Large-scale transcriptome-wide association study identifies new prostate cancer risk regions

Area of Science:

• Genetics
• Oncology
• Bioinformatics

Background:

• Genome-wide association studies (GWAS) have identified over 100 prostate cancer (PrCa) risk regions, but the specific genes involved remain largely unknown.
• Understanding genetic risk factors is crucial for advancing PrCa research and developing targeted therapies.

Purpose of the Study:

• To identify novel genes associated with prostate cancer (PrCa) risk by integrating large-scale PrCa GWAS data with multi-tissue gene expression data.
• To pinpoint potential causal genes within known and novel PrCa risk regions, including those not identified by traditional GWAS.
• To investigate the role of alternative splicing in PrCa pathogenesis.

Main Methods:

• Performed a multi-tissue transcriptome-wide association study (TWAS) by integrating the largest PrCa GWAS (N=142,392) with gene expression data from 45 tissues (N=4458), including normal and tumor prostate tissue.
• Utilized alternative splicing models in prostate tumor tissue to identify genes specifically associated with splicing-driven risk.
• Employed a Bayesian probabilistic approach to estimate credible sets of genes, reducing the number of potential causal genes.

Main Results:

• Identified 217 genes associated with PrCa risk across 84 independent 1 Mb regions, including 9 regions lacking genome-wide significant single nucleotide polymorphisms (SNPs).
• Discovered 23 genes significantly associated with PrCa risk exclusively through alternative splicing models in prostate tumor tissue.
• Reduced the list of 217 candidate genes to 109 genes within a 90% credible set using a Bayesian approach, prioritizing likely causal genes.

Conclusions:

• Integrating gene expression data with PrCa GWAS is a powerful strategy for identifying novel genetic risk loci.
• This study prioritized putative causal genes at known and novel PrCa risk loci, advancing our understanding of PrCa pathogenesis.
• Alternative splicing in prostate tumors may play a significant role in driving PrCa risk and oncogenesis.