Genome-wide identification of cell type-specific susceptibility genes for Juvenile dermatomyositis through the analysis of N6-methyladenosine-associated SNPs.

Abstract

Genome-wide association studies (GWASs) have pinpointed genetic loci associated with juvenile dermatomyositis (JDM). Functional genes within the GWAS loci may be cell type-specific, but their identity remains largely unknown. N⁶-methyladenosine (m⁶A) plays a pivotal role in regulating various cellular processes and is linked to autoimmune diseases. This study aimed to underscore the potential functional genes within the GWAS loci through the analysis of m⁶A-associated SNPs (m⁶A-SNPs), specifically within relevant cell types. JDM-associated m⁶A-SNPs were identified from the GWAS summary dataset. The correlation between m⁶A-SNPs and gene expression was assessed through bulk tissue and single-cell eQTL analyses. To further investigate the relationship between gene expression and JDM, Mendelian randomization analysis was employed. Additionally, differential expression analyses were conducted on bulk tissues, as well as single-cell transcriptomic data comprising 6 JDM patients and 11 juvenile controls (99,396 cells). Seven m⁶A-SNPs associated with JDM were identified. Bulk tissue analysis revealed differential expression of HLA-DPA1, HLA-DPB1, MICB, HLA-A, HLA-F, HLA-DQB2, HLA-DRB5, TAP2, PSMB9, MICA, AIF1, and DDX39B influenced by m⁶A-SNPs, all showing associations with JDM in both differential expression and Mendelian randomization analyses. In single-cell analysis, the six m⁶A-SNPs within the HLA locus acted as cell-type-specific eQTLs, correlating with the expression of HLA-A, HLA-B, HLA-C, HLA-DPB1, HLA-DQA1, HLA-DQB1 and HLA-DRB1 in myeloid, T or B cells. Notably, these genes displayed abnormal expression in T, B, and myeloid cells of JDM patients. The present study identified m⁶A-SNPs within JDM susceptibility genes, shedding light on the intricate interplay between m⁶A-SNPs, gene expression, and JDM.