Non-coding genetic variants underlying higher prostate cancer risk in men of African ancestry

Prostate cancer (PrCa) incidence and severity vary across ancestries; men of African ancestry (AA) are more likely to be diagnosed and die from PrCa than those of European ancestry (EA). Current polygenic risk scores, even from multi-ancestry GWAS, do not fully capture population-specific genetic mechanisms, especially those mediated by non-coding regulatory single nucleotide polymorphisms (SNPs). Using a deep learning model of prostate enhancers, we identify ~ 2000 SNPs, potentially affecting enhancer function, with higher alternate allele frequency in AA men, that may affect PrCa risk. These SNPs may promote cancer via two mechanisms: increased enhancer activity leading to immune suppression and telomere elongation or decreased activity causing de-differentiation and apoptosis inhibition. Identified SNPs predominantly modulate binding of key transcription factors such as FOX, HOX, and AR – the first was experimentally validated. Incorporating these SNPs into a polygenic risk score improves PrCa risk assessment beyond existing GWAS-identified variants.