PRState: Incorporating genetic ancestry in prostate cancer risk scores for men of African ancestry

被引:4
作者
Pagadala, Meghana S. [1 ,2 ,3 ]
Linscott, Joshua A. [4 ]
Talwar, James V. [5 ]
Seibert, Tyler M. [6 ,7 ,8 ,9 ]
Rose, Brent [6 ,7 ,10 ]
Lynch, Julie [11 ,12 ]
Panizzon, Matthew [7 ,13 ]
Hauger, Richard [7 ,13 ,14 ]
Hansen, Moritz H. [4 ]
Sammon, Jesse D. [4 ]
Hayn, Matthew H. [4 ]
Kader, Karim [10 ]
Carter, Hannah [1 ]
Ryan, Stephen T. [4 ]
机构
[1] Univ Calif San Diego, Dept Med, Div Med Genet, 9500 Gilman Dr, La Jolla, CA 92093 USA
[2] Univ Calif San Diego, Med Scientist Training Program, La Jolla, CA USA
[3] Univ Calif San Diego, Biomed Sci Program, La Jolla, CA USA
[4] Maine Med Ctr, Div Urol, Portland, ME USA
[5] Univ Calif San Diego, Bioinformat & Syst Biol Program, La Jolla, CA USA
[6] Univ Calif San Diego, Dept Radiat Med & Appl Sci, La Jolla, CA USA
[7] VA San Diego Healthcare Syst, La Jolla, CA USA
[8] Univ Calif San Diego, Dept Radiol, La Jolla, CA USA
[9] Univ Calif San Diego, Dept Bioengn, La Jolla, CA USA
[10] Univ Calif San Diego, Dept Urol, La Jolla, CA USA
[11] VA Salt Lake City Healthcare Syst, Salt Lake City, UT USA
[12] Univ Utah, Sch Med, Salt Lake City, UT USA
[13] Univ Calif San Diego, Ctr Behav Genet Aging, La Jolla, CA USA
[14] San Diego Healthcare Syst, Ctr Excellence Stress & Mental Hlth CESAMH, San Diego, CA USA
基金
美国国家卫生研究院;
关键词
Prostate Cancer; Prostate Cancer Risk; Single nucleotide polymorphism (SNP); Ancestry; African; Polygenic Risk Score (PRS); ASSOCIATION; HERITABILITY; DISEASE; TWINS; BASE;
D O I
10.1186/s12885-022-10258-3
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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 genomewide 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 poly genic 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.
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页数:11
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