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Disentangling the complexity of psoriasis in the post-genome-wide association era

Genes & Immunity volume 24, pages 236–247 (2023)Cite this article

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Abstract

In recent years, genome-wide association studies (GWAS) have been instrumental in unraveling the genetic architecture of complex diseases, including psoriasis. The application of large-scale GWA studies in psoriasis has illustrated several associated loci that participate in the cutaneous inflammation, however explaining a fraction of the disease heritability. With the advent of high-throughput sequencing technologies and functional genomics approaches, the post-GWAS era aims to unravel the functional mechanisms underlying the inter-individual variability in psoriasis patients. In this review, we present the key advances of psoriasis GWAS in under-represented populations, rare, non-coding and structural variants and epistatic phenomena that orchestrate the interplay between different cell types. We further review the gene-gene and gene-environment interactions contributing to the disease predisposition and development of comorbidities through Mendelian randomization studies and pleiotropic effects of psoriasis-associated loci. We finally examine the holistic approaches conducted in psoriasis through system genetics and state-of-the-art transcriptomic analyses, discussing their potential implication in the expanding field of precision medicine and characterization of comorbidities.

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References

  1. Parisi R, Iskandar IYK, Kontopantelis E, Augustin M, Griffiths CEM, Ashcroft DM. National, regional, and worldwide epidemiology of psoriasis: systematic analysis and modelling study. BMJ 2020;369:m1590.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Antonatos C, Grafanaki K, Asmenoudi P, Xiropotamos P, Nani P, Georgakilas GK, et al. Contribution of the Environment, Epigenetic Mechanisms and Non-Coding RNAs in Psoriasis. Biomedicines 2022;10:1934.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Lønnberg AS, Skov L, Skytthe A, Kyvik KO, Pedersen OB, Thomsen SF. Heritability of psoriasis in a large twin sample. Br J Dermatol. 2013;169:412–6.

    Article  PubMed  Google Scholar 

  4. Capon F. The Genetic Basis of Psoriasis. IJMS 2017;18:2526.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Capon F, Trembath RC, Barker JN. An update on the genetics of psoriasis. Dermatologic Clin. 2004;22:339–47.

    Article  CAS  Google Scholar 

  6. Huang YW, Tsai TF. HLA-Cw1 and Psoriasis. Am J Clin Dermatol. 2021;22:339–47.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Tsoi LC, Stuart PE, Tian C, Gudjonsson JE, Das S, Zawistowski M, et al. Large scale meta-analysis characterizes genetic architecture for common psoriasis associated variants. Nat Commun. 2017;8:15382.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Liu Y, Helms C, Liao W, Zaba LC, Duan S, Gardner J, et al. A Genome-Wide Association Study of Psoriasis and Psoriatic Arthritis Identifies New Disease Loci. Leal SM, editor. PLoS Genet. 2008;4:e1000041.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Thibodaux RJ, Triche MW, Espinoza LR. Ustekinumab for the treatment of psoriasis and psoriatic arthritis: a drug evaluation and literature review. Expert Opin Biol Ther. 2018;18:821–7.

    Article  CAS  PubMed  Google Scholar 

  10. Lewis CM, Vassos E. Polygenic risk scores: from research tools to clinical instruments. Genome Med. 2020;12:44.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Slunecka JL, Van Der Zee MD, Beck JJ, Johnson BN, Finnicum CT, Pool R, et al. Implementation and implications for polygenic risk scores in healthcare. Hum Genomics. 2021;15:46.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Li L, Fu L, Zhang L, Feng Y. Mendelian randomization study of the genetic interaction between psoriasis and celiac disease. Sci Rep. 2022;12:21508.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Luo Q, Chen J, Qin L, Luo Y, Zhang Y, Yang X, et al. Psoriasis may increase the risk of lung cancer: a two‐sample Mendelian randomization study. Acad Dermatol Venereol. 2022;36:2113–9.

    Article  CAS  Google Scholar 

  14. Patrick MT, Stuart PE, Zhang H, Zhao Q, Yin X, He K, et al. Causal Relationship and Shared Genetic Loci between Psoriasis and Type 2 Diabetes through Trans-Disease Meta-Analysis. J Investig Dermatol. 2021;141:1493–502.

    Article  CAS  PubMed  Google Scholar 

  15. Patrick MT, Li Q, Wasikowski R, Mehta N, Gudjonsson JE, Elder JT, et al. Shared genetic risk factors and causal association between psoriasis and coronary artery disease. Nat Commun. 2022;13:6565.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Schaid DJ, Chen W, Larson NB. From genome-wide associations to candidate causal variants by statistical fine-mapping. Nat Rev Genet. 2018;19:491–504.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Trerotola M, Relli V, Simeone P, Alberti S. Epigenetic inheritance and the missing heritability. Hum Genomics. 2015;9:17.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Nair RP, Duffin KC, Helms C, Ding J, Stuart PE, Goldgar D, et al. Genome-wide scan reveals association of psoriasis with IL-23 and NF-κB pathways. Nat Genet. 2009;41:199–204.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Zhang XJ, Huang W, Yang S, Sun LD, Zhang FY, Zhu QX, et al. Psoriasis genome-wide association study identifies susceptibility variants within LCE gene cluster at 1q21. Nat Genet. 2009;41:205–10.

