{"doi":"10.1101/gr.268482.120","title":"Human and rat skeletal muscle single-nuclei multi-omic integrative analyses nominate causal cell types, regulatory elements, and SNPs for complex traits","abstract":"Skeletal muscle accounts for the largest proportion of human body mass, on average, and is a key tissue in complex diseases and mobility. It is composed of several different cell and muscle fiber types. Here, we optimize single-nucleus ATAC-seq (snATAC-seq) to map skeletal muscle cell-specific chromatin accessibility landscapes in frozen human and rat samples, and single-nucleus RNA-seq (snRNA-seq) to map cell-specific transcriptomes in human. We additionally perform multi-omics profiling (gene expression and chromatin accessibility) on human and rat muscle samples. We capture type I and type II muscle fiber signatures, which are generally missed by existing single-cell RNA-seq methods. We perform cross-modality and cross-species integrative analyses on 33,862 nuclei and identify seven cell types ranging in abundance from 59.6% to 1.0% of all nuclei. We introduce a regression-based approach to infer cell types by comparing transcription start site-distal ATAC-seq peaks to reference enhancer maps and show consistency with RNA-based marker gene cell type assignments. We find heterogeneity in enrichment of genetic variants linked to complex phenotypes from the UK Biobank and diabetes genome-wide association studies in cell-specific ATAC-seq peaks, with the most striking enrichment patterns in muscle mesenchymal stem cells (∼3.5% of nuclei). Finally, we overlay these chromatin accessibility maps on GWAS data to nominate causal cell types, SNPs, transcription factor motifs, and target genes for type 2 diabetes signals. These chromatin accessibility profiles for human and rat skeletal muscle cell types are a useful resource for nominating causal GWAS SNPs and cell types.","journal":"Genome Research","year":2021,"id":212912,"datarank":1.8761451687562265,"base_score":4.127134385045092,"endowment":4.127134385045092,"self_citation_contribution":0.6190701577567639,"citation_network_contribution":1.2570750109994626,"self_endowment_contribution":0.6190701577567639,"citer_contribution":1.2570750109994626,"corpus_percentile":88.69033805213894,"corpus_rank":1463,"citation_count":61,"citer_count":54,"citers_with_citation_signal":46,"citers_with_endowment":46,"datacite_reuse_total":0,"is_dataset":true,"is_dataset_confidence":0.5337,"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":804094,"name":"Nandini Manickam","orcid":"0000-0001-9809-9712","position":1,"is_corresponding":false},{"id":804095,"name":"Christa Ventresca","orcid":"0000-0001-7406-2579","position":2,"is_corresponding":false},{"id":255376,"name":"Swarooparani Vadlamudi","orcid":"0000-0001-9650-768X","position":3,"is_corresponding":false},{"id":255366,"name":"Arushi Varshney","orcid":"0000-0001-9177-9707","position":4,"is_corresponding":false},{"id":288807,"name":"Vivek Rai","orcid":"0000-0002-2058-7238","position":5,"is_corresponding":false},{"id":804810,"name":"Jeremy Kaplan","orcid":null,"position":6,"is_corresponding":false},{"id":657064,"name":"Claudia Lalancette","orcid":"0000-0002-6854-4034","position":7,"is_corresponding":false},{"id":11271,"name":"Karen L. Mohlke","orcid":"0000-0001-6721-153X","position":8,"is_corresponding":false},{"id":250816,"name":"Katherine Gallagher","orcid":"0000-0002-8791-6980","position":9,"is_corresponding":false},{"id":246590,"name":"Charles Burant","orcid":"0000-0001-9189-5003","position":10,"is_corresponding":false},{"id":19898,"name":"Stephen C.J. Parker","orcid":"0000-0001-8122-0117","position":11,"is_corresponding":false},{"id":91931,"name":"Peter Orchard","orcid":"0000-0001-6097-1106","position":0,"is_corresponding":true}],"reference_count":122,"raw_metadata":null,"created_at":"2026-07-18T23:52:31.378994Z","pmid":"34815310","pmcid":"PMC8647829","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":[]}