Plasma Metabolomic and Proteomic Profiling of the Mechanisms Underlying the Cumulative Impact of Co-occurring Psychiatric Disorders on Atopic Dermatitis
DOI:
https://doi.org/10.2340/actadv.v106.adv-2025-0181Keywords:
Psychiatric multimorbidity, Atopic dermatitis, Metabolomics, Plasma proteomic, UK BiobankAbstract
Atopic dermatitis (AD) has been linked to psychiatric disorders, but the cumulative contribution of psychiatric multimorbidity to incident AD remains unclear. We integrated genome-wide association study summary statistics with UK Biobank cohort, metabolomic and proteomic data to evaluate genetic relationships, longitudinal associations and putative biological intermediates. High-definition likelihood and bidirectional GSMR assessed shared genetic architecture and directionality. Cox models, multimorbidity counts, weighted composite scores and stratified analyses assessed incident AD, including effect modification by serum vitamin D. Plasma metabolomic and proteomic data were examined using mediation analysis and proteome-wide Mendelian randomization. Genetic liability to 5 psychiatric traits was associated with higher AD risk, whereas reverse AD-to-psychiatric effects were not supported. Psychiatric disorders were prospectively associated with incident AD, with higher risk among participants with co-occurring disorders and higher weighted psychiatric burden. Vitamin D status modified these associations although causality cannot be inferred. A branched-chain amino acid metabolic pattern showed statistically significant but modest mediation (1.04%). Proteomic analyses prioritized HLA-DRA, MMP12, TNFRSF14, and VCAM1 as nonspecific inflammatory proteins associated with AD risk in psychiatric populations. Psychiatric multimorbidity marks a sustained elevation in AD risk, potentially through overlapping inflammatory and metabolic pathways.
Downloads
References
Collaborators GAMD. The epidemiology and burden of ten mental disorders in countries of the Association of Southeast Asian Nations (ASEAN), 1990-2021: findings from the Global Burden of Disease Study 2021. Lancet Public Health 2025; 10: e480–e491.
Cosci F, Fava GA. When anxiety and depression coexist: the role of differential diagnosis using clinimetric criteria. Psychother Psychosom 2021; 90: 308–317. DOI: https://doi.org/10.1159/000517518
Xu X, Li S, Chen Y, Deng X, Li J, Xiong D, et al. Association between allergic diseases and mental health conditions: an umbrella review. J Allergy Clin Immunol 2025; 155: 701–713. DOI: https://doi.org/10.1016/j.jaci.2024.10.030
Biazus Soares G, Mahmoud O, Yosipovitch G, Mochizuki H. The mind-skin connection: a narrative review exploring the link between inflammatory skin diseases and psychological stress. J Eur Acad Dermatol Venereol 2024; 38: 821–834. DOI: https://doi.org/10.1111/jdv.19813
Slominski AT, Zmijewski MA, Zbytek B, Tobin DJ, Theoharides TC, Rivier J. Key role of CRF in the skin stress response system. Endocr Rev 2013; 34: 827–884. DOI: https://doi.org/10.1210/er.2012-1092
Slominski RM, Raman C, Jetten AM, Slominski AT. Neuro-immuno-endocrinology of the skin: how environment regulates body homeostasis. Nat Rev Endocrinol 2025; 21: 495–509. DOI: https://doi.org/10.1038/s41574-025-01107-x
Zhang H, Wang M, Zhao X, Wang Y, Chen X, Su J. Role of stress in skin diseases: a neuroendocrine-immune interaction view. Brain Behav Immun 2024; 116: 286–302. DOI: https://doi.org/10.1016/j.bbi.2023.12.005
