{
  "abstract": "Bulk-tissue transcriptome-wide association studies (TWAS) have identified colorectal cancer (CRC) susceptibility genes, but cell-type-specific regulatory mechanisms remain poorly understood. Here, we performed single-cell TWAS integrating matched germline genotypes and single-cell transcriptomes from normal colorectal mucosa (381 donors) and polyps (84 donors), cell-type-specific chromatin accessibility, and GWAS from 132,261 cases and 1,752,398 controls. We identified 546 gene-cell-type associations implicating 347 candidate susceptibility genes across seven normal and nine polyp epithelial populations, including 213 previously unreported genes, with 74% exhibiting cell-type-specific associations. Integrated co-expression and ChIP-seq analyses revealed distinct TF-risk gene networks, highlighting GATA6, MAX and RAD21 in normal mucosa, and TFAP4- and CEBPB-associated networks in premalignant polyp populations. Further multi-omics analyses supported dysregulation of 233 genes (67%), while drug-target analyses identified 63 potentially druggable genes. DepMap and CRISPR Cas9 analyses implicated 35 genes in CRC cell viability. These findings reveal cell-type-specific susceptibility mechanisms and prioritize candidate therapeutic targets for CRC prevention.",
  "abstract_shown": true,
  "affiliations": [
    "Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashvil"
  ],
  "article_type": "PUBLISHAHEADOFPRINT",
  "arxiv": null,
  "author_total": 29,
  "authors": [
    {
      "name": "Q. Li"
    },
    {
      "name": "C. Li"
    },
    {
      "name": "L. Lyu"
    },
    {
      "name": "J. Wang"
    },
    {
      "name": "F. Yuan"
    },
    {
      "name": "E. Jeong"
    },
    {
      "name": "Q. Song"
    },
    {
      "name": "C. Yan"
    },
    {
      "name": "Y. Chen"
    },
    {
      "name": "J. Choi"
    },
    {
      "name": "S. Xu"
    },
    {
      "name": "Y. Wang"
    },
    {
      "name": "Q. Sheng"
    },
    {
      "name": "W. Wen"
    },
    {
      "name": "M. J. Shrubsole"
    },
    {
      "name": "Q. Cai"
    },
    {
      "name": "X.-O. Shu"
    },
    {
      "name": "G. Gao"
    },
    {
      "name": "B. Singh"
    },
    {
      "name": "Z. Yin"
    },
    {
      "name": "L. A. Coburn"
    },
    {
      "name": "K. K. Ciombor"
    },
    {
      "name": "C. Eng"
    },
    {
      "name": "J. A. Bauer"
    },
    {
      "name": "U. Peters"
    },
    {
      "name": "K. T. Wilson"
    },
    {
      "name": "W. Zheng"
    },
    {
      "name": "K. S. Lau"
    },
    {
      "affs": [
        0
      ],
      "name": "X. Guo"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/13088jea2bhrn.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.10.29.26366877",
  "fulltext_url": "https://www.medrxiv.org/content/10.64898/2026.10.29.26366877v1.full",
  "id": "13088jea2bhrn",
  "issns": [],
  "landing_url": "https://www.medrxiv.org/content/10.64898/2026.10.29.26366877v1",
  "language": "en",
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Article"
    ],
    [
      "medrxiv",
      "genetic and genomic medicine"
    ],
    [
      "openalex",
      "1311|Genetic Associations and Epidemiology"
    ]
  ],
  "openalex": "W7225041684",
  "pdf_url": "https://www.medrxiv.org/content/10.64898/2026.10.29.26366877v1.full.pdf",
  "pmcid": "PMC13734162",
  "pmid": "42990668",
  "published": "2026-10-29",
  "publisher": "Cold Spring Harbor Laboratory Preprints",
  "ris": "https://research.draconitic.com/paper/13088jea2bhrn.ris",
  "sources": [
    {
      "first_seen": "2026-11-02T12:20:44Z",
      "native_id": "10.64898/2026.10.29.26366877",
      "source": "medrxiv",
      "url": "https://www.medrxiv.org/content/10.64898/2026.10.29.26366877v1"
    },
    {
      "first_seen": "2026-11-08T12:23:48Z",
      "native_id": "PMC13734162",
      "source": "pmc",
      "url": "https://doi.org/10.64898/2026.10.29.26366877"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "medrxiv:genetic and genomic medicine",
      "subfield": "human-genetics"
    }
  ],
  "title": "Single-cell transcriptome-wide association analysis reveals epithelial cell-specific genetic susceptibility to colorectal cancer",
  "title_text": "Single-cell transcriptome-wide association analysis reveals epithelial cell-specific genetic susceptibility to colorectal cancer",
  "type": "preprint",
  "updated_at": "2026-11-08T12:23:48Z",
  "url": "https://research.draconitic.com/paper/13088jea2bhrn",
  "venue": "medRxiv",
  "versions": []
}