Center for Data and Computational Sciences (C-DACS), VA Boston Healthcare System, Boston, MA, USA.
Booz Allen Hamilton, McLean, VA, USA.
Nat Commun. 2024 Oct 4;15(1):8629. doi: 10.1038/s41467-024-52129-4.
Lung cancer remains the leading cause of cancer mortality, despite declining smoking rates. Previous lung cancer GWAS have identified numerous loci, but separating the genetic risks of lung cancer and smoking behavioral susceptibility remains challenging. Here, we perform multi-ancestry GWAS meta-analyses of lung cancer using the Million Veteran Program cohort (approximately 95% male cases) and a previous study of European-ancestry individuals, jointly comprising 42,102 cases and 181,270 controls, followed by replication in an independent cohort of 19,404 cases and 17,378 controls. We then carry out conditional meta-analyses on cigarettes per day and identify two novel, replicated loci, including the 19p13.11 pleiotropic cancer locus in squamous cell lung carcinoma. Overall, we report twelve novel risk loci for overall lung cancer, lung adenocarcinoma, and squamous cell lung carcinoma, nine of which are externally replicated. Finally, we perform PheWAS on polygenic risk scores for lung cancer, with and without conditioning on smoking. The unconditioned lung cancer polygenic risk score is associated with smoking status in controls, illustrating a reduced predictive utility in non-smokers. Additionally, our polygenic risk score demonstrates smoking-independent pleiotropy of lung cancer risk across neoplasms and metabolic traits.
尽管吸烟率下降,但肺癌仍是癌症死亡的主要原因。先前的肺癌全基因组关联研究已经确定了许多位点,但将肺癌的遗传风险与吸烟行为易感性区分开来仍然具有挑战性。在这里,我们使用百万退伍军人计划队列(约 95%的男性病例)和先前的欧洲血统个体研究对肺癌进行了多血统全基因组关联研究荟萃分析,共同包含 42102 例病例和 181270 例对照,然后在一个独立的 19404 例病例和 17378 例对照队列中进行了复制。然后,我们对每天吸烟量进行条件荟萃分析,并确定了两个新的、复制的位点,包括鳞状细胞肺癌中的 19p13.11 多效性癌症位点。总的来说,我们报告了十二个新的总体肺癌、肺腺癌和鳞状细胞肺癌风险位点,其中九个是外部复制的。最后,我们对肺癌的多基因风险评分进行了 phewas 分析,条件和不条件都与吸烟有关。未条件的肺癌多基因风险评分与对照组的吸烟状况有关,这表明在不吸烟者中预测能力降低。此外,我们的多基因风险评分还表明,肺癌风险在肿瘤和代谢特征上存在与吸烟无关的多效性。