Genome-Wide Identification of Cell Type-Specific Susceptibility Genes for SLE Through the Analysis of RNA Modification-Associated SNPs

This study aimed to elucidate the functional genes associated with systemic lupus erythematosus (SLE) in various cell types through the utilization of RNAm-SNPs. Utilizing large-scale genetic data, we identified associations between RNAm-SNPs and SLE. The association between RNAm-SNPs and bulk and single-cell mRNA expression (eQTL) and protein levels (pQTL) were examined. Mendelian randomization and differential expression analyses were conducted to explore the links between gene expression, protein levels, and SLE. We identified 41 RNAm-SNPs that were significantly associated with SLE. The GWAS signals exhibited notable enrichment in m⁶A-SNPs and m⁷G-SNPs. These RNAm-SNPs showed both eQTL and pQTL effects. In our single-cell analysis, 16 RNAm-SNPs exhibited associations with gene expression levels across 13 distinct cell types, including <i>HLA-A, HLA-B, HLA-C, HLA-DQA1, HLA-DQB1, HLA-DRB1</i> and <i>IRF7</i>. We identified 58 noteworthy associations between the expression levels of 20 genes and SLE across 12 distinct immune cell types. Notably, <i>HLA-DQB1, HLA-DRB1</i> and <i>IRF7</i> exhibited abnormalities in CD8+ T cells, <i>IRF7</i> displayed abnormal expression in CD4+ T cells, while <i>HLA-DRB1</i> and <i>IRF7</i> were also distinctly perturbed in natural killer cells. This study advances our understanding of the genetic basis of SLE by highlighting the significance of RNAm-SNPs and immune cell gene expression in SLE.