TY - JOUR
T1 - Causal Relationship and Shared Genetic Loci between Psoriasis and Type 2 Diabetes through Trans-Disease Meta-Analysis
AU - Patrick, Matthew T.
AU - Stuart, Philip E.
AU - Zhang, Haihan
AU - Zhao, Qingyuan
AU - Yin, Xianyong
AU - He, Kevin
AU - Zhou, Xu jie
AU - Mehta, Nehal N.
AU - Voorhees, John J.
AU - Boehnke, Michael
AU - Gudjonsson, Johann E.
AU - Nair, Rajan P.
AU - Handelman, Samuel K.
AU - Elder, James T.
AU - Liu, Dajiang J.
AU - Tsoi, Lam C.
N1 - Funding Information:
This work was supported by the Arthritis National Research Foundation and the National Psoriasis Foundation (LCT and MTP) and awards from the National Institutes of Health (R01AR042742, R01AR050511, R01AR054966, R01AR063611, R01AR065183 to JTE; K01AR072129 to LCT; and DK062370 to MB). LCT was also supported by the Dermatology Foundation, and MTP was supported by a Precision Health Scholars Award from the University of Michigan. LCT, PES, JEG, JJV, RPN, and JTE are supported by the Dawn and Dudley Holmes Foundation and the Babcock Memorial Trust. JEG was supported by Doris Duke Foundation (grant number: 2013106) and the National Institute of Health (K08AR060802 and R01AR06907) and the Taubman Medical Research Institute as the Frances and Kenneth Eisenberg Emerging Scholar. LCT and JEG are also supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases grant UM-SBDRC 1P30AR075043, the National Psoriasis Founadtion Psoriasis Prevention Initiative, and the Taubman Institute Innovation Project. JTE is supported by the Ann Arbor Veterans Affairs Hospital. XJZ was supported by the Beijing Natural Science Foundation (Z190023) and the University of Michigan Health System-Peking University Health Science Center Joint Institute for Translational and Clinical Research (BMU2017JI007). Conceptualization: MTP, LCT; Data Curation: MTP, PES, MB, JEG, RPN, JTE, LCT; Formal Analysis: MTP, HZ; Funding Acquisition: MTP, JEG, JTE, LCT; Methodology: MTP, PES, QZ, SKH, LCT; Supervision: LCT, JEG, JTE; Writing - Original Draft Preparation: MTP, LCT; Writing - Review and Editing: MTP, PES, HZ, QZ, XY, KH, XZ, NNM, JJV, MB, JEG, RPN, SKH, JTE, DJL, LCT
Funding Information:
This work was supported by the Arthritis National Research Foundation and the National Psoriasis Foundation (LCT and MTP) and awards from the National Institutes of Health (R01AR042742, R01AR050511, R01AR054966, R01AR063611, R01AR065183 to JTE; K01AR072129 to LCT; and DK062370 to MB). LCT was also supported by the Dermatology Foundation , and MTP was supported by a Precision Health Scholars Award from the University of Michigan . LCT, PES, JEG, JJV, RPN, and JTE are supported by the Dawn and Dudley Holmes Foundation and the Babcock Memorial Trust . JEG was supported by Doris Duke Foundation (grant number: 2013106) and the National Institute of Health (K08AR060802 and R01AR06907) and the Taubman Medical Research Institute as the Frances and Kenneth Eisenberg Emerging Scholar. LCT and JEG are also supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases grant UM-SBDRC 1P30AR075043, the National Psoriasis Founadtion Psoriasis Prevention Initiative, and the Taubman Institute Innovation Project. JTE is supported by the Ann Arbor Veterans Affairs Hospital. XJZ was supported by the Beijing Natural Science Foundation (Z190023) and the University of Michigan Health System- Peking University Health Science Center Joint Institute for Translational and Clinical Research (BMU2017JI007).
Funding Information:
JEG received research grants from AbbVie, AnaptysBio, Pfizer, Novartis, Celgene, and Eli Lilly and serves on advisory board in Novartis, AbbVie, Eli Lilly, MiRagen, and Almirall. NNM is a full-time United States government employee and has served as a consultant for Amgen, Eli Lilly, and Leo Pharma receiving grants and/or other payments; as a principal investigator and/or investigator for AbbVie, Celgene, Janssen Pharmaceuticals, 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.
Publisher Copyright:
© 2021 The Authors
PY - 2021/6
Y1 - 2021/6
N2 - 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.
AB - 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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U2 - 10.1016/j.jid.2020.11.025
DO - 10.1016/j.jid.2020.11.025
M3 - Article
C2 - 33385400
AN - SCOPUS:85100435739
SN - 0022-202X
VL - 141
SP - 1493
EP - 1502
JO - Journal of Investigative Dermatology
JF - Journal of Investigative Dermatology
IS - 6
ER -