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Am J Hum Genet. 2015 Jan 8;96(1):104-20. doi: 10.1016/j.ajhg.2014.12.004.

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

Author information

  • 1Department of Dermatology, Allergology, and Venereology, University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany.
  • 2Department of Medicine II - Grosshadern, Ludwig-Maximilians-University (LMU), 81377 Munich, Germany.
  • 3Department of Gastroenterology, Hepatology and Endocrinology, Charité, Campus Mitte, 10117 Berlin, Germany.
  • 4Neuropsychiatric Genetics Research Group, Department of Psychiatry and Institute of Molecular Medicine, Trinity College Dublin, Dublin 2, Ireland.
  • 5Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, 24105 Kiel, Germany.
  • 6Max-Delbrück-Centrum (MDC) for Molecular Medicine, Berlin-Buch, 13092 Berlin, Germany; Pediatric Allergy, Experimental and Clinical Research Center, Charité Universitätsmedizin Berlin, 10117 Berlin, Germany.
  • 7Institute 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.
  • 8Max-Delbrück-Centrum (MDC) for Molecular Medicine, Berlin-Buch, 13092 Berlin, Germany.
  • 9Research Unit of Molecular Epidemiology, German Research Center for Environmental Health, 85764 Neuherberg, Germany; Hannover Unified Biobank, Hannover Medical School, 30625 Hannover, Germany.
  • 10Department 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.
  • 11Department of Pediatric Pneumology and Allergy, University Children's Hospital Regensburg (KUNO), 93042 Regensburg, Germany.
  • 12Institute of Epidemiology and PopGen Biobank, University Hospital Schleswig-Holstein, 24105 Kiel, Germany.
  • 13Dermatology and Genetic Medicine, College of Life Sciences and College of Medicine, Dentistry & Nursing, University of Dundee, Dundee DD1 5EH, UK.
  • 14Neuropsychiatric 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.
  • 15Department of Dermatology, University of Michigan, Ann Arbor, MI 48109-5675, USA.
  • 16Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany; Department of Genomics, Life & Brain Center, University of Bonn, 53127 Bonn, Germany.
  • 17Department of Dermatology and Allergy, University of Bonn Medical Center, 53105 Bonn, Germany.
  • 18Department of Paediatric Dermatology, Our Lady's Children's Hospital, Crumlin, Dublin 12, Ireland.
  • 19Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, 24105 Kiel, Germany; Department of Internal Medicine, University Medical Center Schleswig-Holstein, 24105 Kiel, Germany.
  • 20Division of Genetics and Molecular Medicine, St John's Institute of Dermatology, Kings College London, London SE1 9RT, UK.
  • 21Institute 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.
  • 22Queen Mary University of London, Barts and the London School of Medicine and Dentistry, London E1 4NS, UK.
  • 23Department of Biostatistics, Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, MI 48109-5314, USA.
  • 24Department of Dermatology, University of Michigan, Ann Arbor, MI 48109-5675, USA; Ann Arbor Veterans Affairs Hospital, Ann Arbor, MI 48105, USA.
  • 25Department of Dermatology, Allergology, and Venereology, University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany. Electronic address: sweidinger@dermatology.uni-kiel.de.
  • 26Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.
  • 27Dermatology 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.

Erratum in

  • Am J Hum Genet. 2015 Dec 3;97(6):933.

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.

PMID:
25574825
PMCID:
PMC4289690
DOI:
10.1016/j.ajhg.2014.12.004
[PubMed - indexed for MEDLINE]
Free PMC Article

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