Integrated analyses of single-cell transcriptome and Mendelian randomization reveal the protective role of FCRL3 in multiple sclerosis

• Published in: Frontiers in immunology 2024-07, Vol.15, p.1428962
• Main Authors: Yu, Kefu, Jiang, Ruiqi, Li, Ziming, Ren, Xiaohui, Jiang, Haihui, Zhao, Zhigang
• Format: Article
• Language: English
• Subjects: biomarkers; colocalization; Gene Expression Profiling; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Immunology; Mendelian randomization; Mendelian Randomization Analysis; multiple sclerosis; Multiple Sclerosis - genetics; Multiple Sclerosis - immunology; pharmaceutical targets; Polymorphism, Single Nucleotide; Quantitative Trait Loci; Receptors, Immunologic - genetics; Receptors, Immunologic - metabolism; Single-Cell Analysis; single-cell transcriptome; Transcriptome
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2024.1428962

Multiple sclerosis (MS) represents a multifaceted autoimmune ailment, prompting the development and widespread utilization of numerous therapeutic interventions. However, extant medications for MS have proven inadequate in mitigating relapses and halting disease progression. Innovative drug targets for preventing multiple sclerosis are still required. The objective of this study is to discover novel therapeutic targets for MS by integrating single-cell transcriptomics and Mendelian randomization analysis. The study integrated MS genome-wide association study (GWAS) data, single-cell transcriptomics (scRNA-seq), expression quantitative trait loci (eQTL), and protein quantitative trait loci (pQTL) data for analysis and utilized two-sample Mendelian randomization study to comprehend the causal relationship between proteins and MS. Sequential analyses involving colocalization and Phenome-wide association studies (PheWAS) were conducted to validate the causal role of candidate genes. Following stringent quality control preprocessing of scRNA-seq data, 1,123 expression changes across seven peripheral cell types were identified. Among the seven most prevalent cell types, 97 genes exhibiting at least one eQTL were discerned. Examination of MR associations between 28 proteins with available index pQTL signals and the risk of MS outcomes was conducted. Co-localization analyses and PheWAS indicated that FCRL3 may exert influence on MS. The integration of scRNA-seq and MR analysis facilitated the identification of potential therapeutic targets for MS. Notably, FCRL3, implicated in immune function, emerged as a significant drug target in the deCODE databases. This research underscores the importance of FCRL3 in MS therapy and advocates for further investigation and clinical trials targeting FCRL3.