    Article  CAS  PubMed  Google Scholar 

  20. Sun LD, Cheng H, Wang ZX, Zhang AP, Wang PG, Xu JH, et al. Association analyses identify six new psoriasis susceptibility loci in the Chinese population. Nat Genet. 2010;42:1005–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Hirata J, Hirota T, Ozeki T, Kanai M, Sudo T, Tanaka T, et al. Variants at HLA-A, HLA-C, and HLA-DQB1 Confer Risk of Psoriasis Vulgaris in Japanese. J Investig Dermatol. 2018;138:542–8.

    Article  CAS  PubMed  Google Scholar 

  22. Sunyaev S. Impact of selection, mutation rate and genetic drift on human genetic variation. Hum Mol Genet. 2003;12:3325–30.

    Article  CAS  PubMed  Google Scholar 

  23. Li YR, Keating BJ. Trans-ethnic genome-wide association studies: advantages and challenges of mapping in diverse populations. Genome Med. 2014;6:91.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Yin X, Low HQ, Wang L, Li Y, Ellinghaus E, Han J, et al. Genome-wide meta-analysis identifies multiple novel associations and ethnic heterogeneity of psoriasis susceptibility. Nat Commun. 2015;6:6916.

    Article  CAS  PubMed  Google Scholar 

  25. Stuart PE, Tsoi LC, Nair RP, Ghosh M, Kabra M, Shaiq PA, et al. Transethnic analysis of psoriasis susceptibility in South Asians and Europeans enhances fine mapping in the MHC and genome wide. Hum Genet Genomics Adv. 2022;3:100069.

    Article  CAS  Google Scholar 

  26. Peterson RE, Kuchenbaecker K, Walters RK, Chen C-Y, Popejoy AB, Periyasamy S, et al. Genome-wide Association Studies in Ancestrally Diverse Populations: Opportunities, Methods, Pitfalls, and Recommendations. Cell. 2019;179:589–603.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Langley RGB. Psoriasis: epidemiology, clinical features, and quality of life. Ann Rheum Dis. 2005;64:ii18–23.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Lu Y, Kane S, Chen H, Leon A, Levin E, Nguyen T, et al. The Role of 39 Psoriasis Risk Variants on Age of Psoriasis Onset. ISRN Dermatol. 2013;2013:1–4.

    Article  Google Scholar 

  29. Prieto-Pérez R, Solano-López G, Cabaleiro T, Román M, Ochoa D, Talegón M, et al. Polymorphisms Associated with Age at Onset in Patients with Moderate-to-Severe Plaque Psoriasis. J Immunol Res. 2015;2015:1–8.

    Article  Google Scholar 

  30. Chen H, Poon A, Yeung C, Helms C, Pons J, Bowcock AM, et al. A Genetic Risk Score Combining Ten Psoriasis Risk Loci Improves Disease Prediction. PLoS ONE. 2011;6:e19454.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Yin X, Cheng H, Lin Y, Wineinger NE, Zhou F, Sheng Y, et al. A Weighted Polygenic Risk Score Using 14 Known Susceptibility Variants to Estimate Risk and Age Onset of Psoriasis in Han Chinese. Fang S, editor. PLoS ONE. 2015 May 1;10:e0125369.

  32. Bui A, Kumar S, Liu J, Orcales F, Gulliver S, Tsoi LC, et al. A partitioned 88-loci psoriasis genetic risk score reveals HLA and non-HLA contributions to clinical phenotypes in a Newfoundland psoriasis cohort. Front Genet. 2023;14:1141010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Bergboer JGM, Zeeuwen PLJM, Schalkwijk J. Genetics of Psoriasis: Evidence for epistatic interaction between skin barrier abnormalities and immune deviation. J Investig Dermatol. 2012;132:2320–31.

    Article  CAS  PubMed  Google Scholar 

  34. Chandra A, Lahiri A, Senapati S, Basu B, Ghosh S, Mukhopadhyay I, et al. Increased Risk of Psoriasis due to combined effect of HLA-Cw6 and LCE3 risk alleles in Indian population. Sci Rep. 2016;6:24059.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Zheng HF, Zuo XB, Lu WS, Li Y, Cheng H, Zhu KJ, et al. Variants in MHC, LCE and IL12B have epistatic effects on psoriasis risk in Chinese population. J Dermatol Sci. 2011;61:124–8.

    Article  CAS  PubMed  Google Scholar 

  36. Yanovsky RL, Chen H, Leslie S, Carrington M, Liao W. The interaction of LILRB2 with HLA-B is associated with Psoriasis susceptibility. J Investig Dermatol. 2020;140:1292–95.e3.

    Article  CAS  PubMed  Google Scholar 

  37. Ahn RS, Moslehi H, Martin MP, Abad-Santos M, Bowcock AM, Carrington M, et al. Inhibitory KIR3DL1 alleles are associated with psoriasis. Br J Dermatol. 2016;174:449–51.

