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Genome-wide Comparative Analysis of Atopic Dermatitis and Psoriasis Gives Insight into Opposing Genetic Mechanisms

Lookup NU author(s): Professor Heather Cordell

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


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.


Publication metadata

Author(s): Baurecht H, Hotze M, Brand S, Buning C, Cormican P, Corvin A, Ellinghaus D, Ellinghaus E, Esparza-Gordillo J, Folster-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, Nothen MM, Novak N, O'Regan GM, Schreiber S, Smith C, Strauch K, Stuart PE, Trembath R, Tsoi LC, Weichenthal M, Barker J, Elder JT, Weidinger S, Cordell HJ, Brown SJ, PAGE Consortium

Publication type: Article

Publication status: Published

Journal: American Journal of Human Genetics

Year: 2015

Volume: 96

Issue: 1

Pages: 104-120

Print publication date: 08/01/2015

Online publication date: 08/01/2015

Acceptance date: 05/12/2014

Date deposited: 07/04/2015

ISSN (print): 0002-9297

ISSN (electronic): 1537-6605

Publisher: Cell Press

URL: http://dx.doi.org/10.1016/j.ajhg.2014.12.004

DOI: 10.1016/j.ajhg.2014.12.004


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Funding

Funder referenceFunder name
Ann Arbor Veterans Affairs Hospital
Babcock Memorial Trust
German Federal Ministry of Education and Research
Helmholtz Zentrum Munchen - German Research Center for Environmental Health
Munich Center of Health Sciences (MC Health), Ludwig-Maximilians-Universitat, as part of LMUinnovativ
National Children's Research Centre, Dublin
State of Bavaria
01ZX1306AGerman Federal Ministry of Education and Research
076113Wellcome Trust
098439/Z/12/ZWellcome Trust
085475Wellcome Trust
102858/Z/13/ZWellcome Trust
087436/Z/08/ZWellcome Trust
092530/Z/10/ZWellcome Trust
EXC306DFG Clusters of Excellence "Inflammation at Interfaces"
EXC306/2DFG Clusters of Excellence "Inflammation at Interfaces"
R01AR042742NIH
R01AR062382NIH
R01AR050511NIH
R01AR054966NIH
R01AR062886-01NIH
WT086398MAWellcome Trust

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