PRState: Incorporating genetic ancestry in prostate cancer risk scores for men of African ancestry
Abstract Background Prostate cancer (PrCa) is one of the most genetically driven solid cancers with heritability estimates as high as 57%. Men of African ancestry are at an increased risk of PrCa; however, current polygenic risk score (PRS) models are based on European ancestry groups and may not be...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2022-12-01
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| Series: | BMC Cancer |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12885-022-10258-3 |
| _version_ | 1811301842825510912 |
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| author | Meghana S. Pagadala Joshua A. Linscott James V. Talwar Tyler M. Seibert Brent Rose Julie Lynch Matthew Panizzon Richard Hauger Moritz H. Hansen Jesse D. Sammon Matthew H. Hayn Karim Kader Hannah Carter Stephen T. Ryan |
| author_facet | Meghana S. Pagadala Joshua A. Linscott James V. Talwar Tyler M. Seibert Brent Rose Julie Lynch Matthew Panizzon Richard Hauger Moritz H. Hansen Jesse D. Sammon Matthew H. Hayn Karim Kader Hannah Carter Stephen T. Ryan |
| author_sort | Meghana S. Pagadala |
| collection | DOAJ |
| description | Abstract Background Prostate cancer (PrCa) is one of the most genetically driven solid cancers with heritability estimates as high as 57%. Men of African ancestry are at an increased risk of PrCa; however, current polygenic risk score (PRS) models are based on European ancestry groups and may not be broadly applicable. The objective of this study was to construct an African ancestry-specific PrCa PRS (PRState) and evaluate its performance. Methods African ancestry group of 4,533 individuals in ELLIPSE consortium was used for discovery of African ancestry-specific PrCa SNPs. PRState was constructed as weighted sum of genotypes and effect sizes from genome-wide association study (GWAS) of PrCa in African ancestry group. Performance was evaluated using ROC-AUC analysis. Results We identified African ancestry-specific PrCa risk loci on chromosomes 3, 8, and 11 and constructed a polygenic risk score (PRS) from 10 African ancestry-specific PrCa risk SNPs, achieving an AUC of 0.61 [0.60–0.63] and 0.65 [0.64–0.67], when combined with age and family history. Performance dropped significantly when using ancestry-mismatched PRS models but remained comparable when using trans-ancestry models. Importantly, we validated the PRState score in the Million Veteran Program (MVP), demonstrating improved prediction of PrCa and metastatic PrCa in individuals of African ancestry. Conclusions African ancestry-specific PRState improves PrCa prediction in African ancestry groups in ELLIPSE consortium and MVP. This study underscores the need for inclusion of individuals of African ancestry in gene variant discovery to optimize PRSs and identifies African ancestry-specific variants for use in future studies. |
| first_indexed | 2024-04-13T07:16:10Z |
| format | Article |
| id | doaj.art-e919dd1e118d496f8be868fe949210a1 |
| institution | Directory Open Access Journal |
| issn | 1471-2407 |
| language | English |
| last_indexed | 2024-04-13T07:16:10Z |
| publishDate | 2022-12-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Cancer |
| spelling | doaj.art-e919dd1e118d496f8be868fe949210a12022-12-22T02:56:44ZengBMCBMC Cancer1471-24072022-12-0122111110.1186/s12885-022-10258-3PRState: Incorporating genetic ancestry in prostate cancer risk scores for men of African ancestryMeghana S. Pagadala0Joshua A. Linscott1James V. Talwar2Tyler M. Seibert3Brent Rose4Julie Lynch5Matthew Panizzon6Richard Hauger7Moritz H. Hansen8Jesse D. Sammon9Matthew H. Hayn10Karim Kader11Hannah Carter12Stephen T. Ryan13Department of Medicine, Division of Medical Genetics, University of CaliforniaDivision of Urology, Maine Medical CenterBioinformatics and Systems Biology Program, University of CaliforniaDepartment of Radiation Medicine and Applied Sciences, University of CaliforniaDepartment of Radiation Medicine and Applied Sciences, University of CaliforniaVA Salt Lake City Healthcare SystemVA San Diego Healthcare SystemVA San Diego Healthcare SystemDivision of Urology, Maine Medical CenterDivision of Urology, Maine Medical CenterDivision of Urology, Maine Medical CenterDepartment of Urology, University of California San DiegoDepartment of Medicine, Division of Medical Genetics, University of CaliforniaDivision of Urology, Maine Medical CenterAbstract Background Prostate cancer (PrCa) is one of the most genetically driven solid cancers with heritability estimates as high as 57%. Men of African ancestry are at an increased risk of PrCa; however, current polygenic risk score (PRS) models are based on European ancestry groups and may not be broadly applicable. The objective of this study was to construct an African ancestry-specific PrCa PRS (PRState) and evaluate its performance. Methods African ancestry group of 4,533 individuals in ELLIPSE consortium was used for discovery of African ancestry-specific PrCa SNPs. PRState was constructed as weighted sum of genotypes and effect sizes from genome-wide association study (GWAS) of PrCa in African ancestry group. Performance was evaluated using ROC-AUC analysis. Results We identified African ancestry-specific PrCa risk loci on chromosomes 3, 8, and 11 and constructed a polygenic risk score (PRS) from 10 African ancestry-specific PrCa risk SNPs, achieving an AUC of 0.61 [0.60–0.63] and 0.65 [0.64–0.67], when combined with age and family history. Performance dropped significantly when using ancestry-mismatched PRS models but remained comparable when using trans-ancestry models. Importantly, we validated the PRState score in the Million Veteran Program (MVP), demonstrating improved prediction of PrCa and metastatic PrCa in individuals of African ancestry. Conclusions African ancestry-specific PRState improves PrCa prediction in African ancestry groups in ELLIPSE consortium and MVP. This study underscores the need for inclusion of individuals of African ancestry in gene variant discovery to optimize PRSs and identifies African ancestry-specific variants for use in future studies.https://doi.org/10.1186/s12885-022-10258-3Prostate CancerProstate Cancer RiskSingle nucleotide polymorphism (SNP)AncestryAfricanPolygenic Risk Score (PRS) |
| spellingShingle | Meghana S. Pagadala Joshua A. Linscott James V. Talwar Tyler M. Seibert Brent Rose Julie Lynch Matthew Panizzon Richard Hauger Moritz H. Hansen Jesse D. Sammon Matthew H. Hayn Karim Kader Hannah Carter Stephen T. Ryan PRState: Incorporating genetic ancestry in prostate cancer risk scores for men of African ancestry BMC Cancer Prostate Cancer Prostate Cancer Risk Single nucleotide polymorphism (SNP) Ancestry African Polygenic Risk Score (PRS) |
| title | PRState: Incorporating genetic ancestry in prostate cancer risk scores for men of African ancestry |
| title_full | PRState: Incorporating genetic ancestry in prostate cancer risk scores for men of African ancestry |
| title_fullStr | PRState: Incorporating genetic ancestry in prostate cancer risk scores for men of African ancestry |
| title_full_unstemmed | PRState: Incorporating genetic ancestry in prostate cancer risk scores for men of African ancestry |
| title_short | PRState: Incorporating genetic ancestry in prostate cancer risk scores for men of African ancestry |
| title_sort | prstate incorporating genetic ancestry in prostate cancer risk scores for men of african ancestry |
| topic | Prostate Cancer Prostate Cancer Risk Single nucleotide polymorphism (SNP) Ancestry African Polygenic Risk Score (PRS) |
| url | https://doi.org/10.1186/s12885-022-10258-3 |
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