A Multi-Omics Study of Comorbid Mechanisms Between Depression and Inflammatory Dermatoses Identifies FADS1 and TMEM258 as Therapeutic Targets.
Source: PubMed, NCBI / U.S. National Library of Medicine
Emerging evidence indicates a robust association between inflammatory dermatoses and mental disorders, likely driven by their combined impact on health and shared pathogenic mechanisms. Establishing the causal relationships between these two types of diseases and investigating their comorbid mechanisms. We performed two-sample Mendelian randomization (TSMR) analyses using genome-wide association study (GWAS) summary statistics, examining causal links between six mental disorders and seven inflammatory dermatoses. To elucidate the underlying molecular basis, we implemented an integrative multi-omics framework comprising summary data-based Mendelian randomization (SMR), three-step SMR, TSMR, Bayesian colocalization, gene enrichment analysis and RNA sequencing data analysis. Meta-analysis and multiple testing correction revealed that genetic predisposition to depression increases the risk of psoriasis, while atopic dermatitis is causally associated with a higher risk of depression. Furthermore, we identified 14 genes potentially mediating the comorbidity between inflammatory dermatoses and mental disorders. Functional enrichment analyses and immune cell colocalization suggested the involvement of immunological pathways. Differential expression of several candidate genes was validated in transcriptomic datasets derived from affected tissues. Mediation analyses identified specific mediators and established their causal relationships with the identified genes. Finally, using geneti
Abstract
Emerging evidence indicates a robust association between inflammatory dermatoses and mental disorders, likely driven by their combined impact on health and shared pathogenic mechanisms. Establishing the causal relationships between these two types of diseases and investigating their comorbid mechanisms. We performed two-sample Mendelian randomization (TSMR) analyses using genome-wide association study (GWAS) summary statistics, examining causal links between six mental disorders and seven inflammatory dermatoses. To elucidate the underlying molecular basis, we implemented an integrative multi-omics framework comprising summary data-based Mendelian randomization (SMR), three-step SMR, TSMR, Bayesian colocalization, gene enrichment analysis and RNA sequencing data analysis. Meta-analysis and multiple testing correction revealed that genetic predisposition to depression increases the risk of psoriasis, while atopic dermatitis is causally associated with a higher risk of depression. Furthermore, we identified 14 genes potentially mediating the comorbidity between inflammatory dermatoses and mental disorders. Functional enrichment analyses and immune cell colocalization suggested the involvement of immunological pathways. Differential expression of several candidate genes was validated in transcriptomic datasets derived from affected tissues. Mediation analyses identified specific mediators and established their causal relationships with the identified genes. Finally, using genetic evidence and druggability assessments, we prioritized the therapeutic potential of these genes. Causal relationships exist between various inflammatory dermatoses and mental disorders, with the most significant associations observed between depression and psoriasis, as well as between atopic dermatitis and depression. Fourteen genes are implicated in their comorbid mechanisms, with FADS1 and TMEM258 exhibiting the greatest potential as therapeutic targets.