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

Author:

Xu JingxiongORCID,Xu Wei,Choi Jiyeon,Brhane Yonathan,Christiani David C.,Kothari JuiORCID,McKay James,Field John K.,Davies Michael P. A.,Liu Geoffrey,Amos Christopher I.,Hung Rayjean J.ORCID,Briollais LaurentORCID

Abstract

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.

Funder

Canadian Institutes of Health Research

Natural Sciences and Engineering Research Council of Canada

Foundation for the National Institutes of Health

Roy Castle Lung Cancer Foundation

Publisher

Public Library of Science (PLoS)

Subject

Cancer Research,Genetics (clinical),Genetics,Molecular Biology,Ecology, Evolution, Behavior and Systematics

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