{
  "abstract": "Understanding how genetic variation influences gene regulation at the single-cell level is crucial for elucidating the mechanisms underlying complex diseases. However, limited large-scale single-cell multi-omics data have constrained our understanding of the regulatory pathways linking variants to cell type-specific gene expression. Here we present chromatin accessibility profiles from 3.5 million peripheral blood mononuclear cells (PBMCs) across 1,042 donors, generated using single-cell ATAC-seq, including ∼100,000 PBMCs from 90 donors using multiome (RNA+ATAC) sequencing, with matched whole-genome sequencing. We identified 440,996 chromatin peaks across 28 immune cell types and mapped 243,225 chromatin accessibility quantitative trait loci (caQTLs), of which 60% were cell type-specific. Rare variant analysis revealed associations with 27,927 peaks, recapitulating the same cell type-specific regulatory architecture. Colocalization with the eQTLs from scRNA-seq data (5.4 million PBMCs) identified 31,688 candidate cis -regulatory elements; around half (44.40%) show evidence of putative mediating effects via chromatin accessibility. Integrating caQTLs with GWAS summary statistics for 16 diseases and 44 blood traits uncovered 4.5% - 22.6% more colocalized signals compared with using eQTLs alone, many of which have not been reported in prior studies. We show that the limited concordance between GWAS and eQTL signals can be substantially improved by incorporating cell type– and tissue-specific context, distal regulatory effects, models allowing for multiple causal variants, and promoter/enhancer priming, together increasing overlap from ∼20% to ∼60%. In addition, using a graph neural network, we inferred peak-to-gene relationships from unpaired multiome data by integrating caQTL and eQTL signals, achieving up to 80% higher accuracy than with paired multiome data lacking QTL information. This gain translated into improved gene regulatory network inference, enabling the identification of 128 additional transcription factors (TF)–target gene pairs (a 22% increase). Together, these results provide a comprehensive single-cell map of chromatin accessibility and genetic variation in human circulating immune cells, establishing a powerful resource for dissecting cell type-specific regulation and advancing our understanding of genetic risk for complex diseases.",
  "abstract_shown": true,
  "affiliations": [
    "Faculty of Medicine and Health, University of New South Wales, Sydney, New South Wales, Australia. a.xue@garvan.org.au",
    "Translational Genomics Program, Garvan Institute of Medical Research, Sydney, New South Wales, Australia. a.xue@garvan.org.au",
    "Faculty of Medicine and Health, University of New South Wales, Sydney, New South Wales, Australia",
    "Translational Genomics Program, Garvan Institute of Medical Research, Sydney, New South Wales, Australia",
    "Faculty of Science, University of Sydney, Sydney, New South Wales, Australia",
    "UNSW Cellular Genomics Futures Institute, University of New South Wales, Sydney, New South Wales, Australia",
    "Illumina Artificial Intelligence Laboratory, Illumina, San Diego, CA, USA",
    "Centre for Population Genomics, Garvan Institute of Medical Research, Sydney, New South Wales, Australia",
    "Centre for Population Genomics, Murdoch Children's Research Institute, Melbourne, Victoria, Australia",
    "Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia",
    "Genomics and Inherited Disease Program, Garvan Institute of Medical Research, Sydney, New South Wales, Australia",
    "Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA",
    "Harvard Medical School, Boston, MA, USA",
    "Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA",
    "Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland",
    "Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA",
    "Massachusetts General Hospital, Boston, MA, USA",
    "The Broad Institute of MIT and Harvard, Cambridge, MA, USA",
    "The Kinghorn Cancer Centre, St Vincent's Hospital, Sydney, New South Wales, Australia",
    "Novo Nordisk Foundation Center for Genomic Mechanisms of Disease, Broad Institute of MIT and Harvard, Cambridge, MA, USA",
    "Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA",
    "Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA",
    "Charles Perkins Centre, University of Sydney, Sydney, New South Wales, Australia",
    "Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney, New South Wales, Australia",
    "Department of Ophthalmology, Royal Hobart Hospital, Hobart, Tasmania, Australia",
    "Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia",
    "Faculty of Medicine and Health, University of New South Wales, Sydney, New South Wales, Australia. j.powell@garvan.org.au",
    "Translational Genomics Program, Garvan Institute of Medical Research, Sydney, New South Wales, Australia. j.powell@garvan.org.au",
    "UNSW Cellular Genomics Futures Institute, University of New South Wales, Sydney, New South Wales, Australia. j.powell@garvan.org.au"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 31,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Angli Xue",
