外显子组测序
外显子组
全基因组关联研究
表达数量性状基因座
遗传学
错义突变
遗传关联
单核苷酸多态性
生物
肺癌
基因
医学
突变
肿瘤科
基因型
作者
Sipeng Shen,Zaiming Li,Yunke Jiang,Weiwei Duan,Hongru Li,Sha Du,Manel Esteller,Hongbing Shen,Zhibin Hu,Yang Zhao,David C. Christiani,Feng Chen
标识
DOI:10.1164/rccm.202212-2199oc
摘要
Rationale: Genome-wide association studies have identified common variants of lung cancer. However, the contribution of rare exome-wide variants, especially protein-coding variants, to cancers remains largely unexplored. Objectives: To evaluate the role of human exomes in genetic predisposition to lung cancer. Methods: We performed exome-wide association studies to detect the association of exomes with lung cancer in 30,312 patients and 652,902 control subjects. A scalable and accurate implementation of a generalized mixed model was used to detect the association signals for loss-of-function, missense, and synonymous variants and gene-level sets. Furthermore, we performed association and Bayesian colocalization analyses to evaluate their relationships with intermediate exposures. Measurements and Main Results: We systematically analyzed 216,739 single-nucleotide variants in the human exome. The loss-of-function variants exhibited the most notable effects on lung cancer risk. We identified four novel variants, including two missense variants (rs202197044TET3 [Pmeta (P values of meta-analysis) = 3.60 × 10−8] and rs202187871POT1 [Pmeta = 2.21 × 10−8]) and two synonymous variants (rs7447927TMEM173 [Pmeta = 1.32 × 10−9] and rs140624366ATRN [Pmeta = 2.97 × 10−9]). rs202197044TET3 was significantly associated with emphysema (odds ratio, 3.55; Pfdr = 0.015), whereas rs7447927POT1 was strongly associated with telomere length (β = 1.08; Pfdr (FDR corrected P value) = 3.76 × 10−53). Functional evidence of expression of quantitative trait loci, splicing quantitative trait loci, and isoform expression was found for the four novel genes. Gene-level association tests identified several novel genes, including POT1 (protection of telomeres 1), RTEL1, BSG, and ZNF232. Conclusions: Our findings provide insights into the genetic architecture of human exomes and their role in lung cancer predisposition.
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