Wu Z, Wu C, Chen X, Qian Q, Yao Z. Bidirectional relationship between atopic dermatitis and psychiatric comorbidities in individuals of European ancestry: a Mendelian randomization study. Acta Derm Venereol 2025; 105: adv43133. DOI: https://doi.org/10.2340/actadv.v105.43133
Wu JY, Wang YS, Hao YH, Duan CC, Xu Y, Zhou FY, et al. Antenatal depressive and anxiety symptoms in early pregnancy and offspring allergic diseases during toddlerhood. World J Pediatr 2025; 21: 478–488. DOI: https://doi.org/10.1007/s12519-025-00911-9
Romero C, Werme J, Jansen PR, Gelernter J, Stein MB, Levey D, et al. Exploring the genetic overlap between twelve psychiatric disorders. Nat Genet 2022; 54: 1795–1802. DOI: https://doi.org/10.1038/s41588-022-01245-2
Zeng Y, Chourpiliadis C, Hammar N, Seitz C, Valdimarsdóttir UA, Fang F, et al. Inflammatory biomarkers and risk of psychiatric disorders. JAMA Psychiatry 2024; 81: 1118–1129. DOI: https://doi.org/10.1001/jamapsychiatry.2024.2185
You H, Liang Y. Atopic dermatitis: the relationship between immune mediators and skin lipid barrier. Clin Rev Allergy Immunol 2025; 68: 49. DOI: https://doi.org/10.1007/s12016-025-09057-y
Guo X, Feng Y, Ji X, Jia N, Maimaiti A, Lai J, et al. Shared genetic architecture and bidirectional clinical risks within the psycho-metabolic nexus. EBioMedicine 2025; 111: 105530. DOI: https://doi.org/10.1016/j.ebiom.2024.105530
Ning Z, Pawitan Y, Shen X. High-definition likelihood inference of genetic correlations across human complex traits. Nat Genet 2020; 52: 859–864. DOI: https://doi.org/10.1038/s41588-020-0653-y
Zhu Z, Zheng Z, Zhang F, Wu Y, Trzaskowski M, Maier R, et al. Causal associations between risk factors and common diseases inferred from GWAS summary data. Nat Commun 2018; 9: 224. DOI: https://doi.org/10.1038/s41467-017-02317-2
Clarke L, Zheng-Bradley X, Smith R, Kulesha E, Xiao C, Toneva I, et al. The 1000 Genomes Project: data management and community access. Nat Methods 2012; 9: 459–462. DOI: https://doi.org/10.1038/nmeth.1974
Sudlow C, Gallacher J, Allen N, Beral V, Burton P, Danesh J, et al. UK biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age. PLoS Med 2015; 12: e1001779. DOI: https://doi.org/10.1371/journal.pmed.1001779
Deng P, Tang S, Zeng J, Lu J. Inflammatory and genetic mechanisms mediate the association between frailty and incident atopic dermatitis in middle-aged and elderly adults. Mech Ageing Dev 2026; 230: 112148. DOI: https://doi.org/10.1016/j.mad.2025.112148
Johns S, Lea-Carnall C, Shryane N, Maharani A. Depression, brain structure and socioeconomic status: A UK Biobank study. J Affect Disord 2025; 368: 295–303. DOI: https://doi.org/10.1016/j.jad.2024.09.102
Singla DR, Silver RK, Vigod SN, Schoueri-Mychasiw N, Kim JJ, La Porte LM, et al. Task-sharing and telemedicine delivery of psychotherapy to treat perinatal depression: a pragmatic, noninferiority randomized trial. Nat Med 2025; 31: 1214–1224. DOI: https://doi.org/10.1038/s41591-024-03482-w
Dutt RK, Hannon K, Easley TO, Griffis JC, Zhang W, Bijsterbosch JD. Mental health in the UK Biobank: A roadmap to self-report measures and neuroimaging correlates. Hum Brain Mapp 2022; 43: 816–832. DOI: https://doi.org/10.1002/hbm.25690
Wan J, Wang S, Shin DB, Syed MN, Abuabara K, Lemeshow AR, et al. Neuropsychiatric disorders in adults with atopic dermatitis: A population-based cohort study. J Eur Acad Dermatol Venereol 2024; 38: 543–548. DOI: https://doi.org/10.1111/jdv.19518
Julkunen H, Cichońska A, Tiainen M, Koskela H, Nybo K, Mäkelä V, et al. Atlas of plasma NMR biomarkers for health and disease in 118,461 individuals from the UK Biobank. Nat Commun 2023; 14: 604. DOI: https://doi.org/10.1038/s41467-023-36231-7
