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Multi-ancestry study reveals 187 recent genetic risk aspects for prostate cancer

In a recent research letter published within the journal Nature Genetics, researchers performed a genome-wide association study (GWAS) meta-analysis of prostate cancer.

Prostate cancer has been essentially the most common non-skin cancer in males. The incidence of prostate cancer varies across populations, with the best in African males, and its risk is extremely 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 enhance risk prediction for prostate cancer.

Letter: Characterizing prostate cancer risk through multi-ancestry genome-wide discovery of 187 novel risk variants. Image Credit: MattL_Images / Shutterstock

The study and findings

The current 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 three,931 Hispanic prostate cancer cases. A hard and fast-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 danger 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 those, five (African), 19 (European), and three (Asian) risk variants were population-specific, with MAF ≤ 1% in other populations. There have been 370 risk variants with MAF above 1% in all populations.

Of those, 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 within the expression of genes in prostate tissues and cell lines.

Next, they performed a permutation test controlling for linkage disequilibrium patterns and MAF to find out 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 best contribution (47%) from expression in normal prostate. Of the 451 GWAS genomic risk regions, 237 co-localized inside 250 kilobases (kb) of proteome- or transcriptome-wide significant associations.

Of the 230 PWAS/TWAS genomic risk regions, 45 didn’t co-localize inside 250 kb of 451 genome-wide significant variants. Next, the team compared the performance of genetic risk scores (GRSs) of past marker sets (GRS100, GRS269, and GRS181) with the present set (GRS451) of 451 risk variants. The project of unaffected males to GRS categories was more stable with the invention of more variants.

That’s, 69% to 70% of males in the best or lowest quintile were in the identical quintile between GRS269 and GRS451, in comparison with 58% between GRS100 and GRS181. As well as, the share of cases increased inside higher categories and decreased inside lower categories in each population. Risk classification with GRS and age by net re-classification index showed substantial improvement from GRS100 to GRS451.

This improved risk prediction of GRS451 was verified in replication studies amongst African and European males not included in GWAS. Age was found to change the association between GRS451 and prostate cancer risk. GRS451 was related to the danger of aggressive and non-aggressive prostate cancer in Hispanic, Asian, and European populations. Nevertheless, in African prostate cancer cases, GRS451 was related to the next risk of aggressive disease.

Fifty-one risk variants were related to the GWAS of prostate-specific antigen (PSA). When these (51) PSA variants were faraway from the evaluation, the GRS was more strongly related to aggressiveness in European, African, and Hispanic males, suggesting that some variants could also be more over-represented in males with less aggressive prostate cancer as a consequence of their association with PSA levels.


Together, this multi-ancestry evaluation demonstrated a 57% increase in non-European case numbers over previous GWASs and revealed 187 novel risk variants. Moreover, the flexibility to distinguish between aggressive and non-aggressive disease highlights the utility of GRS for risk assessment and classification in prostate cancer. Nevertheless, when and the way this information needs to be incorporated in decision-making for screening and early detection of prostate cancer stays to be determined.

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