在过去十年中，已经对与肺癌相关的常见遗传变异进行了广泛研究，然而这些变异只能解释12.3%的遗传度。本研究通过两个大型全外显子测序病例对照研究，探究了罕见变异（minor allele frequency <0.01）对肺癌的贡献。首先，在国际肺癌联盟的发现研究（欧洲，1042例病例对比881例对照）中，我们使用一种新颖的贝叶斯因子统计量进行基因为单位的关联检测。进一步，在英国生物库（欧洲，630例病例对比172,864例对照）进行复制研究对发现的前列基因进行了评估。在控制误发现率的基础上，我们发现两个基因，CTSL和APOE，与肺癌显著相关。在英国生物库的单变异位点检测中，发现CTSL中有4个罕见变异（其中3个为错义变异），APOE中有2个罕见变异（其中1个为错义变异）与肺癌强相关（OR介于2.0和139.0之间）。这些遗传变异在调控CTSL或APOE表达方面的作用仍不明确。如果能够确定这种作用，对于肺癌患者将具有重要的治疗意义。版权：© 2023 Xu等人。本文是一篇开放获取文章，遵循创作共用许可证，可自由使用、分发和复制，前提是保持原始作者和来源的署名。

Common genetic variants associated with lung cancer have been well studied in the past decade. However, only 12.3% heritability has been explained by these variants. In this study, we investigate the contribution of rare variants (RVs) (minor allele frequency <0.01) to lung cancer through two large whole exome sequencing case-control studies. We first performed gene-based association tests using a novel Bayes Factor statistic in the International Lung Cancer Consortium, the discovery study (European, 1042 cases vs. 881 controls). The top genes identified are further assessed in the UK Biobank (European, 630 cases vs. 172 864 controls), the replication study. After controlling for the false discovery rate, we found two genes, CTSL and APOE, significantly associated with lung cancer in both studies. Single variant tests in UK Biobank identified 4 RVs (3 missense variants) in CTSL and 2 RVs (1 missense variant) in APOE stongly associated with lung cancer (OR between 2.0 and 139.0). The role of these genetic variants in the regulation of CTSL or APOE expression remains unclear. If such a role is established, this could have important therapeutic implications for lung cancer patients.Copyright: © 2023 Xu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.