Genome-wide Comparative Analysis of Atopic Dermatitis and Psoriasis Gives Insight into Opposing Genetic Mechanisms
Open accessAbstract
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.
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These results suggest that overall genetic correlations may obscure a more complex set of genetic relationships at the level of specific loci and pathways.
“These results underscore the complexity of genetic relationships among related disorders and suggest that overall genetic correlations may obscure a more complex set of genetic relationships at the level of specific loci and pathways, as seen in immune-mediated diseases (Baurecht et al., 2015; Lettre and Rioux, 2008; Schmitt et al., 2016).”
From Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders (2019) · cites this paper as Baurecht et al., 2015
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Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders
Lee, P. H., Anttila, V., Won, H., Feng, Y.-C. A., Rosenthal, J., Zhu, Z., Tucker-Drob, E. M., Nivard, M. G., Grotzinger, A. D., Posthuma, D., et al. (2019) · Cell · doi:10.1016/j.cell.2019.11.020 · Cited by 1,381 · see citing works
Self-citationTsoi, L. C., Rodriguez, E., Degenhardt, F., Baurecht, H., Wehkamp, U., Volks, N., Szymczak, S., Swindell, W. R., Sarkar, M. K., Raja, K., et al. (2019) · Journal of Investigative Dermatology · doi:10.1016/j.jid.2018.12.018 · Cited by 469 · see citing works
Self-citationUpdate on the Pathogenesis and Therapy of Atopic Dermatitis
Li, H., Zhang, Z., Zhang, H., Guo, Y., & Yao, Z. (2021) · Clinical Reviews in Allergy & Immunology · doi:10.1007/s12016-021-08880-3 · Cited by 277 · see citing works
Replicated methylation changes associated with eczema herpeticum and allergic response
Boorgula, M. P., Taub, M. A., Rafaels, N., Daya, M., Campbell, M., Chavan, S., Shetty, A., Cheadle, C., Barkataki, S., Fan, J., et al. (2019) · Clinical Epigenetics · doi:10.1186/s13148-019-0714-1 · Cited by 28 · see citing works
- Authors
- 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., McLean, W. H. I., Morris, D. W., Mrowietz, U., Nair, R., Nöthen, M. M., Novak, N., O’Regan, G. M., Schreiber, S., Smith, C., Strauch, K., Stuart, P. E., Trembath, R., Tsoi, L. C., Weichenthal, M., Barker, J., Elder, J. T., Weidinger, S., Cordell, H. J., & Brown, S. J.
- Affiliations
- University Hospital Schleswig-Holstein (DE)
- Ludwig-Maximilians-Universität München (DE)
- Stiftung Charité (DE)
- Trinity College Dublin (IE)
- Christian-Albrechts-Universität zu Kiel (DE)
- Max Delbrück Center (DE)
- Helmholtz Munich (DE)
- University Hospital Regensburg (DE)
- University of Dundee (GB)
- Ollscoil na Gaillimhe – University of Galway (IE)
- University of Michigan (US)
- University of Bonn (DE)
- King's College London (GB)
- Queen Mary University of London (GB)
- Newcastle University (GB)
- Corresponding author
- Weidinger, Stephan
- Brown, Sara J.
- ORCID
- Baurecht, Hansjörg
- Brand, Stephan
- Corvin, Aiden
- Ellinghaus, David
- Ellinghaus, Eva
- Gieger, Christian
- Illig, Thomas
- Irvine, Alan D.
- Kabesch, Michael
- Lieb, Wolfgang
- Marenholz, Ingo
- McLean, W.H. Irwin
- Morris, Derek W.
- Mrowietz, Ulrich
- Nair, Rajan
- Nöthen, Markus M.
- Novak, Natalija
- Schreiber, Stefan
- Smith, Catherine
- Strauch, Konstantin
- Stuart, Philip E.
- Trembath, Richard
- Tsoi, Lam C.
- Weichenthal, Michael
- Elder, James T.
- Weidinger, Stephan
- Cordell, Heather J.
- Brown, Sara J.
- Venue
- The American Journal of Human Genetics
- Publisher
- Elsevier BV
- Published
- 2015-01
- Volume
- 96
- Issue
- 1
- Pages
- 104-120
- ISSN
- 0002-9297 (ISSN-L)
- PMC
- PMC4289690
- OpenAlex
- W2147713509
- Cited by
- 193
- References
- 3
- Citations by year
- 2026: 10 · 2025: 11 · 2024: 10 · 2023: 19 · 2022: 24 · 2021: 31 · 2020: 20 · 2019: 17 · 2018: 13 · 2017: 13 · 2016: 16 · 2015: 8 · 2012: 1
- FWCI
- 18.66
- Type
- journal article
- Language
- en
- Update notices
- erratum (2015-12-03)
- Open access
- hybrid
- doi.org
- Locations
- The American Journal of Human Genetics (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Research Portal (King's College London) (publishedVersion, other-oa)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (acceptedVersion)
- Arrow@dit (Dublin Institute of Technology) (submittedVersion)
- ARAN (University of Galway Research Repository) (Ollscoil na Gaillimhe – University of Galway) (submittedVersion, cc-by-nc-nd)
- Discovery Research Portal (University of Dundee) (submittedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by)
- PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion)
- Newcastle University ePrints (Newcastle Univesity) (cc-by)
- Funders
- Wellcome Trust (102858/Z/13/Z, 085475, 098439, 087436/Z/08/Z, 087436, 098439/Z/12/Z, 092530/Z/10/Z, WT086398MA, 076113)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01 AR062382, R01AR050511, R01AR042742, R01AR062886, R01AR065183, R01AR063611, R01AR054966)
- National Center for Research Resources (M01RR000042)
- Topics
- Health Sciences › Medicine › Dermatology › Dermatology and Skin Diseases
- Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- atopic dermatitis, psoriasis, genetic susceptibility loci, pleiotropy, epidermal differentiation complex, major histocompatibility complex, PRKRA, immune response
- MeSH terms
- Alleles, Chromosomes, Human, Pair 1, Chromosomes, Human, Pair 5, Chromosomes, Human, Pair 6, Dermatitis, Atopic, Humans, Major Histocompatibility Complex, Psoriasis, Quality Control, Reproducibility of Results, Cohort Studies, Logistic Models, Case-Control Studies, Polymorphism, Single Nucleotide, Comparative Genomic Hybridization, Genome-Wide Association Study, Genetic Loci
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