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Meta-Analysis
. 2022 Jul 8:11:e78304.
doi: 10.7554/eLife.78304.

Validation of a multi-ancestry polygenic risk score and age-specific risks of prostate cancer: A meta-analysis within diverse populations

Fei Chen #  1 , Burcu F Darst #  1   2 , Ravi K Madduri  3 , Alex A Rodriguez  3 , Xin Sheng  1 , Christopher T Rentsch  4   5   6 , Caroline Andrews  7 , Wei Tang  8 , Adam S Kibel  9 , Anna Plym  9   10 , Kelly Cho  11   12 , Mohamed Jalloh  13 , Serigne Magueye Gueye  13 , Lamine Niang  13 , Olufemi J Ogunbiyi  14 , Olufemi Popoola  14 , Akindele O Adebiyi  14 , Oseremen I Aisuodionoe-Shadrach  15 , Hafees O Ajibola  15 , Mustapha A Jamda  15 , Olabode P Oluwole  15 , Maxwell Nwegbu  15 , Ben Adusei  16 , Sunny Mante  16 , Afua Darkwa-Abrahams  17 , James E Mensah  17 , Andrew Anthony Adjei  17 , Halimatou Diop  18 , Joseph Lachance  19 , Timothy R Rebbeck  7 , Stefan Ambs  8 , J Michael Gaziano  11   12   20 , Amy C Justice  4   5 , David V Conti  1 , Christopher A Haiman  1
Affiliations
Meta-Analysis

Validation of a multi-ancestry polygenic risk score and age-specific risks of prostate cancer: A meta-analysis within diverse populations

Fei Chen et al. Elife. .

Abstract

Background: We recently developed a multi-ancestry polygenic risk score (PRS) that effectively stratifies prostate cancer risk across populations. In this study, we validated the performance of the PRS in the multi-ancestry Million Veteran Program and additional independent studies.

Methods: Within each ancestry population, the association of PRS with prostate cancer risk was evaluated separately in each case-control study and then combined in a fixed-effects inverse-variance-weighted meta-analysis. We further assessed the effect modification by age and estimated the age-specific absolute risk of prostate cancer for each ancestry population.

Results: The PRS was evaluated in 31,925 cases and 490,507 controls, including men from European (22,049 cases, 414,249 controls), African (8794 cases, 55,657 controls), and Hispanic (1082 cases, 20,601 controls) populations. Comparing men in the top decile (90-100% of the PRS) to the average 40-60% PRS category, the prostate cancer odds ratio (OR) was 3.8-fold in European ancestry men (95% CI = 3.62-3.96), 2.8-fold in African ancestry men (95% CI = 2.59-3.03), and 3.2-fold in Hispanic men (95% CI = 2.64-3.92). The PRS did not discriminate risk of aggressive versus nonaggressive prostate cancer. However, the OR diminished with advancing age (European ancestry men in the top decile: ≤55 years, OR = 7.11; 55-60 years, OR = 4.26; >70 years, OR = 2.79). Men in the top PRS decile reached 5% absolute prostate cancer risk ~10 years younger than men in the 40-60% PRS category.

Conclusions: Our findings validate the multi-ancestry PRS as an effective prostate cancer risk stratification tool across populations. A clinical study of PRS is warranted to determine whether the PRS could be used for risk-stratified screening and early detection.

Funding: This work was supported by the National Cancer Institute at the National Institutes of Health (grant numbers U19 CA214253 to C.A.H., U01 CA257328 to C.A.H., U19 CA148537 to C.A.H., R01 CA165862 to C.A.H., K99 CA246063 to B.F.D, and T32CA229110 to F.C), the Prostate Cancer Foundation (grants 21YOUN11 to B.F.D. and 20CHAS03 to C.A.H.), the Achievement Rewards for College Scientists Foundation Los Angeles Founder Chapter to B.F.D, and the Million Veteran Program-MVP017. This research has been conducted using the UK Biobank Resource under application number 42195. This research is based on data from the Million Veteran Program, Office of Research and Development, and the Veterans Health Administration. This publication does not represent the views of the Department of Veteran Affairs or the United States Government.

Keywords: African ancestry; Hispanic; epidemiology; genetics; genomics; global health; health disparities; multi-ancestry; none; polygenic risk scores; prostate cancer.

