@article{db537d019f3f4d94a86b2c9bf589c580,
title = "Performance of African-ancestry-specific polygenic hazard score varies according to local ancestry in 8q24",
abstract = "Background: We previously developed an African-ancestry-specific polygenic hazard score (PHS46+African) that substantially improved prostate cancer risk stratification in men with African ancestry. The model consists of 46 SNPs identified in Europeans and 3 SNPs from 8q24 shown to improve model performance in Africans. Herein, we used principal component (PC) analysis to uncover subpopulations of men with African ancestry for whom the utility of PHS46+African may differ. Materials and methods: Genotypic data were obtained from the PRACTICAL consortium for 6253 men with African genetic ancestry. Genetic variation in a window spanning 3 African-specific 8q24 SNPs was estimated using 93 PCs. A Cox proportional hazards framework was used to identify the pair of PCs most strongly associated with the performance of PHS46+African. A calibration factor (CF) was formulated using Cox coefficients to quantify the extent to which the performance of PHS46+African varies with PC. Results: CF of PHS46+African was strongly associated with the first and twentieth PCs. Predicted CF ranged from 0.41 to 2.94, suggesting that PHS46+African may be up to 7 times more beneficial to some African men than others. The explained relative risk for PHS46+African varied from 3.6% to 9.9% for individuals with low and high CF values, respectively. By cross-referencing our data set with 1000 Genomes, we identified significant associations between continental and calibration groupings. Conclusion: We identified PCs within 8q24 that were strongly associated with the performance of PHS46+African. Further research to improve the clinical utility of polygenic risk scores (or models) is needed to improve health outcomes for men of African ancestry.",
author = "{UKGPCS collaborators} and {The PRACTICAL Consortium} and Karunamuni, {Roshan A.} and Huynh-Le, {Minh Phuong} and Fan, {Chun C.} and Wesley Thompson and Asona Lui and Martinez, {Maria Elena} and Rose, {Brent S.} and Brandon Mahal and Eeles, {Rosalind A.} and Zsofia Kote-Jarai and Kenneth Muir and Artitaya Lophatananon and Tangen, {Catherine M.} and Goodman, {Phyllis J.} and Thompson, {Ian M.} and Blot, {William J.} and Wei Zheng and Kibel, {Adam S.} and Drake, {Bettina F.} and Olivier Cussenot and G{\'e}raldine Cancel-Tassin and Florence Menegaux and Th{\'e}r{\`e}se Truong and Park, {Jong Y.} and Lin, {Hui Yi} and Taylor, {Jack A.} and Bensen, {Jeannette T.} and Mohler, {James L.} and Fontham, {Elizabeth T.H.} and Luc Multigner and Pascal Blanchet and Laurent Brureau and Marc Romana and Leach, {Robin J.} and John, {Esther M.} and Fowke, {Jay H.} and Bush, {William S.} and Aldrich, {Melinda C.} and Crawford, {Dana C.} and Jennifer Cullen and Gyorgy Petrovics and Parent, {Marie {\'E}lise} and Hu, {Jennifer J.} and Maureen Sanderson and Mills, {Ian G.} and Andreassen, {Ole A.} and Dale, {Anders M.} and Seibert, {Tyler M.}",
note = "Funding Information: Funding This study was funded in part by grants from the University of California (#C21CR2060), the United States National Institute of Health/National Institute of Biomedical Imaging and Bioengineering (#K08EB026503), the Research Council of Norway (#223273), KG Jebsen Stiftelsen, and South East Norway Health Authority. Funding for the PRACTICAL consortium member studies is detailed in Appendix A2. The content is solely the responsibility of the authors and does not necessarily represent the official views of any of the funding agencies, who had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Funding Information: Competing interests All authors declare no support from any organization for the submitted work except as follows: AMD and TMS report a research grant from the US Department of Defense. OAA reports research grants from K.G Jebsen Stiftelsen, Research Council of Norway, and South East Norway Health Authority. Authors declare no financial relationships with any organizations that might have an interest in the submitted work in the previous three years except as follows, with all of these relationships outside the present study: TMS reports honoraria from Multimodal Imaging Services Corporation for imaging segmentation, honoraria from WebMD, Inc. for educational content, as well as a past research grant from Varian Medical Systems. OAA reports speaker honoraria from Lundbeck. Authors declare no other relationships or activities that could appear to have influenced the submitted work except as follows: OAA has a patent application # U. S. 20150356243 pending; AMD also applied for this patent application and assigned it to UC San Diego. AMD has additional disclosures outside the present work: founder, equity holder, and advisory board member for CorTechs Labs, Inc.; founder and equity holder in HealthLytix, Inc., advisory board member of Human Longevity, Inc.; recipient of nonfinancial research support from General Electric Healthcare. OAA is a consultant for HealthLytix, Inc. Additional acknowledgments for the PRACTICAL consortium and contributing studies are described in Appendix A3. Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Nature Limited.",
year = "2022",
month = feb,
doi = "10.1038/s41391-021-00403-7",
language = "English (US)",
volume = "25",
pages = "229--237",
journal = "Prostate Cancer and Prostatic Diseases",
issn = "1365-7852",
publisher = "Nature Publishing Group",
number = "2",
}