    Article  CAS  PubMed  Google Scholar 

  38. Chandra A, Das S, Mazumder S, Senapati S, Chatterjee G, Chatterjee R. Functional Mapping of Genetic Interactions between HLA-Cw6 and LCE3A in Psoriasis. J Investig Dermatol. 2021;141:2630–38.e7.

    Article  CAS  PubMed  Google Scholar 

  39. Das A, Chandra A, Chakraborty J, Chattopadhyay A, Senapati S, Chatterjee G, et al. Associations of ERAP1 coding variants and domain specific interaction with HLA-C∗06 in the early onset psoriasis patients of India. Hum Immunol. 2017;78:724–30.

    Article  CAS  PubMed  Google Scholar 

  40. Genetic Analysis of Psoriasis Consortium & the Wellcome Trust Case Control Consortium 2. A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1. Nat Genet. 2010;42:985–90.

  41. Yin XY, Zhang R, Cheng H, Pan Q, Shen CB, Fan X, et al. Gene-gene interactions between HLA-C, ERAP 1, TNFAIP3 and TRAF3IP2 and the risk of psoriasis in the Chinese Han population. Br J Dermatol. 2013;169:941–3.

    Article  CAS  PubMed  Google Scholar 

  42. Wei WH, Massey J, Worthington J, Barton A, Warren RB. Genotypic variability-based genome-wide association study identifies non-additive loci HLA-C and IL12B for psoriasis. J Hum Genet. 2018;63:289–96.

    Article  CAS  PubMed  Google Scholar 

  43. Wang WJ, Yin XY, Zuo XB, Cheng H, Du WD, Zhang FY, et al. Gene-gene interactions in IL23/Th17 pathway contribute to psoriasis susceptibility in Chinese Han population: Gene-gene interactions in IL23/Th17 with psoriasis. J Eur Acad Dermatol Venereol. 2013;27:1156–62.

    Article  CAS  PubMed  Google Scholar 

  44. Zhang C, Qin Q, Li Y, Zheng X, Chen W, Zhen Q, et al. Multifactor dimensionality reduction reveals the effect of interaction between ERAP1 and IFIH1 polymorphisms in psoriasis susceptibility genes. Front Genet. 2022;13:1009589.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Sweeney CM, Tobin AM, Kirby B. Innate immunity in the pathogenesis of psoriasis. Arch Dermatol Res. 2011;303:691–705.

    Article  CAS  PubMed  Google Scholar 

  46. Birnbaum RY, Hayashi G, Cohen I, Poon A, Chen H, Lam ET, et al. Association analysis identifies ZNF750 regulatory variants in psoriasis. BMC Med Genet. 2011;12:167.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. McNab F, Mayer-Barber K, Sher A, Wack A, O’Garra A. Type I interferons in infectious disease. Nat Rev Immunol. 2015;15:87–103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Dand N, Mucha S, Tsoi LC, Mahil SK, Stuart PE, Arnold A, et al. Exome-wide association study reveals novel psoriasis susceptibility locus at TNFSF15 and rare protective alleles in genes contributing to type I IFN signalling. Hum Mol Genet. 2017;26:4301–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Li Y, Liao W, Cargill M, Chang M, Matsunami N, Feng BJ, et al. Carriers of Rare Missense Variants in IFIH1 Are Protected from Psoriasis. J Investig Dermatol. 2010;130:2768–72.

    Article  CAS  PubMed  Google Scholar 

  50. Zervou MI, Andreou AC, Eliopoulos EE, Goulielmos GN. Functional significance of the rare rs35667974 IFIH1 gene polymorphism, associated with multiple autoimmune diseases, using a structural biological approach. Autoimmunity 2022;55:455–61.

    Article  CAS  PubMed  Google Scholar 

  51. Andreou A, Papakyriakou A, Zervou MI, Goulielmos GN, Eliopoulos EE. Is the Association of the Rare rs35667974 IFIH1 Gene Polymorphism With Autoimmune Diseases a Case of RNA Epigenetics? J Mol Evol. 2023;91:204–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Yang C, Chen M, Huang H, Li X, Qian D, Hong X, et al. Exome-Wide Rare Loss-of-Function Variant Enrichment Study of 21,347 Han Chinese Individuals Identifies Four Susceptibility Genes for Psoriasis. J Investig Dermatol. 2020;140:799–805.e1.

    Article  CAS  PubMed  Google Scholar 

  53. Tang H, Jin X, Li Y, Jiang H, Tang X, Yang X, et al. A large-scale screen for coding variants predisposing to psoriasis. Nat Genet. 2014;46:45–50.

    Article  CAS  PubMed  Google Scholar 

  54. Li J, Lin H, Hou R, Shen J, Li X, Xing J, et al. Multi-omics study in monozygotic twins confirm the contribution of de novo mutation to psoriasis. J Autoimmun. 2020;106:102349.

