Abstract
BackgroundPsoriasis is a complex multi-factorial disease, involving both genetic susceptibilities and environmental triggers. Genome-wide association studies (GWAS) and epigenome-wide association studies (EWAS) have been carried out to identify genetic and epigenetic variants that are associated with psoriasis. However, these loci cannot fully explain the disease pathogenesis.MethodsTo achieve a comprehensive mechanistic understanding of psoriasis, we conducted a systems biology study, integrating multi-omics datasets including GWAS, EWAS, tissue-specific transcriptome, expression quantitative trait loci (eQTLs), gene networks, and biological pathways to identify the key genes, processes, and networks that are genetically and epigenetically associated with psoriasis risk.ResultsThis integrative genomics study identified both well-characterized (e.g., the IL17 pathway in both GWAS and EWAS) and novel biological processes (e.g., the branched chain amino acid catabolism process in GWAS and the platelet and coagulation pathway in EWAS) involved in psoriasis. Finally, by utilizing tissue-specific gene regulatory networks, we unraveled the interactions among the psoriasis-associated genes and pathways in a tissue-specific manner and detected potential key regulatory genes in the psoriasis networks.ConclusionsThe integration and convergence of multi-omics signals provide deeper and comprehensive insights into the biological mechanisms associated with psoriasis susceptibility.
Highlights
Psoriasis is a complex multi-factorial disease, involving both genetic susceptibilities and environmental triggers
Modules from normal skins can be disrupted in disease conditions, and pathogenic modules may uniquely form in psoriatic skins; both types of modules can be informative for disease pathogenesis
These modules were involved in diverse biological processes, such as “IL12 pathway”, “T Cell Receptor (TCR) signaling”, and “branched chain amino acid (BCAA) catabolism” (Additional file 1: Table S3)
Summary
Psoriasis is a complex multi-factorial disease, involving both genetic susceptibilities and environmental triggers. In addition to genetic factors, environmental factors such as Conventional GWAS and EWAS examine individual genetic and epigenetic markers one at a time and typically only reveal a small number of top signals due to severe multiple testing penalty. As such, they are not adequately powered to identify genes and loci with moderate to subtle effect sizes that are part of the missing heritability [6], nor are they designed to investigate tissue-specific gene-gene (2019) 13:8 interactions that are increasingly recognized to play critical roles in complex disease development [7,8,9]. GWAS and EWAS of psoriasis have not been comprehensively examined for inter-connections or compared for commonalities and differences in the mechanistic insights inferred
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