A Splicing Transcriptome-Wide Association Study Identifies Candidate Altered Splicing for Prostate Cancer Risk

Area of Science:

• Genetics
• Oncology
• Molecular Biology

Background:

• Prostate cancer (PCa) poses a significant public health challenge globally.
• Numerous genetic factors contributing to PCa susceptibility remain unidentified.
• Understanding the genetic underpinnings of PCa is crucial for developing effective prevention and treatment strategies.

Purpose of the Study:

• To identify novel genetic loci and splicing introns associated with prostate cancer risk.
• To develop predictive models for PCa risk based on alternative splicing.
• To enhance the understanding of PCa etiology through genetic analysis.

Main Methods:

• Conducted a large-scale splicing transcriptome-wide association study (spTWAS) across multiple consortia.
• Utilized three distinct modeling strategies for genetic prediction of alternative splicing.
• Analyzed data from 79,194 PCa cases and 61,112 controls of European ancestry.
• Applied false discovery rate (FDR) correction for statistical significance.

Main Results:

• Identified 120 splicing introns in 97 genes associated with PCa risk (FDR <0.05).
• Fine-mapping implicated 21 splicing introns in 19 genes as potentially causal for PCa risk.
• Discovered 35 splicing introns in 34 novel genes newly associated with PCa susceptibility.
• Found 33 genes enriched in PCa-related disease and functional categories.
• Observed 11 newly identified genes enriched within cancer-related networks.

Conclusions:

• This spTWAS successfully identified novel genetic loci and splicing introns linked to prostate cancer risk.
• The findings contribute to a deeper comprehension of the genetic factors influencing PCa development.
• The identified splicing patterns and genes offer potential targets for future research into PCa etiology and management.