Causal Relationship and Shared Genetic Loci between Psoriasis and Type 2 Diabetes through Trans-Disease Meta-Analysis

Affiliations

¹ Department of Dermatology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
² Department of Dermatology, University of Michigan Medical School, Ann Arbor, Michigan, USA; Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA.
³ Statistical Laboratory, Centre for Mathematical Sciences, University of Cambridge, Cambridge, United Kingdom.
⁴ Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA.
⁵ Renal Division, Peking University First Hospital, Beijing, China.
⁶ National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA.
⁷ Division of Gastroenterology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA.
⁸ Department of Dermatology, University of Michigan Medical School, Ann Arbor, Michigan, USA; Ann Arbor Veterans Affairs Hospital, Ann Arbor, Michigan, USA.
⁹ Department of Public Health Sciences, Pennsylvania State University College of Medicine, Pennsylvania, USA.
¹⁰ Department of Dermatology, University of Michigan Medical School, Ann Arbor, Michigan, USA; Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor Michigan, USA. Electronic address: alextsoi@med.umich.edu.

PMID: 33385400
PMCID: PMC8154633
DOI: 10.1016/j.jid.2020.11.025

Meta-Analysis

Causal Relationship and Shared Genetic Loci between Psoriasis and Type 2 Diabetes through Trans-Disease Meta-Analysis

Matthew T Patrick et al. J Invest Dermatol. 2021 Jun.

. 2021 Jun;141(6):1493-1502.

doi: 10.1016/j.jid.2020.11.025. Epub 2020 Dec 30.

Authors

Affiliations

¹ Department of Dermatology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
² Department of Dermatology, University of Michigan Medical School, Ann Arbor, Michigan, USA; Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA.
³ Statistical Laboratory, Centre for Mathematical Sciences, University of Cambridge, Cambridge, United Kingdom.
⁴ Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA.
⁵ Renal Division, Peking University First Hospital, Beijing, China.
⁶ National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA.
⁷ Division of Gastroenterology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA.
⁸ Department of Dermatology, University of Michigan Medical School, Ann Arbor, Michigan, USA; Ann Arbor Veterans Affairs Hospital, Ann Arbor, Michigan, USA.
⁹ Department of Public Health Sciences, Pennsylvania State University College of Medicine, Pennsylvania, USA.
¹⁰ Department of Dermatology, University of Michigan Medical School, Ann Arbor, Michigan, USA; Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor Michigan, USA. Electronic address: alextsoi@med.umich.edu.

PMID: 33385400
PMCID: PMC8154633
DOI: 10.1016/j.jid.2020.11.025

Abstract

Psoriasis and type 2 diabetes (T2D) are complex conditions with significant impacts on health. Patients with psoriasis have a higher risk of T2D (∼1.5 OR) and vice versa, controlling for body mass index; yet, there has been a limited study comparing their genetic architecture. We hypothesized that there are shared genetic components between psoriasis and T2D. Trans-disease meta-analysis was applied to 8,016,731 well-imputed genetic markers from large-scale meta-analyses of psoriasis (11,024 cases and 16,336 controls) and T2D (74,124 cases and 824,006 controls), adjusted for body mass index. We confirmed our findings in a hospital-based study (42,112 patients) and tested for causal relationships with multivariable Mendelian randomization. Mendelian randomization identified a causal relationship between psoriasis and T2D (P = 1.6 × 10^‒4, OR = 1.01) and highlighted the impact of body mass index. Trans-disease meta-analysis further revealed four genome-wide significant loci (P < 5 × 10^‒8) with evidence of colocalization and shared directions of effect between psoriasis and T2D not present in body mass index. The proteins coded by genes in these loci (ACTR2, ERLIN1, TRMT112, and BECN1) are connected through NF-κB signaling. Our results provide insight into the immunological components that connect immune-mediated skin conditions and metabolic diseases, independent of confounding factors.

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Conflict of interest statement

Conflict of interest

JEG received research grants from AbbVie, AnaptysBio, Pfizer, Novartis, Celgene, and Eli Lilly, and serves as advisory board in Novartis, AbbVie, Eli Lilly, MiRagen, and Almirall. NNM is a full-time US government employee and has served as a consultant for Amgen, Eli Lilly, and Leo Pharma receiving grants/other payments; as a principal investigator and/or investigator for AbbVie, Celgene, Janssen Pharmaceuticals, Inc, and Novartis receiving grants and/or research funding; and as a principal investigator for the National Institute of Health receiving grants and/or research funding.

Figures

**Figure 1:. Trans-disease Meta-analysis.**
a) Vertical Manhattan plots of the meta-analysis association results for psoriasis and T2D, showing genome-wide significant (p≤5x10⁻⁸) markers in **red** and shared loci identified by our trans-disease meta-analysis in **blue**. b) Regional association plots for the chromosome 10 locus in psoriasis and T2D (with the lead marker in purple). The locus is suggestive significant for each disease and genome-wide significant in the trans-disease meta-analysis.

**Figure 2:. Cell Type Enrichment for Trans-Disease Meta-Analysis Markers Outside the MHC.**
a) Calculated using DNAse hotspots in GARFIELD. b) Using H3K27ac marks from Farh et al.(Farh et al., 2015) The enrichment results illustrate immune-cell involvement.

See this image and copyright information in PMC

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Causal Relationship and Shared Genetic Loci between Psoriasis and Type 2 Diabetes through Trans-Disease Meta-Analysis

Affiliations

Causal Relationship and Shared Genetic Loci between Psoriasis and Type 2 Diabetes through Trans-Disease Meta-Analysis

Authors

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Abstract

Conflict of interest statement

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