Fig. 4

Genotype-dependent candidate DMRs that mediate genetic risk in multiple sclerosis (MS). a Summary workflow and results for identifying epigenetically mediated genetic risk factors for MS. The diagrams on the right represent the relationships between genotype (G), DNA methylation (M), and  MS (phenotype, Y). Dashed lines, the association relationship; arrows, the causal relationship. b Association between candidate genetic risk-mediating DMRs and genotype. Each dashed line represents a potential mediation relationship between an SNP and a DMR as determined by the CIT. c Association between DNA methylation levels at DMR4 chr6:32552039-32552350 (located in exon 2 of HLA-DRB1) that mediates genetic risk in MS and phenotype (top panels), with red and blue colors representing cases and controls, respectively, in blood cells (n = 279) (top left), and in sorted CD14⁺ monocytes (n = 36), CD19⁺ B cells (n = 29), CD4⁺ (n = 33), and CD8⁺ (n = 29) T cells for cg08578320 (top right), or genotype rs3135338 (bottom left panel) with blue, black, and red colors denoting AA, Aa, and aa genotypes. Bottom right panels: association between genotype (rs3135338) and phenotype and CIT. Red horizontal bars mark percentage of cases for each genotype. Coefficient (β) represents the dependence of the MS phenotype on genotype, with or without adjusting for DNA methylation. The error bars represent the 95% confidence interval for the coefficient β. In the case of the methylation-mediated model, the absolute value of the observed G:Y relationship strength reduces toward zero when adjusting for methylation. DMR: differentially methylated region, SNP: single nucleotide polymorphism, CIT: causal inference test. The full list of SNP-DMR pairs is shown in Supplementary Data 4