In a recent research letter published in the journal Nature Genetics, researchers performed a genome-wide association study (GWAS) meta-analysis of prostate cancer.
Prostate cancer has been the most common non-skin cancer in males. The incidence of prostate cancer varies across populations, with the highest in African males, and its risk is highly influenced by genetics. GWASs have identified 278 prostate cancer risk variants, albeit most samples were from people of European ancestry. Multi-ancestry analyses have been suggested to improve risk prediction for prostate cancer.
The study and findings
The present study performed a GWAS meta-analysis of prostate cancer in people of multiple ancestry groups. The study included 122,188 European, 10,809 East Asian, 19,391 African, and 3,931 Hispanic prostate cancer cases. A fixed-effect meta-analysis was performed per ancestry group. In total, > 42.4 million variants with minor allele frequency (MAF) > 0.1% were assessed for associations with the risk of prostate cancer.
The team identified 451 risk variants, including 187 novel variants, with genome-wide significance. MAF of most risk variants (84% to 95% across ancestry groups) was > 1%. Of these, five (African), 19 (European), and three (Asian) risk variants were population-specific, with MAF ≤ 1% in other populations. There were 370 risk variants with MAF above 1% in all populations.
Of these, 125, 208, 247, and 369 were nominally significant in Hispanic, Asian, African, and European populations, respectively. The effect sizes for risk variants with MAF above 1% were correlated across populations. The heterogeneity in effect sizes was significant for 78 variants. Many lead risk variants were implicated in the expression of genes in prostate tissues and cell lines.
Next, they performed a permutation test controlling for linkage disequilibrium patterns and MAF to determine the extent to which risk variants exhibited prostate-specific regulatory function. Risk variants were enriched in regions of prostate-specific regulatory activity across candidate cis-regulatory elements and splicing (sQTLs) and expression (eQTLs) quantitative trait loci.
Further, proteome- (PWAS) and transcriptome-wide association studies (TWAS) were performed to explore the molecular mechanisms of prostate cancer risk. This revealed 746 associations across 230 genomic regions and 528 genes, with the highest contribution (47%) from expression in normal prostate. Of the 451 GWAS genomic risk regions, 237 co-localized within 250 kilobases (kb) of proteome- or transcriptome-wide significant associations.
You can read more in an article by Tarun Sai Lomte published in the news-medical.net web site at: https://tinyurl.com/yv7wvucp.