A Multi-Omics Study of Comorbid Mechanisms Between Depression and Inflammatory Dermatoses Identifies FADS1 and TMEM258 as Therapeutic Targets

Yibo Feng,1, Xiang Chen,1, Xinlan Qiu,1, Runlin Zhang,2 Zhiyu Cui,3 Xiaohui Mo,1 Qiang Ju1 1Department of Dermatology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 2Department of Dermatology, The First Affiliated Hospital of Harbin Medical University, Harbin, People’s Republic of China; 3Medical College, Shanxi Datong University, Datong, People’s Republic of ChinaThese authors contributed equally to this workCorrespondence: Xiaohui Mo, Department of Dermatology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Pujian Road 160, Shanghai, 200127, People’s Republic of China, Email moxiaohui2012@sina.cn Qiang Ju, Department of Dermatology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Pujian Road 160, Shanghai, 200127, People’s Republic of China, Email qiangju@aliyun.comBackground: Emerging evidence indicates a robust association between inflammatory dermatoses and mental disorders, likely driven by their combined impact on health and shared pathogenic mechanisms.Purpose: Establishing the causal relationships between these two types of diseases and investigating their comorbid mechanisms.Methods: 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.Results: 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.Conclusion: 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.Plain Language Summary: Psychodermatological disorders refer to skin diseases that are triggered or exacerbated by the interaction between skin conditions and psychological factors. These disorders include skin symptoms caused by psychological factors and psychological issues triggered by skin diseases. Both aspects intertwine, creating a vicious cycle. To date, no research has comprehensively explained the causal relationships and potential mechanisms behind the comorbidity of inflammatory skin diseases and mental disorders.Our study aims to further investigate these disorders. We examined six common mental disorders—anxiety, depression, bipolar disorder, schizophrenia, post-traumatic stress disorder, and obsessive-compulsive disorder—and seven high-prevalence inflammatory skin diseases, including acne, rosacea, hidradenitis suppurativa, atopic dermatitis, contact dermatitis, eczema, and psoriasis. Through a comprehensive analysis of 26 Genome-Wide Association Study datasets from European populations, we confirmed that depression increases the risk of psoriasis, and that there is a causal relationship between atopic dermatitis and the high risk of depression. We then used Summary-based Mendelian Randomization analysis to identify 14 genes associated with these two comorbidities. The functions of these genes were validated through a series of data at the cellular, DNA, and RNA transcription levels. Finally, we evaluated the druggability of these genes using multiple drug databases. We identified Fatty Acid Desaturase 1 (FADS1) and Transmembrane Protein 258 (TMEM258) as the most promising therapeutic targets.In summary, our findings provide new insights into the comorbid mechanisms between inflammatory skin diseases and mental disorders, paving the way for the development of targeted treatment strategies. The infographic titled ’Causal Multi-omics Framework’ outlines a series of steps involved in the framework. The first step, ’Bidirectional TSMR’, involves 26 GWAS studies focusing on conditions like psoriasis, depression and atopic dermatitis. The second step, ’SMR analysis’, examines 5 tissues and 14 selected genes. The third step, ’Sensitivity analysis’, includes 2 analyses: colocalization and TSMR. The fourth step, ’Multi-omics validation’, uses 3 methods: KEGG and GO, immune cell colocalization and RNA sequencing. The fifth step, ’Mediation analysis’, identifies 2 mediators: insomnia and unsaturated fatty acids. The final step, ’Priority ranking’, categorizes into 3 tiers based on scores: Tier 1 (score greater than or equal to 6), Tier 2 (score between 4.5 and 6) and Tier 3 (score less than 4.5), with a visual representation of total scores across tiers.Causal multi-omics: TSMR, SMR, sensitivity, validation, mediation, ranking.Keywords: inflammatory dermatoses, mental disorders, summary data-based Mendelian randomization, atopic dermatitis, psoriasis, depression