{"id":479,"title":"Single-cell transcriptome-wide association analysis reveals epithelial cell-specific genetic susceptibility to colorectal cancer","title_zh":"单细胞转录组关联分析揭示结直肠癌的上皮细胞特异性遗传易感性","url":"https://medrxiv.org/content/10.64898/2026.10.29.26366877v1","doi":"10.64898/2026.10.29.26366877","pmid":null,"journal":"medrxiv","kind":"preprint","lang":"en","published_at":"2026-11-01T00:00:00+00:00","fetched_at":"2026-11-08T03:44:20+00:00","authors":["Li, Q.","Li, C.","Lyu, L.","Wang, J.","Yuan, F.","Jeong, E.","Song, Q.","Yan, C.","Chen, Y.","Choi, J.","Xu, S.","Wang, Y.","Sheng, Q.","Wen, W.","Shrubsole, M. J.","Cai, Q.","Shu, X.-O.","Gao, G.","Singh, B.","Yin, Z.","Coburn, L. A.","Ciombor, K. K.","Eng, C.","Bauer, J. A.","Peters, U.","Wilson, K. T.","Zheng, W.","Lau, K. S.","Guo, X."],"primary_topic":"repro-genetics","topics":[{"slug":"omics-methods","score":10.0,"hits":["chip-seq","multi-omics","single-cell","transcriptome"]},{"slug":"repro-genetics","score":2.0,"hits":["chromatin accessibility","gwas"]},{"slug":"ethics-policy","score":2.0,"hits":["crispr","regulatory"]},{"slug":"ivg-stem","score":1.0,"hits":["germline"]}],"topic_score":10.0,"preference_score":10.0,"preference_labels":["多组学整合分析（任意生殖对象）"],"llm_score":58.0,"final_score":68.0,"score_dims":{"novelty":72,"rigor":78,"impact":30,"relevance":12,"translation":22},"recommend_reason":"方法学上展示了单细胞TWAS整合多组学解析细胞类型特异性遗传易感性的范式，样本量大、验证较充分；但研究对象为结直肠癌，与生殖医学和辅助生殖无直接关联，仅对多组学方法学参考有价值。","keywords":["单细胞TWAS","结直肠癌","细胞类型特异性","多组学整合","遗传易感性","药物靶点"],"selected":1,"story_id":230,"llm_provider":"deepseek","llm_model":"deepseek-flash","llm_effort":"low","source_key":"medrxiv-obgyn","source_name":"medRxiv · 妇产科（领域过滤）","source_tier":1,"mention_count":1,"has_interpretation":false,"journal_key":"medrxiv","journal_tier":"standard","journal_if":null,"is_mock":false,"summary_zh":"该预印本研究整合381例正常结直肠黏膜与84例息肉供者的生殖系基因型与单细胞转录组、细胞类型特异性染色质可及性，以及13.2万例病例与175万例对照的GWAS数据，开展单细胞转录组关联分析（scTWAS）。共鉴定出546个基因-细胞类型关联，涉及347个候选易感基因，其中213个为此前未报道基因，74%呈细胞类型特异性；共表达与ChIP-seq分析提示正常黏膜中GATA6、MAX、RAD21及息肉中TFAP4、CEBPB相关调控网络，多组学支持233个基因失调，药物靶点分析提示63个可成药基因，DepMap与CRISPR-Cas9提示35个基因影响癌细胞活力。","summary":"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.","interpretation_basis":null,"fulltext_status":null,"interpretation":null,"fulltext":{"available":false,"status":null,"reason":"尚未抓取全文（未入选、分数未达阈值，或还没跑 fulltext 步骤）","pmcid":null,"license":null,"chars":0,"source":null,"fetched_at":null}}