    Article  CAS  PubMed  Google Scholar 

  55. Maurano MT, Humbert R, Rynes E, Thurman RE, Haugen E, Wang H, et al. Systematic Localization of Common Disease-Associated Variation in Regulatory DNA. Science. 2012;337:1190–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Chung CCY, Hue SPY, Ng NYT, Doong PHL, Chu ATW, Chung BHY. Meta-analysis of the diagnostic and clinical utility of exome and genome sequencing in pediatric and adult patients with rare diseases across diverse populations. Genet Med. 2023;25:100896.

    Article  CAS  PubMed  Google Scholar 

  57. Tam V, Patel N, Turcotte M, Bossé Y, Paré G, Meyre D. Benefits and limitations of genome-wide association studies. Nat Rev Genet. 2019;20:467–84.

    Article  CAS  PubMed  Google Scholar 

  58. Pajic P, Lin YL, Xu D, Gokcumen O. The psoriasis-associated deletion of late cornified envelope genes LCE3B and LCE3C has been maintained under balancing selection since Human Denisovan divergence. BMC Evol Biol. 2016;16:265.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Hollox EJ, Huffmeier U, Zeeuwen PLJM, Palla R, Lascorz J, Rodijk-Olthuis D, et al. Psoriasis is associated with increased β-defensin genomic copy number. Nat Genet. 2008;40:23–5.

    Article  CAS  PubMed  Google Scholar 

  60. Zeng X, Chen H, Gupta R, Paz-Altschul O, Bowcock AM, Liao W. Deletion of the activating NKG2C receptor and a functional polymorphism in its ligand HLA-E in psoriasis susceptibility. Exp Dermatol. 2013;22:679–81.

    Article  CAS  PubMed  Google Scholar 

  61. Ahn R, Vukcevic D, Motyer A, Nititham J, Squire DM, Hollenbach JA, et al. Large-Scale Imputation of KIR Copy Number and HLA Alleles in North American and European Psoriasis Case-Control Cohorts Reveals Association of Inhibitory KIR2DL2 With Psoriasis. Front Immunol. 2021;12:684326.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Zhen Q, Zhang Y, Yu Y, Yang H, Zhang T, Li X, et al. Three novel structural variations at the major histocompatibility complex and IL12B predispose to psoriasis*. Br J Dermatol. 2022;186:307–17.

    Article  CAS  PubMed  Google Scholar 

  63. Mukamel RE, Handsaker RE, Sherman MA, Barton AR, Zheng Y, McCarroll SA, et al. Protein-coding repeat polymorphisms strongly shape diverse human phenotypes. 2021.

  64. GTEx Consortium, Chiang C, Scott AJ, Davis JR, Tsang EK, Li X, et al. The impact of structural variation on human gene expression. Nat Genet. 2017;49:692–9.

  65. Pang H, Lin J, Luo S, Huang G, Li X, Xie Z, et al. The missing heritability in type 1 diabetes. Diabetes Obes Metab. 2022;24:1901–11.

    Article  PubMed  PubMed Central  Google Scholar 

  66. Ho SS, Urban AE, Mills RE. Structural variation in the sequencing era. Nat Rev Genet. 2020;21:171–89.

    Article  CAS  PubMed  Google Scholar 

  67. Theunissen F, Flynn LL, Anderton RS, Mastaglia F, Pytte J, Jiang L, et al. Structural Variants May Be a Source of Missing Heritability in sALS. Front Neurosci. 2020;14:47.

    Article  PubMed  PubMed Central  Google Scholar 

  68. Kainer D, Templeton AR, Prates ET, Jacboson D, Allan ERO, Climer S, et al. Structural variants identified using non-Mendelian inheritance patterns advance the mechanistic understanding of autism spectrum disorder. Hum Genet Genomics Adv. 2023;4:100150.

    Article  CAS  Google Scholar 

  69. Zhou F, Shen C, Xu J, Gao J, Zheng X, Ko R, et al. Epigenome-wide association data implicates DNA methylation-mediated genetic risk in psoriasis. Clin Epigenet. 2016;8:131.

    Article  Google Scholar 

  70. Zhou F, Wang W, Shen C, Li H, Zuo X, Zheng X, et al. Epigenome-Wide Association Analysis Identified Nine Skin DNA Methylation Loci for Psoriasis. J Investig Dermatol. 2016;136:779–87.

    Article  CAS  PubMed  Google Scholar 

  71. Zhao Y, Jhamb D, Shu L, Arneson D, Rajpal DK, Yang X. Multi-omics integration reveals molecular networks and regulators of psoriasis. BMC Syst Biol. 2019;13:8.

    Article  PubMed  PubMed Central  Google Scholar 

  72. Volkov P, Olsson AH, Gillberg L, Jørgensen SW, Brøns C, Eriksson K-F, et al. A Genome-Wide mQTL Analysis in Human Adipose Tissue Identifies Genetic Variants Associated with DNA Methylation, Gene Expression and Metabolic Traits. PLoS ONE. 2016;11:e0157776.

    Article  PubMed  PubMed Central  Google Scholar 

  73. Veenstra J, Kalsbeek A, Koster K, Ryder N, Bos A, Huisman J, et al. Epigenome wide association study of SNP–CpG interactions on changes in triglyceride levels after pharmaceutical intervention: a GAW20 analysis. BMC Proc. 2018;12:58.

