Large-scale whole exome sequencing studies identify two genes,CTSL and APOE, associated with lung cancer.

Common genetic variants associated with lung cancer have been well studied in the past decade. However, only 12.3% heritability has been explained by these variants. In this study, we investigate the contribution of rare variants (RVs) (minor allele frequency <0.01) to lung cancer through two large whole exome sequencing case-control studies. We first performed gene-based association tests using a novel Bayes Factor statistic in the International Lung Cancer Consortium, the discovery study (European, 1042 cases vs. 881 controls). The top genes identified are further assessed in the UK Biobank (European, 630 cases vs. 172 864 controls), the replication study. After controlling for the false discovery rate, we found two genes, CTSL and APOE, significantly associated with lung cancer in both studies. Single variant tests in UK Biobank identified 4 RVs (3 missense variants) in CTSL and 2 RVs (1 missense variant) in APOE stongly associated with lung cancer (OR between 2.0 and 139.0). The role of these genetic variants in the regulation of CTSL or APOE expression remains unclear. If such a role is established, this could have important therapeutic implications for lung cancer patients

Results of single RV-based association analysis in the genes <i>CTSL</i> and <i>APOE</i> using UK Biobank data.

Results of single RV-based association analysis in the genes CTSL and APOE using UK Biobank data.</p

Population Structure shown in top 3 principal components.

Population Structure shown in top 3 principal components.</p

Results of gene-based analyses using BF_SKAT^a in the discovery and replication studies.

Results of gene-based analyses using BFSKATa in the discovery and replication studies.</p

Method Supplement.

Common genetic variants associated with lung cancer have been well studied in the past decade. However, only 12.3% heritability has been explained by these variants. In this study, we investigate the contribution of rare variants (RVs) (minor allele frequency CTSL and APOE, significantly associated with lung cancer in both studies. Single variant tests in UK Biobank identified 4 RVs (3 missense variants) in CTSL and 2 RVs (1 missense variant) in APOE stongly associated with lung cancer (OR between 2.0 and 139.0). The role of these genetic variants in the regulation of CTSL or APOE expression remains unclear. If such a role is established, this could have important therapeutic implications for lung cancer patients.</div

QQ plot of ILCCO WES study.

The departure of the right tail from the 45 degree line represents the association signals from the study. (A) illustrates results using BF with KS prior. Under the null hypothesis (no association between genes and phenotype), 2logBFks~χ2(3). (B) shows results using BF with SKAT prior. Similarly, 2logBFSKAT ~ χ2(3) under the null hypothesis.</p

Results of gene-based analyses using BF_KS test^a in the discovery and replication studies.

Results of gene-based analyses using BFKS testa in the discovery and replication studies.</p

Genetic region of rs112682750 (pos: 87727608, build 38) within <i>CTSL</i> gene.

Genetic region of rs112682750 (pos: 87727608, build 38) within CTSL gene.</p

Relationship between QUAL and mean GQ vs. Ts/Tv ratio.

Relationship between QUAL and mean GQ vs. Ts/Tv ratio.</p

Basic demographic characteristics in the discovery and validation studies.

Basic demographic characteristics in the discovery and validation studies.</p