Single-Cell Transcriptome-Wide Mendelian Randomization and Colocalization Uncover Potential Immunocytes-Related Therapeutic Targets for Obesity

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

• Level A · Stronger Clinical Evidence
• Level B · Emerging clinical evidence with positive signals
• Level C · Early human research exploring benefits
• Level D · Scientific groundwork from lab and animal studies
• Emerging · Emerging topic under active research

Abstract (original English)

Weight-loss treatment is crucial for individuals with obesity to prevent various complications. The role of Immune cells in obesity has been recently recognized, whereas its translation into therapy requires identifying key target genes. We performed Mendelian randomization (MR) analysis to assess causal relationships between expression quantitative trait loci (eQTL) of 14 immune cells and obesity-related traits (obesity, body mass index and body fat percentage), and validated the results in colocalization analysis. For the putative causal genes identified by the MR and colocalization analyses, we conducted pathway enrichment, differential expressed gene (DEG) analysis and search of druggable evidence, and utilized a Tier system to prioritize drug targets for obesity. MR and colocalization evidence was observed for 1630 genes associated with one or more obesity-related traits, mainly expressed in CD4 + naive/central memory T cells and enriched in antigen processing and presentation pathways. Forty-one genes showed causal relationship with all three outcomes, among which 19 genes have not been reported for obesity previously. DEG analysis using single-cell RNA sequencing data of blood or adipose tissue indicated that the differential expression of UBE2Z in monocytes, ZCCHC7 in T cells, and FNBP4 in B cells between lean and obese individuals were consistent with the MR results. B

Evidence level

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

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