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

Abstract

<b>Rationale:</b> 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. <b>Objectives:</b> To evaluate the role of human exomes in genetic predisposition to lung cancer. <b>Methods:</b> 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. <b>Measurements and Main Results:</b> 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 [<i>P</i>_<i>meta</i> (<i>P</i> values of meta-analysis) = 3.60 × 10^-8] and rs202187871_POT1 [<i>P</i>_<i>meta</i> = 2.21 × 10^-8]) and two synonymous variants (rs7447927_TMEM173 [<i>P</i>_<i>meta</i> = 1.32 × 10^-9] and rs140624366_ATRN [<i>P</i>_<i>meta</i> = 2.97 × 10^-9]). rs202197044_TET3 was significantly associated with emphysema (odds ratio, 3.55; <i>P_fdr</i> = 0.015), whereas rs7447927<i>_POT1</i> was strongly associated with telomere length (β = 1.08; <i>P_fdr</i> (FDR corrected <i>P</i> 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 <i>POT1</i> (protection of telomeres 1), <i>RTEL1</i>, <i>BSG</i>, and <i>ZNF232</i>. <b>Conclusions:</b> Our findings provide insights into the genetic architecture of human exomes and their role in lung cancer predisposition.