Identification of immune cell type-specific susceptibility genes in multiple cancers using transcriptome-wide...

Area of Science:

• Genomics
• Cancer Research
• Immunology

Background:

• Transcriptome-wide association studies (TWAS) integrate gene expression and genome-wide association studies (GWAS) to identify disease susceptibility genes.
• Gene expression variability across cell types necessitates cell type-specific prediction models to enhance TWAS power.

Purpose of the Study:

• To conduct cell type-specific TWAS for identifying novel cancer susceptibility loci.
• To develop an improved modeling framework for TWAS that accounts for shared gene expression effects across cell types.

Main Methods:

• Leveraged single-cell RNA sequencing data from the OneK1K cohort (14 immune cell types, 1.27 million cells).
• Utilized GWAS summary statistics for seven cancers (>290,000 cases).
• Developed a novel modeling framework incorporating shared gene expression effects across cell types to boost prediction accuracy.

Main Results:

• Identified numerous previously unreported loci for breast, prostate, lung, melanoma, ovarian cancers, and diffuse large B-cell lymphoma.
• Most identified genes exhibited cell type specificity, with 139 significant genes shared across at least two cancer types and enriched in specific immune cell types.
• Validated significant genes for lung cancer using additional lung tissue single-cell RNA sequencing data.

Conclusions:

• Cell type-specific TWAS significantly improves the identification of novel cancer susceptibility loci.
• The study provides valuable insights into the immune landscape's role in cancer etiology.