已经证实剪接数量性状位点（sQTLs）通过影响剪接而对疾病病因有贡献。然而，sQTLs在非小细胞肺癌（NSCLC）发展中的作用尚不清楚。因此，我们进行了一项全基因组sQTL研究，以发现影响中国血统116名个体肺组织剪接的遗传变异，结果鉴定了1,385个含有378,210个显著变异内含子对的sQTL基因（sGenes）。对这些sQTL进行的综合分析表明，它们富集在活跃转录区域、遗传调控元件和剪接因子结合位点中。此外，sQTLs与表达数量性状位点（eQTLs）有很大区别，并且在NSCLC潜在风险位点中显著富集。我们还利用剪接转录组范围关联研究（spTWAS）将sQTLs整合到NSCLC GWAS数据集（13,327例患者和13,328例对照）中，并鉴别出与NSCLC风险显著相关的19个基因的选择性剪接事件。通过功能注释和实验，我们确认了一个sQTL变异位点rs35861926，该变异通过促进FARP1外显子20跳跃剪接降低了肺腺癌风险（rs35861926-T，OR = 0.88，95％置信区间[CI]：0.82-0.93，p = 1.87 × 10^-5），从而下调了长转录本FARP1-011的表达水平。转录本FARP1-011促进了肺腺癌细胞的迁移和增殖。总体而言，我们的研究提供了有关肺sQTL资源的信息和对将sQTL变异与NSCLC风险相联系的分子机制的见解。版权所有© 2023美国人类遗传学会。由Elsevier公司出版。保留所有权利。

Splicing quantitative trait loci (sQTLs) have been demonstrated to contribute to disease etiology by affecting alternative splicing. However, the role of sQTLs in the development of non-small-cell lung cancer (NSCLC) remains unknown. Thus, we performed a genome-wide sQTL study to identify genetic variants that affect alternative splicing in lung tissues from 116 individuals of Chinese ancestry, which resulted in the identification of 1,385 sQTL-harboring genes (sGenes) containing 378,210 significant variant-intron pairs. A comprehensive characterization of these sQTLs showed that they were enriched in actively transcribed regions, genetic regulatory elements, and splicing-factor-binding sites. Moreover, sQTLs were largely distinct from expression quantitative trait loci (eQTLs) and showed significant enrichment in potential risk loci of NSCLC. We also integrated sQTLs into NSCLC GWAS datasets (13,327 affected individuals and 13,328 control individuals) by using splice-transcriptome-wide association study (spTWAS) and identified alternative splicing events in 19 genes that were significantly associated with NSCLC risk. By using functional annotation and experiments, we confirmed an sQTL variant, rs35861926, that reduced the risk of lung adenocarcinoma (rs35861926-T, OR = 0.88, 95% confidence interval [CI]: 0.82-0.93, p = 1.87 × 10-5) by promoting FARP1 exon 20 skipping to downregulate the expression level of the long transcript FARP1-011. Transcript FARP1-011 promoted the migration and proliferation of lung adenocarcinoma cells. Overall, our study provided informative lung sQTL resources and insights into the molecular mechanisms linking sQTL variants to NSCLC risk.Copyright © 2023 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.