A Large-Scale Exome-Wide Association Study Identifies Novel Germline Mutations in Lung Cancer.
Am J Respir Crit Care Med
; 208(3): 280-289, 2023 08 01.
Article
em En
| MEDLINE
| ID: mdl-37167549
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 MainResults:
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 (ß = 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.Palavras-chave
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Base de dados:
MEDLINE
Assunto principal:
Exoma
/
Neoplasias Pulmonares
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article