireland.
authors.forename: Derek W
authors.initials: DW
authors.lastname: Morris
authors.affiliation: Department of Dermatology, Allergology, and Venereology, University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Mrowietz
authors.affiliation: Department of Dermatology, University of Michigan, Ann Arbor, MI 48109-5675, USA.
authors.forename: Rajan
authors.initials: R
authors.lastname: Nair
authors.affiliation: Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany; Department of Genomics, Life & Brain Center, University of Bonn, 53127 Bonn, Germany.
authors.forename: Markus M
authors.initials: MM
authors.lastname: Nöthen
authors.affiliation: Department of Dermatology and Allergy, University of Bonn Medical Center, 53105 Bonn, Germany.
authors.forename: Natalija
authors.initials: N
authors.lastname: Novak
authors.affiliation: Department of Paediatric Dermatology, Our Lady's Children's Hospital, Crumlin, Dublin 12, Ireland.
authors.forename: Grainne M
authors.initials: GM
authors.lastname: O'Regan
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, 24105 Kiel, Germany; Department of Internal Medicine, University Medical Center Schleswig-Holstein, 24105 Kiel, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Schreiber
authors.affiliation: Division of Genetics and Molecular Medicine, St John's Institute of Dermatology, Kings College London, London SE1 9RT, UK.
authors.forename: Catherine
authors.initials: C
authors.lastname: Smith
authors.affiliation: Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany; Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität, 80539 Munich, Germany.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Strauch
authors.affiliation: Department of Dermatology, University of Michigan, Ann Arbor, MI 48109-5675, USA.
authors.forename: Philip E
authors.initials: PE
authors.lastname: Stuart
authors.affiliation: Queen Mary University of London, Barts and the London School of Medicine and Dentistry, London E1 4NS, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Trembath
authors.affiliation: Department of Biostatistics, Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, MI 48109-5314, USA.
authors.forename: Lam C
authors.initials: LC
authors.lastname: Tsoi
authors.affiliation: Department of Dermatology, Allergology, and Venereology, University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Weichenthal
authors.affiliation: Division of Genetics and Molecular Medicine, St John's Institute of Dermatology, Kings College London, London SE1 9RT, UK.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Barker
authors.affiliation: Department of Dermatology, University of Michigan, Ann Arbor, MI 48109-5675, USA; Ann Arbor Veterans Affairs Hospital, Ann Arbor, MI 48105, USA.
authors.forename: James T
authors.initials: JT
authors.lastname: Elder
authors.affiliation: Department of Dermatology, Allergology, and Venereology, University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany. Electronic address: sweidinger@dermatology.uni-kiel.de.
authors.forename: Stephan
authors.initials: S
authors.lastname: Weidinger
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.
authors.forename: Heather J
authors.initials: HJ
authors.lastname: Cordell
authors.affiliation: Dermatology and Genetic Medicine, Medical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, UK. Electronic address: s.j.brown@dundee.ac.uk.
authors.forename: Sara J
authors.initials: SJ
authors.lastname: Brown
mesh_terms: D000483:Alleles; D016022:Case-Control Studies; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics; D015331:Cohort Studies; D055028:Comparative Genomic Hybridization; D003876:Dermatitis, Atopic / Q000235:genetics*; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D006801:Humans; D016015:Logistic Models; D008285:Major Histocompatibility Complex / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011565:Psoriasis / Q000235:genetics*; D011786:Quality Control; D015203:Reproducibility of Results