选择性RNA剪切是连接基因变异和人类疾病的重要机制。尽管全基因组关联研究（GWAS）的信号被和表达量量性状差异定位（eQTLs）联系起来，但需要进一步研究来更好地阐明其与其他基因调控机制的关系，如剪接QTLs（sQTLs）。在这里，我们进行了一个基因组范围的sQTL分析，以鉴定可能影响来自The Cancer Genome Atlas（TCGA）中1,010个非小细胞肺癌（NSCLC）样本的RNA剪切的变异。识别的sQTLs主要独立于eQTLs，而且主要富集于外显子区域、基因调控元件、RNA结合蛋白（RBP）结合位点和已知的NSCLC风险位点。此外，受sQTLs影响的靶基因（sGenes）参与多种癌症过程，包括细胞生长、凋亡、代谢、免疫浸润和药物反应。在NSCLC中，sGenes频繁地被遗传性改变。使用来自15,474个病例和12,375个对照的GWAS数据系统地筛选与NSCLC风险相关的sQTLs，发现一个sQTL变异rs156697-G等位基因与NSCLC风险显著增加相关。rs156697-G变异与NSCLC风险的关联在另外两个大型人群中得到了进一步验证。这个风险变异促进了GSTO2剪接的可选外显子5的包含，从而导致GSTO2全长亚型（GSTO2-V1）表达量增加和截断的GSTO2亚型（GSTO2-V2）表达量降低。截断的GSTO2-V2是由RBP quaking（QKI）诱导的。机理上，与GSTO2-V1相比，GSTO2-V2通过增加AKT1的S-谷胱甘肽化，从而阻止AKT1磷酸化和激活，抑制了NSCLC细胞的增殖。总的来说，本研究提供了与NSCLC风险相关的剪接变异的全面视角，并提供了一组具有治疗潜力的遗传靶标。

Alternative RNA splicing is an essential mechanism linking genetic variation to human diseases. While the signals from genome-wide association studies(GWAS) have been linked to expression quantitative trait loci(eQTLs) in previous studies,further work is needed to better elucidate the relationship to other genetic regulatory mechanisms,such as splicing QTLs(sQTLs). Here,we performed a genome-wide sQTL analysis to identify variants that might affect RNA splicing in 1,010 non-small cell lung cancer(NSCLC) samples from The Cancer Genome Atlas(TCGA).The identified sQTLs were largely independent of eQTLs and were predominantly enriched in exonic regions,genetic regulatory elements,RNA binding protein(RBP) binding sites, and known NSCLC risk loci. Additionally, target genes affected by sQTLs(sGenes) were involved in multiple processes in cancer,including cell growth,apoptosis,metabolism,immune infiltration,and drug responses,and sGenes were frequently altered genetically in NSCLC. Systematic screening of sQTLs associated with NSCLC risk using GWAS data from 15,474 cases and 12,375 controls identified an sQTL variant rs156697-G allele that was significantly associated with an increased risk of NSCLC. The association between the rs156697-G variant and NSCLC risk was further validated in two additional large population cohorts. The risk variant promoted inclusion of GSTO2 alternative exon 5 and led to higher expression of the GSTO2 full-length isoform(GSTO2-V1) and lower expression of the truncated GSTO2 isoform(GSTO2-V2),which was induced by RBP quaking(QKI). Mechanistically,compared with GSTO2-V1,GSTO2-V2 inhibited NSCLC cells proliferation by increasing S-glutathionylation of AKT1 and thereby functionally blocking AKT1 phosphorylation and activation. Overall,this study provides a comprehensive view of splicing variants linked to NSCLC risk and provides a set of genetic targets with therapeutic potential.