{"doi":"10.1101/2025.10.14.682299","title":"Genome-wide mapping of sex-associated autosomal DNA methylation in major blood cell types","abstract":"ABSTRACT Sex differences shape human physiology and disease risk, yet their autosomal epigenetic basis remains incompletely understood. Using whole genome bisulfite sequencing data from iMETHYL database (∼100 adults) across three purified blood cell types (CD4⁺ T cells, monocytes, neutrophils), we performed comprehensive mapping of cell-type specific sex-associated DNA methylation. Using genome-wide Z -test and confidence-interval method, we identified thousands of autosomal differentially methylated sites (DMSs), the majority of which were cell type-specific. We found that neutrophils exhibited pronounced female-biased hypermethylation, whereas CD4⁺ T cells and monocytes showed more balanced patterns. DMSs were enriched within gene bodies and annotated to neuronal and adhesion functions, with T-cell activation uniquely associated in CD4⁺ T cells. Transcription factor binding site enrichment indicated hematopoietic regulators, suggesting that sex-associated methylation is tightly linked to early developmental processes within blood lineages. Differentially methylated regions overlapped genome-wide association study loci for lifetime smoking, multiple sclerosis, and psoriasis, indicating convergence between sex-associated epigenetic states and genetic susceptibility. Evolutionary analysis revealed limited conservation but identified a conserved intronic CpG within FIGN . This study provides the first genome-wide, cell type-resolved map of autosomal sex-associated DNA methylation in human blood and establishes a foundation for mechanistic and translational studies in sex-informed biology and medicine. GRAPHICAL ABSTRACT","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":578089,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.6933,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":77710,"name":"Yutaka Nakachi","orcid":"0000-0003-1964-2495","position":1,"is_corresponding":false},{"id":1487779,"name":"Miki Bundo","orcid":"0000-0002-5786-0509","position":2,"is_corresponding":false},{"id":1488157,"name":"Syohei Komaki","orcid":null,"position":3,"is_corresponding":false},{"id":206569,"name":"Atsushi Shimizu","orcid":null,"position":4,"is_corresponding":false},{"id":1487780,"name":"Kazuya Iwamoto","orcid":"0000-0002-1780-692X","position":5,"is_corresponding":false},{"id":1488156,"name":"Yutaro Yanagida","orcid":null,"position":0,"is_corresponding":true}],"reference_count":73,"raw_metadata":null,"created_at":"2026-07-19T02:58:20.638044Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}