African-specific improvement of a polygenic hazard score for age at diagnosis of prostate cancer.
Karunamuni RA., Huynh-Le M-P., Fan CC., Thompson W., Eeles RA., Kote-Jarai Z., Muir K., UKGPCS collaborators None., Lophatananon A., Tangen CM., Goodman PJ., Thompson IM., Blot WJ., Zheng W., Kibel AS., Drake BF., Cussenot O., Cancel-Tassin G., Menegaux F., Truong T., Park JY., Lin H-Y., Bensen JT., Fontham ETH., Mohler JL., Taylor JA., Multigner L., Blanchet P., Brureau L., Romana M., Leach RJ., John EM., Fowke J., Bush WS., Aldrich M., Crawford DC., Srivastava S., Cullen JC., Petrovics G., Parent M-É., Hu JJ., Sanderson M., Mills IG., Andreassen OA., Dale AM., Seibert TM., PRACTICAL Consortium None.
Polygenic hazard score (PHS) models are associated with age at diagnosis of prostate cancer. Our model developed in Europeans (PHS46), showed reduced performance in men with African genetic ancestry. We used a cross-validated search to identify SNPs that might improve performance in this population. Anonymized genotypic data were obtained from the PRACTICAL consortium for 6,253 men with African genetic ancestry. Ten iterations of a ten-fold cross-validation search were conducted, to select SNPs that would be included in the final PHS46+African model. The coefficients of PHS46+African were estimated in a Cox proportional hazards framework using age at diagnosis as the dependent variable and PHS46, and selected SNPs as predictors. The performance of PHS46 and PHS46+African were compared using the same cross-validated approach. Three SNPs (rs76229939, rs74421890, and rs5013678) were selected for inclusion in PHS46+African. All three SNPs are located on chromosome 8q24. PHS46+African showed substantial improvements in all performance metrics measured, including a 75% increase in the relative hazard of those in the upper 20% compared to the bottom 20% (2.47 to 4.34) and a 20% reduction in the relative hazard of those in the bottom 20% compared to the middle 40% (0.65 to 0.53). In conclusion, we identified three SNPs that substantially improved the association of PHS46 with age at diagnosis of prostate cancer in men with African genetic ancestry to levels comparable to Europeans. This article is protected by copyright. All rights reserved.