A Large-Scale Exome-Wide Association Study Identifies Novel Germline Mutations in Lung Cancer

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 · 发表于：American Journal of Respiratory and Critical Care Medicine · 年份：2023 · DOI：10.1164/rccm.202212-2199oc · 被引用次数：11 · 研究领域：Genetic Associations and Epidemiology、RNA modifications and cancer、Epigenetics and DNA Methylation

Abstract 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 [P meta (P values of meta-analysis) = 3.60 × 10−8] and rs202187871POT1 [P meta = 2.21 × 10−8]) and two synonymous variants (rs7447927TMEM173 [P meta = 1.32 × 10−9] and rs140624366ATRN [P meta = 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...