African-specific improvement of a polygenic hazard score for age at diagnosis of prostate cancer
By
Roshan Karunamuni,
Minh-Phuong Huynh-Le,
Chun Fan,
Wesley Thompson,
Rosalind Eeles,
Zsofia Kote-Jarai,
Kenneth Muir,
UKGPCS collaborators,
Artitaya Lophatananon,
Catherine Tangen,
Phyllis Goodman,
Ian Thompson,
William Blot,
Wei Zheng,
Adam Kibel,
Bettina Drake,
Olivier Cussenot,
Geraldine Cancel-Tassin,
Florence Menegaux,
Therese Truong,
Jong Park,
Hui-Yi Lin,
Jeannette Bensen,
Elizabeth Fontham,
James Mohler,
Jack Taylor,
Luc Multigner,
Pascal Blanchet,
Laurent Brureau,
Marc Romana,
Robin Leach,
Esther John,
Jay Fowke,
William S Bush,
Melinda Aldrich,
Dana Crawford,
Shiv Srivastava,
Jennifer Cullen,
Gyorgy Petrovics,
Marie-Elise Parent,
Jennifer Hu,
Maureen Sanderson,
Ian Mills,
Ole Andreassen,
Anders Dale,
Tyler M Seibert,
The PRACTICAL Consortium
Posted 23 Apr 2020
medRxiv DOI: 10.1101/2020.04.20.20072926
Introduction: 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. Material and Methods: 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. Results: 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). Conclusions: 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 and Asians. A strategy of building on established statistical models might benefit ancestral groups generally under-represented in genome-wide association studies.
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