    Article  PubMed  PubMed Central  Google Scholar 

  74. Stevens ML, Zhang Z, Johansson E, Ray S, Jagpal A, Ruff BP, et al. Disease-associated KIF3A variants alter gene methylation and expression impacting skin barrier and atopic dermatitis risk. Nat Commun. 2020;11:4092.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Zhang J, Tan H, Cao Q, Su G, Yang P. Meta-Analysis of miRNA Variants Associated with Susceptibility to Autoimmune Disease. Avgeris M, editor. Disease Markers. 2021;8:1–21.

  76. Rakhshan A, Zarrinpour N, Moradi A, Ahadi M, Omrani MD, Ghafouri‐Fard S, et al. A single nucleotide polymorphism within HOX Transcript Antisense RNA (HOTAIR) is associated with risk of psoriasis. Int J Immunogenet. 2020;47:430–4.

  77. Yao X, Hao S, Xue T, Zhou K, Zhang Y, Li H. Association of HOTAIR Polymorphisms with Susceptibility to Psoriasis in a Chinese Han Population. Reich A, editor. BioMed Research International. 2021;4;2021:1–5.

  78. Hao S, Zhou K, Yu P, Tian J, Zhang Y, Dang L, et al. ANRIL polymorphisms in psoriasis vulgaris patients in northern China. Eur J Dermatol. 2022;32:259–68.

    Article  CAS  PubMed  Google Scholar 

  79. Rakhshan A, Zarrinpour N, Moradi A, Ahadi M, Omrani MD, Ghafouri-Fard S, et al. Genetic variants within ANRIL (antisense non coding RNA in the INK4 locus) are associated with risk of psoriasis. Int Immunopharmacol. 2020;78:106053.

    Article  CAS  PubMed  Google Scholar 

  80. Ghafouri-Fard S, Gholipour M, Abak A, Hussen BM, Kholghi Oskooei V, Taheri M, et al. Association analysis of MALAT1 polymorphisms and risk of psoriasis among Iranian patients. Int J Immunogenet. 2022;49:83–7.

    Article  CAS  PubMed  Google Scholar 

  81. He R, Wu S, Gao R, Chen J, Peng Q, Hu H, et al. Identification of a Long Noncoding RNA TRAF3IP2-AS1 as Key Regulator of IL-17 Signaling through the SRSF10–IRF1–Act1 Axis in Autoimmune Diseases. J Immunol. 2021;206:2353–65.

    Article  CAS  PubMed  Google Scholar 

  82. Davies NM, Holmes MV, Davey Smith G. Reading Mendelian randomisation studies: a guide, glossary, and checklist for clinicians. BMJ. 2018;362:k601.

    Article  PubMed  PubMed Central  Google Scholar 

  83. Oliveira M, de FSP, de, Rocha B, de O, Duarte GV. Psoriasis: classical and emerging comorbidities. Bras Dermatol. 2015;90:9–20.

    Article  Google Scholar 

  84. Shen M, Xiao Y, Jing D, Zhang G, Su J, Lin S, et al. Associations of combined lifestyle and genetic risks with incident psoriasis: A prospective cohort study among UK Biobank participants of European ancestry. J Am Acad Dermatol. 2022;87:343–50.

    Article  PubMed  Google Scholar 

  85. Jin JQ, Elhage KG, Spencer RK, Davis MS, Hakimi M, Bhutani T, et al. Mendelian Randomization Studies in Psoriasis and Psoriatic Arthritis: A Systematic Review. J Investig Dermatol. 2023;143:762–76.e3.

    Article  CAS  PubMed  Google Scholar 

  86. Chalitsios CV, Georgiou A, Bouras E, Evangelou E, Gill D, Tsilidis KK, et al. Investigating modifiable pathways in psoriasis: A Mendelian randomization study. J Am Acad Dermatol. 2023;88:593–601.

    Article  CAS  PubMed  Google Scholar 

  87. Ren Y, Liu J, Li W, Zheng H, Dai H, Qiu G, et al. Causal Associations between Vitamin D Levels and Psoriasis, Atopic Dermatitis, and Vitiligo: A Bidirectional Two-Sample Mendelian Randomization Analysis. Nutrients 2022;14:5284.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Zhang Y, Jing D, Zhou G, Xiao Y, Shen M, Chen X, et al. Evidence of a Causal Relationship Between Vitamin D Status and Risk of Psoriasis From the UK Biobank Study. Front Nutr. 2022;9:807344.

    Article  PubMed  PubMed Central  Google Scholar 

  89. Barrea L, Savanelli MC, Di Somma C, Napolitano M, Megna M, Colao A, et al. Vitamin D and its role in psoriasis: An overview of the dermatologist and nutritionist. Rev Endocr Metab Disord. 2017;18:195–205.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. De Jong EMGJ, Mork NJ, Seijger MMB, De La Brassine M, Lauharanta J, Jansen CT, et al. The combination of calcipotriol and methotrexate compared with methotrexate and vehicle in psoriasis: results of a multicentre placebo-controlled randomized trial. Br J Dermatol. 2003;148:318–25.