      "orcid": "0000-0002-0285-0426"
    },
    {
      "affs": [
        2,
        3
      ],
      "name": "Jianan Fan"
    },
    {
      "affs": [
        4,
        3
      ],
      "name": "Oscar A Dong",
      "orcid": "0009-0009-8275-2989"
    },
    {
      "affs": [
        2,
        3,
        5
      ],
      "name": "Hao Lawrence Huang",
      "orcid": "0000-0001-8960-8941"
    },
    {
      "affs": [
        6
      ],
      "name": "Ling Chen",
      "orcid": "0009-0005-1326-4069"
    },
    {
      "affs": [
        2,
        3
      ],
      "name": "Peter C. Allen",
      "orcid": "0000-0002-3950-9539"
    },
    {
      "affs": [
        2,
        3
      ],
      "name": "Eleanor Spenceley",
      "orcid": "0009-0000-5543-2810"
    },
    {
      "affs": [
        3
      ],
      "name": "Eszter Sagi-Zsigmond",
      "orcid": "0000-0002-7703-2153"
    },
    {
      "affs": [
        2,
        3
      ],
      "name": "Blake Bowen"
    },
    {
      "affs": [
        2,
        3
      ],
      "name": "Albert Henry",
      "orcid": "0000-0001-7422-2288"
    },
    {
      "affs": [
        7,
        8,
        2,
        3,
        5
      ],
      "name": "Anna S. E. Cuomo",
      "orcid": "0000-0001-5168-6979"
    },
    {
      "affs": [
        7,
        8,
        2,
        9
      ],
      "name": "Hope A. Tanudisastro",
      "orcid": "0000-0002-4561-305X"
    },
    {
      "affs": [
        2,
        10,
        3
      ],
      "name": "Zhen Qiao"
    },
    {
      "affs": [
        11,
        12,
        13
      ],
      "name": "Elizabeth Dorans",
      "orcid": "0000-0002-8360-9764"
    },
    {
      "affs": [
        6
      ],
      "name": "Eyal David",
      "orcid": "0000-0002-9020-2364"
    },
    {
      "affs": [
        6
      ],
      "name": "Kyle Kai‐How Farh",
      "orcid": "0000-0001-6947-8537"
    },
    {
      "affs": [
        14,
        13,
        15
      ],
      "name": "Linfeng Hu"
    },
    {
      "affs": [
        14,
        13,
        15
      ],
      "name": "Yijia Christiana Liu",
      "orcid": "0009-0001-2078-651X"
    },
    {
      "affs": [
        3
      ],
      "name": "Drew R. Neavin",
      "orcid": "0000-0002-1783-6491"
    },
    {
      "affs": [
        16,
        17
      ],
      "name": "Arthur S. Lee",
      "orcid": "0000-0002-4513-4630"
    },
    {
      "affs": [
        2,
        3
      ],
      "name": "Anne Senabouth",
      "orcid": "0000-0002-8798-9821"
    },
    {
      "affs": [
        3
      ],
      "name": "Caitlin Bartie"
    },
    {
      "affs": [
        3
      ],
      "name": "Rachael A. McCloy",
      "orcid": "0000-0001-7791-4044"
    },
    {
      "affs": [
        2,
        18,
        3
      ],
      "name": "Venessa T. Chin",
      "orcid": "0000-0002-4630-4451"
    },
    {
      "affs": [
        14,
        19,
        13,
        20,
        15
      ],
      "name": "Wei Zhou",
      "orcid": "0000-0001-7719-0859"
    },
    {
      "affs": [
        21,
        11,
        13
      ],
      "name": "Alkes L. Price",
      "orcid": "0000-0002-2971-7975"
    },
    {
      "affs": [
        7,
        8
      ],
      "name": "Katrina M. de Lange"
    },
    {
      "affs": [
        22,
        23
      ],
      "name": "Gemma A. Figtree"
    },
    {
      "affs": [
        24,
        25
      ],
      "name": "Alex William Hewitt",
      "orcid": "0000-0002-5123-5999"
    },
    {
      "affs": [
        7,
        8,
        2
      ],
      "name": "Daniel G. MacArthur",
      "orcid": "0000-0002-5771-2290"
    },
    {
      "affs": [
        26,
        27,
        28
      ],
      "name": "Joseph E. Powell",
      "orcid": "0000-0002-5070-4124"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/a45j42yhtzz6w.bib",
  "cited_by": 8,
  "doi": "10.1038/s41586-026-11173-4",
  "fulltext_url": null,
  "id": "a45j42yhtzz6w",
  "issns": [
    "0028-0836",
    "1476-4687"
  ],
  "landing_url": "https://doi.org/10.1038/s41586-026-11173-4",
  "language": "en",
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1312|Genomics and Chromatin Dynamics"
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  "openalex": "W7224084810",
  "pdf_url": null,
  "pmcid": null,
  "pmid": "42951970",
  "published": "2026-10-28",
  "publisher": "Nature Portfolio",
  "ris": "https://research.draconitic.com/paper/a45j42yhtzz6w.ris",
  "sources": [
    {
      "first_seen": "2026-11-04T13:21:07Z",
      "native_id": "W7224084810",
      "source": "openalex",
      "url": "https://doi.org/10.1038/s41586-026-11173-4"
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  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|Genomics and Chromatin Dynamics",
      "subfield": "molecular-biology"
    }
  ],
  "title": "Genetic variants shape single-cell chromatin accessibility and disease risk",
  "title_text": "Genetic variants shape single-cell chromatin accessibility and disease risk",
  "type": "peer-reviewed",
  "updated_at": "2026-11-04T13:21:07Z",
  "url": "https://research.draconitic.com/paper/a45j42yhtzz6w",
  "venue": "Nature",
  "versions": []
}