Integrative splicing quantitative trait locus analysis reveals risk loci for non-small-cell lung cancer.
Integrative splicing quantitative trait locus analysis reveals risk loci for non-small-cell lung cancer.
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DOI：
10.1016/j.ajhg.2023.07.008
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发表时间：
2023-08
影响因子：
9.8
通讯作者：
Yuzhuo Wang;Yue Ding;Supriya K Liu;Cheng Wang;E. Zhang;Congcong Chen;M. Zhu;Jing Zhang;Chen Zhu;M. Ji;J. Dai;G. Jin;Zhibin Hu;Hongbing Shen;Hongxia Ma
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文献类型：
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作者：
Yuzhuo Wang;Yue Ding;Supriya K Liu;Cheng Wang;E. Zhang;Congcong Chen;M. Zhu;Jing Zhang;Chen Zhu;M. Ji;J. Dai;G. Jin;Zhibin Hu;Hongbing Shen;Hongxia Ma
剪接数量性状基因座（sQTL）已被证明有助于疾病的病因，通过影响选择性剪接。然而，sQTL在非小细胞肺癌（NSCLC）发生中的作用仍不清楚。因此，我们进行了全基因组sQTL研究，以确定影响116名中国血统个体肺组织中选择性剪接的遗传变异，结果鉴定了1，385个含有sQTL的基因（sGenes），其中包含378，210个显著的变异内含子对。这些sQTL的综合表征表明，他们丰富的活跃转录区域，遗传调控元件，剪接因子结合位点。此外，sQTLs在很大程度上不同于表达数量性状位点（eQTLs），并显示出显着富集的潜在风险位点的NSCLC。我们还通过剪接-转录组关联研究（spTWAS）将sQTL整合到NSCLC GWAS数据集（13，327名受影响个体和13，328名对照个体）中，并在19个与NSCLC风险显著相关的基因中鉴定了选择性剪接事件。通过使用功能注释和实验，我们证实了一个sQTL变体rs35861926，它通过促进FARP 1外显子20跳跃来下调长转录本FARP 1 -011的表达水平，从而降低肺腺癌的风险（rs35861926-T，OR = 0.88，95%置信区间[CI]：0.82-0.93，p = 1.87 × 10−5）。转录本FARP 1 -011促进肺腺癌细胞的迁移和增殖。总的来说，我们的研究提供了信息丰富的肺sQTL资源，并深入了解了sQTL变异与NSCLC风险相关的分子机制。
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 promotingFARP1exon 20 skipping to downregulate the expression level of the long transcriptFARP1-011. TranscriptFARP1-011 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.