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

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. To evaluate the role of human exomes in genetic predisposition to lung cancer. 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. 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 [ ( values of meta-analysis) = 3.60 × 10] and rs202187871 [ = 2.21 × 10]) and two synonymous variants (rs7447927 [ = 1.32 × 10] and rs140624366 [ = 2.97 × 10]). rs202197044 was significantly associated with emphysema (odds ratio, 3.55;  = 0.015), whereas rs7447927 was strongly associated with telomere length (β = 1.08; (FDR corrected value) = 3.76 × 10). 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 (protection of telomeres 1), , , and . Our findings provide insights into the genetic architecture of human exomes and their role in lung cancer predisposition.