    Article  PubMed  Google Scholar 

  91. Gollnick H, Altmeyer P, Kaufmann R, Ring J, Christophers E, Pavel S, et al. Topical Calcipotriol plus Oral Fumaric Acid Is More Effective and Faster Acting than Oral Fumaric Acid Monotherapy in the Treatment of Severe Chronic Plaque Psoriasis vulgaris. Dermatology 2002;205:46–53.

    Article  CAS  PubMed  Google Scholar 

  92. Thaçi D, Ortonne JP, Chimenti S, Ghislain PD, Arenberger P, Kragballe K, et al. A phase IIIb, multicentre, randomized, double-blind, vehicle-controlled study of the efficacy and safety of adalimumab with and without calcipotriol/betamethasone topical treatment in patients with moderate to severe psoriasis: the BELIEVE study: Adalimumab and topical treatment in psoriasis. Br J Dermatol. 2010;163:402–11.

    Article  PubMed  Google Scholar 

  93. Zhao P, Zhang J, Liu B, Tang Y, Wang L, Wang G, et al. Causal Effects of Circulating Cytokines on the Risk of Psoriasis Vulgaris: A Mendelian Randomization Study. Front Genet. 2022;13:941961.

    Article  PubMed  PubMed Central  Google Scholar 

  94. Zhang L, Wang Y, Qiu L, Wu J. Psoriasis and cardiovascular disease risk in European and East Asian populations: evidence from meta-analysis and Mendelian randomization analysis. BMC Med. 2022;20:421.

    Article  PubMed  PubMed Central  Google Scholar 

  95. Antonatos C, Stavrou EF, Evangelou E, Vasilopoulos Y. Exploring pharmacogenetic variants for predicting response to anti-TNF therapy in autoimmune diseases: a meta-analysis. Pharmacogenomics 2021;22:435–45.

    Article  CAS  PubMed  Google Scholar 

  96. Patrick MT, Nair RP, He K, Stuart PE, Billi AC, Zhou X, et al. Shared Genetic Risk Factors for Multiple Sclerosis/Psoriasis Suggest Involvement of Interleukin-17 and Janus Kinase-Signal Transducers and Activators of Transcription Signaling. Ann Neurol. 2023;94:384–97.

    Article  CAS  PubMed  Google Scholar 

  97. Näslund-Koch C, Bojesen SE, Gluud LL, Skov L, Vedel-Krogh S. Non-alcoholic fatty liver disease is not a causal risk factor for psoriasis: A Mendelian randomization study of 108,835 individuals. Front Immunol. 2022;13:1022460.

    Article  PubMed  PubMed Central  Google Scholar 

  98. Li WQ, Han JL, Zhang MF, Qureshi AA. Interactions between adiposity and genetic polymorphisms on the risk of psoriasis: Adiposity and genetic polymorphisms on psoriasis. Br J Dermatol. 2013;168:639–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Kisielnicka A, Sobalska-Kwapis M, Purzycka-Bohdan D, Nedoszytko B, Zabłotna M, Seweryn M, et al. The Analysis of a Genome-Wide Association Study (GWAS) of Overweight and Obesity in Psoriasis. IJMS 2022;23:7396.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Xu C, Ji J, Su T, Wang HW, Su ZL. The Association of Psoriasis and Obesity: Focusing on IL-17A-Related Immunological Mechanisms. Int J Dermatol Venereol. 2021;4:116–21.

    Article  Google Scholar 

  101. Witoelar A, Jansen IE, Wang Y, Desikan RS, Gibbs JR, Blauwendraat C, et al. Genome-wide Pleiotropy Between Parkinson Disease and Autoimmune Diseases. JAMA Neurol. 2017;74:780.

    Article  PubMed  PubMed Central  Google Scholar 

  102. Ellinghaus D, Ellinghaus E, Nair RP, Stuart PE, Esko T, Metspalu A, et al. Combined Analysis of Genome-wide Association Studies for Crohn Disease and Psoriasis Identifies Seven Shared Susceptibility Loci. Am J Hum Genet. 2012;90:636–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Tsoi LC, Spain SL, Knight J, Ellinghaus E, Stuart PE, Capon F, et al. Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity. Nat Genet. 2012;44:1341–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Zhu Z, Anttila V, Smoller JW, Lee PH. Statistical power and utility of meta-analysis methods for cross-phenotype genome-wide association studies. PLoS ONE. 2018;13:e0193256.

    Article  PubMed  PubMed Central  Google Scholar 

  105. Ogawa K, Tsoi LC, Tanaka H, Kanai M, Stuart PE, Nair RP, et al. A Cross-Trait Genetic Correlation Study Identified Eight Diseases and Traits Associated with Psoriasis. J Invest Dermatol. 2023;143:1813–16.e2.

