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.
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Data availability
The data used in this work were obtained from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium. Readers who are interested in accessing the data must first submit a proposal to the Data Access Committee. If the reader is not a member of the consortium, their concept form must be sponsored by a principal investigator (PI) of one of the PRACTICAL consortium member studies. If approved by the Data Access Committee, PIs within the consortium, each of whom retains ownership of their data submitted to the consortium, can then choose to participate in the specific proposal. In addition, portions of the data are available for request from dbGaP (database of Genotypes and Phenotypes) which is maintained by the National Center for Biotechnology Information (NCBI): https://www.ncbi.nlm.nih.gov/gap/?term=Icogs+prostatehttps://www.ncbi.nlm.nih.gov/gap/?term=Icogs+prostate. Anyone can apply to join the consortium. The eligibility requirements are listed here: http://www.practical.icr.ac.uk/blog/?page_id=9. Joining the consortium would not guarantee access, as a proposal for access would still be submitted to the Data Access Committee, but there would be no need for a separate member sponsor. Readers may find information about the application by using the contact information below: Rosalind Eeles. Principal Investigator for PRACTICAL. Professor of Oncogenetics. Institute of Cancer Research (ICR). Sutton, UK. Email: PRACTICAL@icr.ac.uk. URL: http://www.practical.icr.ac.uk. Tel: ++44 (0)20 8722 4094.
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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.
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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.
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The present analyses used de-identified data from the PRACTICAL consortium and have been approved by the Institutional Review Board at the University of California San Diego. All contributing studies were approved by the relevant ethics committees and performed in accordance with the Declaration of Helsinki.
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Karunamuni, R.A., Huynh-Le, MP., Fan, C.C. et al. Performance of African-ancestry-specific polygenic hazard score varies according to local ancestry in 8q24. Prostate Cancer Prostatic Dis 25, 229–237 (2022). https://doi.org/10.1038/s41391-021-00403-7
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DOI: https://doi.org/10.1038/s41391-021-00403-7
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