{"doi":"10.17615/grnx-4j28","title":"Integrative analysis of 3604 GWAS reveals multiple novel cell type-specific regulatory associations","abstract":"Background: Genome-wide association study (GWAS) single nucleotide polymorphisms (SNPs) are known to preferentially co-locate to active regulatory elements in tissues and cell types relevant to disease aetiology. Further characterisation of associated cell type-specific regulation can broaden our understanding of how GWAS signals may contribute to disease risk. Results: To gain insight into potential functional mechanisms underlying GWAS associations, we developed FORGE2 (https://forge2.altiusinstitute.org/), which is an updated version of the FORGE web tool. FORGE2 uses an expanded atlas of cell type-specific regulatory element annotations, including DNase I hotspots, five histone mark categories and 15 hidden Markov model (HMM) chromatin states, to identify tissue- and cell type-specific signals. An analysis of 3,604 GWAS from the NHGRI-EBI GWAS catalogue yielded at least one significant disease/trait-tissue association for 2,057 GWAS, including > 400 associations specific to epigenomic marks in immune tissues and cell types, > 30 associations specific to heart tissue, and > 60 associations specific to brain tissue, highlighting the key potential of tissue- and cell type-specific regulatory elements. Importantly, we demonstrate that FORGE2 analysis can separate previously observed accessible chromatin enrichments into different chromatin states, such as enhancers or active transcription start sites, providing a greater understanding of underlying regulatory mechanisms. Interestingly, tissue-specific enrichments for repressive chromatin states and histone marks were also detected, suggesting a role for tissue-specific repressed regions in GWAS-mediated disease aetiology. Conclusion: In summary, we demonstrate that FORGE2 has the potential to uncover previously unreported disease-tissue associations and identify new candidate mechanisms. FORGE2 is a transparent, user-friendly web tool for the integrative analysis of loci discovered from GWAS.","journal":"UNC Libraries","year":2024,"id":498978,"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":0.9401,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":14757,"name":"Qing Lan","orcid":"0000-0001-9302-6805","position":1,"is_corresponding":false},{"id":632212,"name":"Andrew E. Teschendorff","orcid":"0000-0001-7410-6527","position":2,"is_corresponding":false},{"id":18775,"name":"J Stamatoyannopoulos","orcid":"0000-0002-2664-5769","position":3,"is_corresponding":false},{"id":19904,"name":"Ian Dunham","orcid":"0000-0003-2525-5598","position":4,"is_corresponding":false},{"id":227392,"name":"Guillaume Bourque","orcid":"0000-0002-3933-9656","position":5,"is_corresponding":false},{"id":271314,"name":"Jenny van Dongen","orcid":"0000-0003-2063-8741","position":6,"is_corresponding":false},{"id":11627,"name":"Eric Haugen","orcid":"0000-0001-7444-8981","position":7,"is_corresponding":false},{"id":21999,"name":"Sonja I. Berndt","orcid":"0000-0001-5230-0652","position":8,"is_corresponding":false},{"id":360915,"name":"Nathaniel Rothman","orcid":"0000-0002-0866-9943","position":9,"is_corresponding":false},{"id":555743,"name":"Charles E. Breeze","orcid":"0000-0002-5294-915X","position":10,"is_corresponding":false},{"id":24742,"name":"Nora Franceschini","orcid":"0009-0001-8346-3662","position":11,"is_corresponding":false},{"id":51473,"name":"Stephan Beck","orcid":"0000-0001-5290-2151","position":12,"is_corresponding":false},{"id":54982,"name":"Andy Reynolds","orcid":null,"position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-19T02:09:45.971055Z","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":[]}