    Article  PubMed  Google Scholar 

  106. Khunsriraksakul C, Markus H, Olsen NJ, Carrel L, Jiang B, Liu DJ. Construction and Application of Polygenic Risk Scores in Autoimmune Diseases. Front Immunol. 2022;13:889296.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Glanville KP, Coleman JRI, O’Reilly PF, Galloway J, Lewis CM. Investigating Pleiotropy Between Depression and Autoimmune Diseases Using the UK Biobank. Biol Psychiatry Glob Open Sci. 2021;1:48–58.

    Article  PubMed  PubMed Central  Google Scholar 

  108. Werner MCF, Wirgenes KV, Shadrin A, Lunding SH, Rødevand L, Hjell G, et al. Immune marker levels in severe mental disorders: associations with polygenic risk scores of related mental phenotypes and psoriasis. Transl Psychiatry. 2022;12:38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Khan Z, Di Nucci F, Kwan A, Hammer C, Mariathasan S, Rouilly V, et al. Polygenic risk for skin autoimmunity impacts immune checkpoint blockade in bladder cancer. Proc Natl Acad Sci USA. 2020;117:12288–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Merleev A, Ji-Xu A, Toussi A, Tsoi LC, Le ST, Luxardi G, et al. Proprotein convertase subtilisin/kexin type 9 is a psoriasis-susceptibility locus that is negatively related to IL36G. JCI Insight. 2022;7:e141193.

    Article  PubMed  PubMed Central  Google Scholar 

  111. Gamazon ER, Wheeler HE, Shah KP, Mozaffari SV, Aquino-Michaels K, Carroll RJ, et al. A gene-based association method for mapping traits using reference transcriptome data. Nat Genet. 2015;47:1091–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Zhu D, Yao S, Wu H, Ke X, Zhou X, Geng S, et al. A transcriptome-wide association study identifies novel susceptibility genes for psoriasis. Hum Mol Genet. 2021;31:300–8.

    Article  PubMed  Google Scholar 

  113. Jeong Y, Song J, Lee Y, Choi E, Won Y, Kim B, et al. A Transcriptome-Wide Analysis of Psoriasis: Identifying the Potential Causal Genes and Drug Candidates. IJMS. 2023;24:11717.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Li YI, van de Geijn B, Raj A, Knowles DA, Petti AA, Golan D, et al. RNA splicing is a primary link between genetic variation and disease. Science. 2016;352:600–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Zhang X, Joehanes R, Chen BH, Huan T, Ying S, Munson PJ, et al. Identification of common genetic variants controlling transcript isoform variation in human whole blood. Nat Genet. 2015;47:345–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. McGovern A, Schoenfelder S, Martin P, Massey J, Duffus K, Plant D, et al. Capture Hi-C identifies a novel causal gene, IL20RA, in the pan-autoimmune genetic susceptibility region 6q23. Genome Biol. 2016;17:212.

    Article  PubMed  PubMed Central  Google Scholar 

  117. Ray-Jones H, Duffus K, McGovern A, Martin P, Shi C, Hankinson J, et al. Mapping DNA interaction landscapes in psoriasis susceptibility loci highlights KLF4 as a target gene in 9q31. BMC Biol. 2020;18:47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Shi C, Ray-Jones H, Ding J, Duffus K, Fu Y, Gaddi VP, et al. Chromatin Looping Links Target Genes with Genetic Risk Loci for Dermatological Traits. J Investig Dermatol. 2021;141:1975–84.

    Article  CAS  PubMed  Google Scholar 

  119. Sahlén P, Spalinskas R, Asad S, Mahapatra KD, Höjer P, Anil A, et al. Chromatin interactions in differentiating keratinocytes reveal novel atopic dermatitis– and psoriasis-associated genes. J Allergy Clin Immunol. 2021;147:1742–52.

    Article  PubMed  Google Scholar 

  120. Kim SH, Oh J, Roh WS, Park J, Chung KB, Lee GH, et al. Pellino-1 promotes intrinsic activation of skin-resident IL-17A-producing T cells in psoriasis. J Allergy Clin Immunol. 2023;151:1317–28.

    Article  CAS  PubMed  Google Scholar 

  121. Jin JQ, Wu D, Spencer R, Elhage KG, Liu J, Davis M, et al. Biologic insights from single-cell studies of psoriasis and psoriatic arthritis. Expert Opin Biol Ther. 2022;22:1449–61.

    Article  CAS  PubMed  Google Scholar 

  122. Chen Y-L, Ng JSW, Ottakandathil Babu R, Woo J, Nahler J, Hardman CS, et al. Group A Streptococcus induces CD1a-autoreactive T cells and promotes psoriatic inflammation. Sci Immunol. 2023;8:eadd9232.

    Article  CAS  PubMed  Google Scholar 

  123. Frost B, Schmidt M, Klein B, Loeffler‐Wirth H, Krohn K, Reidenbach T, et al. Single‐cell transcriptomics reveals prominent expression of IL‐14, IL‐18, and IL‐32 in psoriasis. Eur J Immunol. 2023;e2250354.

  124. Liu X, Wang J, Shen L, Wang R, Zhang L, Li C. Single-cell atlas reveals a high selection of IgA1- or IgG1-expressing plasma cells in patients with psoriasis. Mol Immunol. 2023;153:85–93.

