Transcriptome-wide association study reveals candidate causal genes for lung cancer

Area of Science:

• Genomics
• Cancer Research
• Molecular Biology

Background:

• Genome-Wide Association Studies (GWAS) have identified numerous genetic loci associated with lung cancer risk.
• Integrating GWAS with expression quantitative trait loci (eQTL) data can help identify causal genes underlying these associations.

Purpose of the Study:

• To identify candidate causal genes for lung cancer by integrating GWAS results with large-scale eQTL mapping.
• To perform transcriptome-wide association studies (TWAS) for lung cancer across different subtypes and smoking behaviors.

Main Methods:

• Conducted the largest GWAS on lung cancer to date (29,266 cases, 56,450 controls).
• Performed TWAS integrating GWAS data with lung tissue eQTL data (n=1,038).
• Utilized Genotype-Tissue Expression (GTEx) data for replication and performed DNA damage assays.

Main Results:

• Identified a strong TWAS signal for IREB2 on chromosome 15q25, where lower predicted expression increases lung cancer risk.
• Discovered a novel lung adenocarcinoma locus on 9p13.3 associated with AQP3, where higher predicted expression increases risk.
• Mapped candidate target genes for 17 of 45 previously described lung cancer GWAS loci; AQP3-adenocarcinoma association was replicated.

Conclusions:

• Gene expression levels in lung tissue directly influence lung cancer risk.
• IREB2 and AQP3 are identified as key candidate causal genes for lung cancer.
• Functional assays showed that altered expression of IREB2 and AQP3 impacts DNA damage, supporting their role in lung carcinogenesis.