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
Single-cell transcriptome-wide association analysis reveals epithelial cell-specific genetic susceptibility to colorectal cancer
摘要
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。
原文摘要
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.
推荐理由：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。
文献解读
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