Burcu F. Darst
Postdoctoral Research Associate, University of Southern California
Polygenic risk score developed in multiethnic prostate cancer GWAS meta-analysis and further investigated with metabolomics
Prostate cancer (PCa) is a highly heritable disease with large disparities in incidence rates across racial and ethnic populations. We conducted the largest multiethnic GWAS meta-analysis to date with 107,247 PCa cases and 127,006 controls from PRACTICAL, including men from European, African, Asian, and Hispanic populations. We identified 269 variants independently associated with PCa risk and constructed a polygenic risk score (PRS) using conditional multiethnic weights from these variants. Compared to the 40-60% PRS category, the OR for men in the top PRS decile (90-100%) ranged from 3.74 [95% CI 3.36-4.17] for African ancestry men to 5.06 [95% CI 4.84-5.29] for European ancestry men. Lifetime absolute risk of PCa for men in the top PRS decile ranged from 26% [95% CI 22-30%] for Asians to 38% for both African [95% CI 36-41%] and European [95% CI 37-39%] ancestry men. To understand the biological mechanisms impacted by genetic risk of PCa, we evaluated associations between the PRS and serum metabolomics in 611 African ancestry men. A higher PRS was associated with lower sphingolipid levels (Beta=-0.08, P=3.1×10-4) and higher sarcosine levels (Beta=0.11, P=0.002). These findings could offer an approach for personalized risk prediction across populations and inform the biological mechanisms of PCa.
