A large proportion of the heritability of pancreatic cancer risk remains elusive, and the contribution of specific mRNA splicing events to pancreatic cancer susceptibility has not been systematically evaluated. In this study, we performed a large splicing transcriptome-wide association study (spTWAS) using three modeling strategies (Enet, LASSO, and MCP) to develop alternative splicing genetic prediction models for identifying novel susceptibility loci and splicing introns for pancreatic cancer risk by assessing 8,275 pancreatic cancer cases and 6,723 controls of European ancestry. Data from 305 subjects of whom the majority are of European descent in the Genotype-Tissue Expression Project (GTEx) were used and both cis-acting and promoter-enhancer interaction regions were considered to build these models. We identified nine splicing events of seven genes (ABO, UQCRC1, STARD3, ETAA1, CELA3B, LGR4, and SFT2D1) that showed an association of genetically predicted expression with pancreatic cancer risk at a false discovery rate (FDR) ≤ 0.05. Of these genes, UQCRC1 and LGR4 have not yet been reported to be associated with pancreatic cancer risk. Fine-mapping analyses supported likely causal associations corresponding to six splicing events of three genes (P4HTM, ABO and PGAP3). Our study identified novel genes and splicing events associated with pancreatic cancer risk, which can improve our understanding of the etiology of this deadly malignancy.

中文翻译：

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剪接转录组范围关联研究，以确定胰腺癌风险的剪接事件。

胰腺癌风险的遗传性很大一部分仍然难以捉摸，并且特定 mRNA 剪接事件对胰腺癌易感性的贡献尚未得到系统评估。在这项研究中，我们使用三种建模策略（Enet、LASSO 和 MCP）进行了一项大型剪接转录组范围关联研究 (spTWAS)，以开发替代剪接遗传预测模型，通过评估胰腺癌风险来识别新的易感位点和剪接内含子。 8,275 例胰腺癌病例和 6,723 例欧洲血统对照病例。使用基因型组织表达项目 (GTEx) 中 305 名受试者的数据，其中大多数是欧洲血统，并考虑顺式作用区域和启动子-增强子相互作用区域来构建这些模型。我们鉴定了 7 个基因（ABO、UQCRC1、STARD3、ETAA1、CELA3B、LGR4 和 SFT2D1）的 9 个剪接事件，这些事件显示基因预测表达与胰腺癌风险之间存在关联，错误发现率 (FDR) ≤ 0.05。在这些基因中，UQCRC1 和 LGR4 尚未被报道与胰腺癌风险相关。精细作图分析支持了与三个基因（P4HTM、ABO 和 PGAP3）的六个剪接事件相对应的可能因果关系。我们的研究发现了与胰腺癌风险相关的新基因和剪接事件，这可以提高我们对这种致命恶性肿瘤病因学的理解。