    Article  CAS  PubMed  Google Scholar 

  125. Castillo RL, Sidhu I, Dolgalev I, Chu T, Prystupa A, Subudhi I, et al. Spatial transcriptomics stratifies psoriatic disease severity by emergent cellular ecosystems. Sci Immunol. 2023;8:eabq7991.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Ma F, Plazyo O, Billi AC, Tsoi LC, Xing X, Wasikowski R, et al. Single cell and spatial sequencing define processes by which keratinocytes and fibroblasts amplify inflammatory responses in psoriasis. Nat Commun. 2023;14:3455.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Cai X, Han M, Lou F, Sun Y, Yin Q, Sun L, et al. Tenascin C+ papillary fibroblasts facilitate neuro-immune interaction in a mouse model of psoriasis. Nat Commun. 2023;14:2004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Fries A, Saidoune F, Kuonen F, Dupanloup I, Fournier N, Guerra De Souza AC, et al. Differentiation of IL-26+ TH17 intermediates into IL-17A producers via epithelial crosstalk in psoriasis. Nat Commun. 2023;14:3878.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Brandão LAC, Tricarico PM, Gratton R, Agrelli A, Zupin L, Abou-Saleh H, et al. Multiomics Integration in Skin Diseases with Alterations in Notch Signaling Pathway: PlatOMICs Phase 1 Deployment. IJMS 2021;22:1523.

    Article  PubMed  PubMed Central  Google Scholar 

  130. Argelaguet R, Arnol D, Bredikhin D, Deloro Y, Velten B, Marioni JC, et al. MOFA+: a statistical framework for comprehensive integration of multi-modal single-cell data. Genome Biol. 2020;21:111.

    Article  PubMed  PubMed Central  Google Scholar 

  131. Rao S, Yao Y, Bauer DE. Editing GWAS: experimental approaches to dissect and exploit disease-associated genetic variation. Genome Med. 2021;13:41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Krause MD, Huang R-T, Wu D, Shentu T-P, Harrison DL, Whalen MB, et al. Genetic variant at coronary artery disease and ischemic stroke locus 1p32.2 regulates endothelial responses to hemodynamics. Proc Natl Acad Sci USA. 2018;115:E11349–E11358.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Wünnemann F, Fotsing Tadjo T, Beaudoin M, Lalonde S, Lo KS, Kleinstiver BP, et al. Multimodal CRISPR perturbations of GWAS loci associated with coronary artery disease in vascular endothelial cells. PLoS Genet. 2023;19:e1010680.

    Article  PubMed  PubMed Central  Google Scholar 

  134. Pippin JA, Chesi A, Wagley Y, Su C, Pahl MC, Hodge KM, et al. CRISPR‐Cas9 –Mediated Genome Editing Confirms EPDR1 as an Effector Gene at the BMD GWAS ‐Implicated ‘ STARD3NL ’ Locus. JBMR Plus 2021;5. https://doi.org/10.1002/jbm4.10531.

  135. Li S, Li Y, Li X, Liu J, Huo Y, Wang J, et al. Regulatory mechanisms of major depressive disorder risk variants. Mol Psychiatry. 2020;25:1926–45.

    Article  PubMed  Google Scholar 

  136. Rubin AJ, Parker KR, Satpathy AT, Qi Y, Wu B, Ong AJ, et al. Coupled Single-Cell CRISPR screening and epigenomic profiling reveals causal gene regulatory networks. Cell. 2019;176:361–76.e17.

    Article  CAS  PubMed  Google Scholar 

  137. Lin X, Liu Y, Liu S, Zhu X, Wu L, Zhu Y, et al. Nested epistasis enhancer networks for robust genome regulation. Science. 2022;377:1077–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Author notes

  1. Deceased: Evangelos Evangelou.

Authors and Affiliations

  1. Laboratory of Genetics, Section of Genetics, Cell Biology and Development, Department of Biology, University of Patras, 26504, Patras, Greece

    Charalabos Antonatos & Yiannis Vasilopoulos

  2. Department of Dermatology-Venereology, School of Medicine, University of Patras, 26504, Patras, Greece

    Katerina Grafanaki & Sophia Georgiou

  3. Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, 45110, Greece

    Evangelos Evangelou

  4. Biomedical Research Institute, Foundation for Research and Technology-Hellas, 45110, Ioannina, Greece

    Evangelos Evangelou

  5. Department of Epidemiology & Biostatistics, MRC Centre for Environment and Health, Imperial College London, London, W2 1PG, UK

    Evangelos Evangelou

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Conceptualization: CA, EE, YV; Writing-original draft preparation: CA; Writing-review and editing: CA, EE, KG, SG, YV; Supervision: YV. All authors agree to the final version of the manuscript.

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Antonatos, C., Grafanaki, K., Georgiou, S. et al. Disentangling the complexity of psoriasis in the post-genome-wide association era. Genes Immun 24, 236–247 (2023). https://doi.org/10.1038/s41435-023-00222-x

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