Desquilbet L, Mariotti F. Dose-response analyses using restricted cubic spline functions in public health research. Stat Med 2010; 29: 1037–1057. DOI: https://doi.org/10.1002/sim.3841
Nguyen CD, Carlin JB, Lee KJ. Practical strategies for handling breakdown of multiple imputation procedures. Emerg Themes Epidemiol 2021; 18: 5. DOI: https://doi.org/10.1186/s12982-021-00095-3
Eldjarn GH, Ferkingstad E, Lund SH, Helgason H, Magnusson OT, Gunnarsdottir K, et al. Large-scale plasma proteomics comparisons through genetics and disease associations. Nature 2023; 622: 348–358. DOI: https://doi.org/10.1038/s41586-023-06563-x
Zhao J, Stewart ID, Baird D, Mason D, Wright J, Zheng J, et al. Causal effects of maternal circulating amino acids on offspring birthweight: a Mendelian randomisation study. EBioMedicine 2023; 88: 104441. DOI: https://doi.org/10.1016/j.ebiom.2023.104441
Minhas S, Chandan JS, Knibb R, Diwakar L, Adderley N. Association between atopic disorders and mental ill health: a UK-based retrospective cohort study. BMJ Open 2025; 15: e089181. DOI: https://doi.org/10.1136/bmjopen-2024-089181
Mann C, Wollenberg A, Ständer S, Staubach P, Thaçi D, Zirpel H. Risk of developing sleep disorders and psychologic comorbidity in children with inflammatory skin diseases—A population-based study. J Am Acad Dermatol 2025; 92: 1261–1268. DOI: https://doi.org/10.1016/j.jaad.2025.02.001
Zhou J, Wu P, Cai W, Lu J, Guo Y, Teng Y, et al. The impact of maternal anxiety during pregnancy on children’s eczema and allergic rhinitis: The Ma’anshan birth cohort study. J Psychosom Res 2024; 181: 111621. DOI: https://doi.org/10.1016/j.jpsychores.2024.111621
Mo N, Yang Y, Wang W, Zhou P, Liu F, Zhang Y, et al. Causal associations between psoriasis, eczema, urticaria, and mental illness: a bidirectional Mendelian randomization study of the European population. Medicine 2024; 103: e38586. DOI: https://doi.org/10.1097/MD.0000000000038586
Antonatos C, Pontikas A, Akritidis A, Mitsoudi D, Georgiou S, Stratigos AJ, et al. A genome-wide pleiotropy study between atopic dermatitis and neuropsychiatric disorders. Hum Genomics 2025; 19: 86. DOI: https://doi.org/10.1186/s40246-025-00801-1
Momen NC, Plana-Ripoll O, Agerbo E, Benros ME, Børglum AD, Christensen MK, et al. Association between mental disorders and subsequent medical conditions. N Engl J Med 2020; 382: 1721–1731. DOI: https://doi.org/10.1056/NEJMoa1915784
Xiong Y, Xia Y, Zhang X, Jiang B, Zhang Z, Xie C, et al. Joint exposure to multiple air pollutants, genetic risk and incident psoriasis: a large-scale prospective cohort study. Br J Dermatol 2025; 192: 420–429. DOI: https://doi.org/10.1093/bjd/ljae391
Drodge DR, Budu-Aggrey A, Paternoster L. Causal analysis shows evidence of atopic dermatitis leading to an increase in vitamin D levels. J Invest Dermatol 2021; 141: 1339–1341. DOI: https://doi.org/10.1016/j.jid.2020.09.013
Chu DK, Koplin JJ, Ahmed T, Islam N, Chang CL, Lowe AJ. How to prevent atopic dermatitis (eczema) in 2024: theory and evidence. J Allergy Clin Immunol Pract 2024; 12: 1695–1704. DOI: https://doi.org/10.1016/j.jaip.2024.04.048
Slominski AT, Kim TK, Janjetovic Z, Slominski RM, Li W, Jetten AM, et al. Biological effects of CYP11A1-derived vitamin D and lumisterol metabolites in the skin. J Invest Dermatol 2024; 144: 2145–2161. DOI: https://doi.org/10.1016/j.jid.2024.04.022
