{"doi":"10.1101/2021.01.13.426472","title":"Large-scale genetic association and single cell accessible chromatin mapping defines cell type-specific mechanisms of type 1 diabetes risk","abstract":"ABSTRACT Translating genome-wide association studies (GWAS) of complex disease into mechanistic insight requires a comprehensive understanding of risk variant effects on disease-relevant cell types. To uncover cell type-specific mechanisms of type 1 diabetes (T1D) risk, we combined genetic association mapping and single cell epigenomics. We performed the largest to-date GWAS of T1D in 489,679 samples imputed into 59.2M variants, which identified 74 novel association signals including several large-effect rare variants. Fine-mapping of 141 total signals substantially improved resolution of causal variant credible sets, which primarily mapped to non-coding sequence. To annotate cell type-specific regulatory mechanisms of T1D risk variants, we mapped 448,142 candidate cis- regulatory elements (cCREs) in pancreas and peripheral blood mononuclear cell types using snATAC-seq of 131,554 nuclei. T1D risk variants were enriched in cCREs active in CD4+ T cells as well as several additional cell types including pancreatic exocrine acinar and ductal cells. High-probability T1D risk variants at multiple signals mapped to exocrine-specific cCREs including novel loci near CEL, GP2 and CFTR . At the CFTR locus, the likely causal variant rs7795896 mapped in a ductal-specific distal cCRE which regulated CFTR and the risk allele reduced transcription factor binding, enhancer activity and CFTR expression in ductal cells. These findings support a role for the exocrine pancreas in T1D pathogenesis and highlight the power of combining large-scale GWAS and single cell epigenomics to provide insight into the cellular origins of complex disease.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":215309,"datarank":0.3714992614060415,"base_score":1.9459101490553132,"endowment":1.9459101490553132,"self_citation_contribution":0.29188652235829704,"citation_network_contribution":0.07961273904774449,"self_endowment_contribution":0.29188652235829704,"citer_contribution":0.07961273904774449,"corpus_percentile":null,"corpus_rank":null,"citation_count":6,"citer_count":6,"citers_with_citation_signal":5,"citers_with_endowment":5,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.6862,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":323899,"name":"Ryan J. Geusz","orcid":"0000-0002-4897-9305","position":1,"is_corresponding":false},{"id":617299,"name":"Mei-Lin Okino","orcid":null,"position":2,"is_corresponding":false},{"id":229829,"name":"Jee Yun Han","orcid":null,"position":3,"is_corresponding":false},{"id":23914,"name":"Michael Miller","orcid":"0000-0003-0781-7868","position":4,"is_corresponding":false},{"id":587344,"name":"Paola Benaglio","orcid":null,"position":5,"is_corresponding":false},{"id":616026,"name":"Serina Huang","orcid":"0000-0002-0126-3502","position":6,"is_corresponding":false},{"id":23918,"name":"Katha Korgaonkar","orcid":null,"position":7,"is_corresponding":false},{"id":616027,"name":"Sandra Heller","orcid":"0000-0002-8704-2646","position":8,"is_corresponding":false},{"id":266366,"name":"Alexander Kleger","orcid":"0000-0003-0592-5232","position":9,"is_corresponding":false},{"id":23930,"name":"Sebastian Preissl","orcid":"0000-0001-8971-5616","position":10,"is_corresponding":false},{"id":42996,"name":"David U. Gorkin","orcid":"0000-0003-4944-4107","position":11,"is_corresponding":false},{"id":7364,"name":"Maike Sander","orcid":"0000-0001-5308-7785","position":12,"is_corresponding":false},{"id":16068,"name":"Kyle J. Gaulton","orcid":"0000-0003-1318-7161","position":13,"is_corresponding":false},{"id":23921,"name":"Joshua Chiou","orcid":"0000-0002-4618-0647","position":0,"is_corresponding":true}],"reference_count":108,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:52:55.971300Z","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":[]}