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Conflict of interest statement

FC, AR, XS, CR, CA, WT, AK, AP, KC, MJ, SG, LN, OO, OP, AA, OA, HA, MJ, OO, MN, BA, SM, AD, JM, AA, HD, JL, TR, SA, JG, AJ, DC, CH No competing interests declared, BD received honorarium for presentations at Society of Urology Oncology Annual Meeting (2021) and the Social Genomics Group at the University of Wisconsin, Madison (2021). The author has no other competing interests to declare, RM has stock or stock options in Navipoint Genomics LLC. The author has no other competing interests to declare

Figures

Figure 1.
Figure 1.. Association between the multi-ancestry polygenic risk score (PRS) of 269 variants and prostate cancer risk in men from European, African, and Hispanic populations.
The European ancestry replication studies included Million Veteran Program (MVP), UK Biobank (Conti, Darst et al., Nature Genetics, 2021), and Mass General Brigham (MGB) Biobank (Plym et al., JNCI, 2021). The African ancestry replication studies included MVP, California and Uganda Prostate Cancer Study (CA UG) (Conti, Darst et al., Nature Genetics, 2021), Men of African Descent and Carcinoma of the Prostate (MADCaP) Network, Maryland Prostate Cancer Case–Control Study (NCI-MD), and MGB Biobank (Plym et al., JNCI, 2021). Replication in Hispanic men was conducted in MVP. Results from individual replication studies are shown in Figure 1—figure supplement 1. The x-axis indicates the PRS category. Additional analysis was performed to evaluate the PRS association in men with extremely high genetic risk (99–100%). The y-axis indicates OR with error bars representing 95% CIs for each PRS category compared to the 40–60% PRS. The dotted horizontal line corresponds to an OR of 1. ORs and 95% CIs for each decile are provided in Figure 1—source data 1.
Figure 1—figure supplement 1.
Figure 1—figure supplement 1.. Association between the multi-ancestry polygenic risk score (PRS) of 269 variants and prostate cancer risk from individual replication studies of European (A) and African ancestry (B).
Replication studies in men of European and African ancestry included Million Veteran Program (MVP) (13,643 cases and 210,214 controls of European ancestry and 6353 cases and 53,362 controls of African ancestry), UK Biobank (6852 cases and 193,117 controls of European ancestry), Mass General Brigham (MGB) Biobank (67 cases and 457 controls of African ancestry and 1554 cases and 10,918 controls of European ancestry), California and Uganda Prostate Cancer Study (CA UG) (1586 cases and 1047 controls of African ancestry), Men of African Descent and Carcinoma of the Prostate (MADCaP) Network (405 cases and 396 controls of African ancestry), and Maryland Prostate Cancer Case–Control Study (NCI-MD) (383 cases and 395 controls of African ancestry). The x-axis indicates the PRS category. Additional analysis was performed to evaluate the PRS association in men with extremely high genetic risk (99–100%) in all individual studies except the MGB Biobank. The y-axis indicates OR with error bars representing the 95% CIs for each PRS category compared to the 40–60% PRS category. The dotted horizontal line corresponds to an OR of 1.
Figure 2.
Figure 2.. Association between the multi-ancestry polygenic risk score (PRS) of 269 variants and prostate cancer risk stratified by age.
PRS associations in men of European ancestry (A) were meta-analyzed from UK Biobank (6852 cases and 193,117 controls) and Million Veteran Program (MVP) (13,643 cases and 210,214 controls; Figure 2—figure supplement 1), whereas PRS associations in men of African ancestry (B) were estimated from MVP (6353 cases and 53,362 controls). The x-axis indicates the PRS category. Additional analyses were performed to evaluate the PRS association in men with extremely high genetic risk (top percentile, 99–100%). The y-axis indicates the OR with error bars representing the 95% CIs for each PRS category compared to the 40–60% PRS category. The dotted horizontal line corresponds to an OR of 1. The number of cases and controls, ORs, and 95% CIs for each PRS category in each age stratum are provided in Figure 2—source data 1.
Figure 2—figure supplement 1.
Figure 2—figure supplement 1.. Association between the multi-ancestry polygenic risk score (PRS) of 269 variants and prostate cancer risk stratified by age in men of European ancestry from UK Biobank (A) and Million Veteran Program (MVP) (B).
The x-axis indicates the PRS category. Additional analysis was performed to evaluate the PRS association in men with extremely high genetic risk (99–100%). The y-axis indicates OR with error bars representing the 95% CIs for each PRS category compared to the 40–60% PRS category. The dotted horizontal line corresponds to an OR of 1.
Figure 3.
Figure 3.. Absolute risk of prostate cancer by polygenic risk score (PRS) category in men from European (A), African (B), and Hispanic populations (C).
The absolute risks were estimated using the age- and population-specific PRS associations from Figure 2—source data 1, the Surveillance, Epidemiology, and End Results (SEER) incidence rates, and the CDC mortality rates corresponding to non-Hispanic White, Black, and Hispanic men. The dotted line indicates the 5% absolute risk of prostate cancer.
Appendix 1—figure 1.
Appendix 1—figure 1.. Individual studies of European, African, or Hispanic population included in the polygenic risk score (PRS) association analysis.
Results from previous replication studies (*) in UK Biobank, Mass General Brigham (MGB) Biobank, and California and Uganda Prostate Cancer Study (CA UG) were meta-analyzed with results from Million Veteran Program (MVP), Maryland Prostate Cancer Case–Control Study (NCI-MD), and Men of African Descent and Carcinoma of the Prostate (MADCaP) Network within each ancestry population.
See this image and copyright information in PMC

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