Morrow MR, Batchuluun B, Wu J, Ahmadi E, Leroux JM, Mohammadi-Shemirani P, et al. Inhibition of ATP-citrate lyase improves NASH, liver fibrosis, and dyslipidemia. Cell Metab 2022; 34: 919–936. DOI: https://doi.org/10.1016/j.cmet.2022.05.004
Yu D, Richardson NE, Green CL, Spicer AB, Murphy ME, Flores V, et al. The adverse metabolic effects of branched-chain amino acids are mediated by isoleucine and valine. Cell Metab 2021; 33: 905–922. DOI: https://doi.org/10.1016/j.cmet.2021.03.025
Cameron S, Donnelly A, Broderick C, Arichi T, Bartsch U, Dazzan P, et al. Mind and skin: exploring the links between inflammation, sleep disturbance and neurocognitive function in patients with atopic dermatitis. Allergy 2024; 79: 26–36. DOI: https://doi.org/10.1111/all.15818
Dworzak MN, Fröschl G, Printz D, Fleischer C, Pötschger U, Fritsch G, et al. Skin-associated lymphocytes in the peripheral blood of patients with atopic dermatitis: signs of subset expansion and stimulation. J Allergy Clin Immunol 1999; 103: 901–906. DOI: https://doi.org/10.1016/S0091-6749(99)70436-7
Herro R, Antunes RDS, Aguilera AR, Tamada K, Croft M. The tumor necrosis factor superfamily molecule LIGHT promotes keratinocyte activity and skin fibrosis. J Invest Dermatol 2015; 135: 2109–2118. DOI: https://doi.org/10.1038/jid.2015.110
Hyun YS, Jo HA, Lee YH, Kim SM, Baek IC, Sohn HJ, et al. Comprehensive analysis of CD4+ T cell responses to CMV pp65 antigen restricted by single HLA-DR, -DQ, and -DP allotype within an individual. Front Immunol 2020; 11: 602014. DOI: https://doi.org/10.3389/fimmu.2020.602014
Cook-Mills JM, Emmerson LN. Epithelial barrier regulation, antigen sampling, and food allergy. J Allergy Clin Immunol 2022; 150: 493–502. DOI: https://doi.org/10.1016/j.jaci.2022.06.018
Dorjay Tamang JS, Banerjee S, Baidya SK, Das S, Ghosh B, Jha T, et al. An overview of matrix metalloproteinase-12 in multiple disease conditions, potential selective inhibitors, and drug designing strategies. Eur J Med Chem 2025; 283: 117154. DOI: https://doi.org/10.1016/j.ejmech.2024.117154
Pereira da Fonseca A, Traidl S, Gutzmer R, Schaper-Gerhardt K, Werfel T, Mommert S. Histamine and Th2 cytokines independently and synergistically upregulate MMP12 expression in human M2 macrophages. Front Immunol 2024; 15: 1429009. DOI: https://doi.org/10.3389/fimmu.2024.1429009
Machoń NJ, Zdanowska N, Klimek-Trojan P, Owczarczyk-Saczonek A. Vascular cell adhesion molecule 1 and E-selectin as potential cardiovascular risk biomarkers in psoriasis. Int J Mol Sci 2025; 26: 26. DOI: https://doi.org/10.3390/ijms26020792
Marinović Kulišić S, Takahashi M, Himelreich Perić M, Mužić Radović V, Jurakić Tončić R. Immunohistochemical analysis of adhesion molecules E-selectin, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 in inflammatory lesions of atopic dermatitis. Life 2023; 13: 13. DOI: https://doi.org/10.3390/life13040933
Additional Files
Published
How to Cite
License
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
All digitalized ActaDV contents is available freely online. The Society for Publication of Acta Dermato-Venereologica owns the copyright for all material published until volume 88 (2008) and as from volume 89 (2009) the journal has been published fully Open Access, meaning the authors retain copyright to their work.
Unless otherwise specified, all Open Access articles are published under CC-BY-NC licences, allowing third parties to copy and redistribute the material in any medium or format and to remix, transform, and build upon the material for non-commercial purposes, provided proper attribution to the original work.
