Acne is a chronic inflammatory skin disease that affects the pilosebaceous follicle and is influenced by heredity, hormones, inflammation, and the environment. At present, the recognized pathogenesis mainly includes four categories: excessive sebum secretion, excessive Cutibacterium acnes proliferation, excessive keratinization of sebaceous glands in hair follicles, and inflammatory mechanisms. Previous studies have found that DNA methylation is closely related to some chronic inflammatory skin diseases, and there is evidence that DNA methylation is controlled by genetic factors, making us want to know the relationship between DNA methylation, genetic variation and acne. In our previous study, we performed genome-wide DNA methylation analysis in peripheral blood samples from 44 patients with severe acne and 44 unaffected normal subjects, and identified 23 differentially methylated probes (DMPs). In this study, we identified single nucleotide polymorphisms (SNPs) associated with severe acne by genome-wide association analysis in these 88 samples. To test the association between SNPs and DMPs, we conducted DNA methylation quantitative trait loci (methQTL) analysis. Next, causal inference testing (CIT) was used to determine whether genetic variation influences DNA methylation, which impacts disease phenotypes. We found 38,269 SNPs associated with severe acne. By methQTL analysis, we obtained 24 SNP-CpG pairs that reached the threshold (FDR < 0.05), which included 7 unique CpGs and 22 unique methQTL SNPs. After CIT analysis, we found that 11 out of 24 pairs of SNP-CpG showed a weakened SNP effect after adjustment for methylation, indicating a methylation-mediated relationship between SNPs and severe acne. These 11 SNP-CpG pairs consist of four unique CpG sites and 11 SNPs, of which three CpG sites, cg03020863, cg20652636, and cg19964325, are located on the gene body of PDGFD, the intron of SH2D6, and the 5'UTR of the IL1R1 gene, respectively. During this study, the DNA methylation of certain genes was found to be influenced by genetic factors and mediated the risk of severe acne in a young Chinese male population, providing a new perspective on the pathogenesis of severe acne.