A Transcriptome-Wide Association Study Identifies Candidate Susceptibility Loci and Genes for Lung Cancer Risk

Area of Science:

• Genetics
• Genomics
• Cancer Research

Background:

• Genome-wide association studies (GWAS) have identified numerous lung cancer risk loci.
• The specific genes responsible for these associations are largely unidentified.

Purpose of the Study:

• To identify novel lung cancer susceptibility genes using a transcriptome-wide association study (TWAS).
• To investigate the genetic underpinnings of lung cancer risk by integrating gene expression data with GWAS.

Main Methods:

• Conducted a large TWAS leveraging gene expression data from GTEx (v8) for lung and other tissues.
• Built lung-tissue and joint-tissue gene expression prediction models using up to 706 European ancestry samples.
• Applied models to GWAS data (29,266 cases, 56,450 controls) to assess genetically predicted gene expression and lung cancer risk.

Main Results:

• Developed prediction models for 8,624 single-tissue and 11,341 joint-tissue genes (12,133 unique).
• Identified 40 genes associated with overall lung cancer risk, including ZKSCAN4 located distally to GWAS variants.
• Found 53 genes associated with lung cancer subtypes, with several located distally or independent of known GWAS variants.

Conclusions:

• The TWAS successfully identified over 50 candidate susceptibility genes for lung cancer.
• These findings offer new genetic insights into lung cancer development and risk.
• The study highlights the utility of TWAS in uncovering genes missed by traditional GWAS.