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 (rs202197044(TET3) [P(meta) (P values of meta-analysis) = 3.60 × 10(-8)] and rs202187871(POT1) [P(meta) = 2.21 × 10(-8)]) and two synonymous variants (rs7447927(TMEM173) [P(meta) = 1.32 × 10(-9)] and rs140624366(ATRN) [P(meta) = 2.97 × 10(-9)]). rs202197044(TET3) was significantly associated with emphysema (odds ratio, 3.55; P(fdr) = 0.015), whereas rs7447927(POT1) was strongly associated with telomere length (β = 1.08; P(fdr) (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.