Validation of a multi-ancestry polygenic risk score and age-specific risks of prostate cancer: a meta-analysis within diverse populations
- University of Southern California, United States
- Fred Hutchinson Cancer Research Center, United States
- Argonne National Laboratory, United States
- Yale School of Medicine, United States
- Dana-Farber Cancer Institute, United States
- National Institutes of Health, United States
- Brigham and Women's Hospital, United States
- Harvard TH Chan School of Public Health, United States
- VA Boston Healthcare System, United States
- Hôpital Général Idrissa Pouye, Senegal
- University of Ibadan, Nigeria
- University of Abuja Teaching Hospital, Nigeria
- 37 Military Hospital, Ghana
- Korle-Bu Teaching Hospital, Ghana
- Hôpital Aristide Le Dantec, Senegal
- Georgia Institute of Technology, United States
- VA Connecticut Healthcare System, United States
- University of Southern California, Spain
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 (MVP) 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 (8,794 cases, 55,657 controls), and Hispanic (1,082 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 non-aggressive 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 if 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.
Data availability
This investigation included published results from the following studies under DOI numbers 10.1038/s41588-020-00748-0 and 10.1093/jnci/djab058. For the MVP data, the final data sets underlying this study cannot be shared outside the VA, except as required under the Freedom of Information Act (FOIA), per VA policy. However, upon request through the formal mechanisms in place and pending approval from the VHA Office of Research Oversight (ORO), a de-identified, anonymized dataset underlying this study can be created. Upon request through the formal mechanisms provided by the VHA ORO, we would be able to provide sufficiently detailed variable names and definitions to allow replication of our work. Any requests for data access should be directed to the VHA ORO (OROCROW@va.gov), and should reference the following project and analysis: 'MVP017: A VA-DOE Exemplar Project on Cancer'. Publicly available data described in this manuscript can be found from the following websites: 1000 Genomes Project (https://www.internationalgenome.org/); SEER (https://seer.cancer.gov/); National Center for Health Statistics, and CDC (https://www.cdc.gov/nchs/index.htm).
Article and author information
Author details
Olufemi J Ogunbiyi
Afua Darkwa-Abrahams
Christopher A Haiman
Funding
National Cancer Institute (U19 CA214253)
- Christopher A Haiman
Million Veteran Program (MVP017)
- J Michael Gaziano
- Amy C Justice
National Cancer Institute (U01 CA257328)
- Christopher A Haiman
National Cancer Institute (U19 CA148537)
- Christopher A Haiman
National Cancer Institute (R01 CA165862)
- Christopher A Haiman
National Cancer Institute (K99 CA246063)
- Burcu F Darst
National Cancer Institute (T32CA229110)
- Fei Chen
Prostate Cancer Foundation (20CHAS03)
- Christopher A Haiman
Prostate Cancer Foundation (21YOUN11)
- Burcu F Darst
Achievement Rewards for College Scientists Foundation
- Burcu F Darst
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- C Daniela Robles-Espinoza, International Laboratory for Human Genome Research, Mexico
Ethics
Human subjects: All study protocols were approved by each site's Institutional Review Board, and informedconsent was obtained from all study participants in accordance with the principles outlined in theDeclaration of Helsinki.
Version history
- Received: March 1, 2022
- Preprint posted: May 3, 2022 (view preprint)
- Accepted: July 7, 2022
- Accepted Manuscript published: July 8, 2022 (version 1)
- Version of Record published: July 26, 2022 (version 2)
Copyright
This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
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Validation of a multi-ancestry polygenic risk score and age-specific risks of prostate cancer: a meta-analysis within diverse populations
eLife 11:e78304.
https://doi.org/10.7554/eLife.78304
Further reading
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- Epidemiology and Global Health
Background:
The Zanzibar archipelago of Tanzania has become a low-transmission area for Plasmodium falciparum. Despite being considered an area of pre-elimination for years, achieving elimination has been difficult, likely due to a combination of imported infections from mainland Tanzania and continued local transmission.
Methods:
To shed light on these sources of transmission, we applied highly multiplexed genotyping utilizing molecular inversion probes to characterize the genetic relatedness of 282 P. falciparum isolates collected across Zanzibar and in Bagamoyo district on the coastal mainland from 2016 to 2018.
Results:
Overall, parasite populations on the coastal mainland and Zanzibar archipelago remain highly related. However, parasite isolates from Zanzibar exhibit population microstructure due to the rapid decay of parasite relatedness over very short distances. This, along with highly related pairs within shehias, suggests ongoing low-level local transmission. We also identified highly related parasites across shehias that reflect human mobility on the main island of Unguja and identified a cluster of highly related parasites, suggestive of an outbreak, in the Micheweni district on Pemba island. Parasites in asymptomatic infections demonstrated higher complexity of infection than those in symptomatic infections, but have similar core genomes.
Conclusions:
Our data support importation as a main source of genetic diversity and contribution to the parasite population in Zanzibar, but they also show local outbreak clusters where targeted interventions are essential to block local transmission. These results highlight the need for preventive measures against imported malaria and enhanced control measures in areas that remain receptive to malaria reemergence due to susceptible hosts and competent vectors.
Funding:
This research was funded by the National Institutes of Health, grants R01AI121558, R01AI137395, R01AI155730, F30AI143172, and K24AI134990. Funding was also contributed from the Swedish Research Council, Erling-Persson Family Foundation, and the Yang Fund. RV acknowledges funding from the MRC Centre for Global Infectious Disease Analysis (reference MR/R015600/1), jointly funded by the UK Medical Research Council (MRC) and the UK Foreign, Commonwealth & Development Office (FCDO), under the MRC/FCDO Concordat agreement and is also part of the EDCTP2 program supported by the European Union. RV also acknowledges funding by Community Jameel.
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- Computational and Systems Biology
- Epidemiology and Global Health
The chemical composition of foods is complex, variable, and dependent on many factors. This has a major impact on nutrition research as it foundationally affects our ability to adequately assess the actual intake of nutrients and other compounds. In spite of this, accurate data on nutrient intake are key for investigating the associations and causal relationships between intake, health, and disease risk at the service of developing evidence-based dietary guidance that enables improvements in population health. Here, we exemplify the importance of this challenge by investigating the impact of food content variability on nutrition research using three bioactives as model: flavan-3-ols, (–)-epicatechin, and nitrate. Our results show that common approaches aimed at addressing the high compositional variability of even the same foods impede the accurate assessment of nutrient intake generally. This suggests that the results of many nutrition studies using food composition data are potentially unreliable and carry greater limitations than commonly appreciated, consequently resulting in dietary recommendations with significant limitations and unreliable impact on public health. Thus, current challenges related to nutrient intake assessments need to be addressed and mitigated by the development of improved dietary assessment methods involving the use of nutritional biomarkers.
