Fig. 4: cis and trans DNA methylation effects of MS MHC polygenic score.

a Manhattan plot shows association p-values between CpG methylation levels and MS-associated MHC polygenic score. Red horizontal line shows the significance threshold (FDR < 5%). Top CpGs in the two significant regions are specified. b t-statistics for positive and negative associations between the methylation levels of the CpGs located inside the extended MHC region and the MHC polygenic score are shown (red: positive, blue: negative). The inset illustrates the genomic location of the significant CpGs in the MHC class II region in relation to nearby CpGs, genes, and modeled chromatin states. Blue/red vertical lines represent the locations for CpGs with negative/positive associations with the MHC polygenic score, respectively. Association between the top identified CpG, cg09139047 located in the HLA-DRB1 gene, and MHC polygenic score (shown in Z-scores) is visualized in the top right corner. Colors represent the number of HLA-DRB1*1501 alleles. c The genomic location for cg03805787 (associated with the MHC polygenic score in chromosome 17, red vertical line) is shown in relation to surrounding CpGs, genes, and modeled chromatin states. Bottom panel illustrates the association between cg03805787 methylation levels (M-values) and MHC polygenic score (Z-scores) in our main study of MS subjects, as well as the replication in the healthy subjects of the PhenoGenetic study. Error bands (b, c) represent 95% confidence interval. MHC = Major Histocompatibility Complex.