Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Multicenter Study
. 2021 Aug 2;4(8):e2119084.
doi: 10.1001/jamanetworkopen.2021.19084.

Generalizability of Polygenic Risk Scores for Breast Cancer Among Women With European, African, and Latinx Ancestry

Cong Liu  1 , Nur Zeinomar  2   3 , Wendy K Chung  4 , Krzysztof Kiryluk  5 , Ali G Gharavi  5 , George Hripcsak  1 , Katherine D Crew  5 , Ning Shang  1 , Atlas Khan  5 , David Fasel  1 , Teri A Manolio  6 , Gail P Jarvik  7 , Robb Rowley  6 , Ann E Justice  8 , Alanna K Rahm  9 , Stephanie M Fullerton  10 , Jordan W Smoller  11 , Eric B Larson  12 , Paul K Crane  7 , Ozan Dikilitas  13 , Georgia L Wiesner  14 , Alexander G Bick  14 , Mary Beth Terry  2 , Chunhua Weng  1
Affiliations
Multicenter Study

Generalizability of Polygenic Risk Scores for Breast Cancer Among Women With European, African, and Latinx Ancestry

Cong Liu et al. JAMA Netw Open. .

Abstract

Importance: Multiple polygenic risk scores (PRSs) for breast cancer have been developed from large research consortia; however, their generalizability to diverse clinical settings is unknown.

Objective: To examine the performance of previously developed breast cancer PRSs in a clinical setting for women of European, African, and Latinx ancestry.

Design, setting, and participants: This cohort study using the Electronic Medical Records and Genomics (eMERGE) network data set included 39 591 women from 9 contributing medical centers in the US that had electronic medical records (EMR) linked to genotype data. Breast cancer cases and controls were identified through a validated EMR phenotyping algorithm.

Main outcomes and measures: Multivariable logistic regression was used to assess the association between breast cancer risk and 7 previously developed PRSs, adjusting for age, study site, breast cancer family history, and first 3 ancestry informative principal components.

Results: This study included 39 591 women: 33 594 with European, 3801 with African, and 2196 with Latinx ancestry. The mean (SD) age at breast cancer diagnosis was 60.7 (13.0), 58.8 (12.5), and 60.1 (13.0) years for women with European, African, and Latinx ancestry, respectively. PRSs derived from women with European ancestry were associated with breast cancer risk in women with European ancestry (highest odds ratio [OR] per 1-SD increase, 1.46; 95% CI, 1.41-1.51), women with Latinx ancestry (highest OR, 1.31; 95% CI, 1.09-1.58), and women with African ancestry (OR, 1.19; 95% CI, 1.05-1.35). For women with European ancestry, this association with breast cancer risk was largest in the extremes of the PRS distribution, with ORs ranging from 2.19 (95% CI, 1.84-2.53) to 2.48 (95% CI, 1.89-3.25) for the 3 different PRSs examined for those in the highest 1% of the PRS compared with those in the middle quantile. Among women with Latinx and African ancestries at the extremes of the PRS distribution, there were no statistically significant associations.

Conclusions and relevance: This cohort study found that PRS models derived from women with European ancestry for breast cancer risk generalized well for women with European, Latinx, and African ancestries across different clinical settings, although the effect sizes for women with African ancestry were smaller, likely because of differences in risk allele frequencies and linkage disequilibrium patterns. These results highlight the need to improve representation of diverse population groups, particularly women with African ancestry, in genomic research cohorts.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest Disclosures: Dr Gharavi reported receiving grants from Renal Research Institute and Natera, and reported service on the advisory board for Goldfinch Bio outside the submitted work. Dr Smoller reported receiving an honorarium for an internal seminar from Biogen, Inc outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Association of Polygenic Risk Scores (PRSs) With Breast Cancer Risk in Women With European, African, and Latinx Ancestry in the eMERGE Cohorts
Odds ratios (ORs) are adjusted for the first 3 ancestry-specific principal components, age, family history, and study site. Breast Cancer Association Consortium with small variant total (BCAC-S) includes 313 variants in the original PRS, BCAC with large variant total (BCAC-L) includes 3820 variants in the original PRS, Women’s Health Initiative for women with Latinx ancestry (WHI-LA) includes 71 variants in the original PRS and was optimized for women with Latinx ancestry, WHI for women with African ancestry (WHI-AA) includes 75 variants in the original PRS and was optimized for women with African ancestry, UKBiobank (UKBB) includes 5218 variants in the original PRS, African Diaspora study (ROOT) includes 34 variants in the original PRS and was optimized to women with African ancestry, and the LATINAS model includes 179 variants from multiple cohorts in the original PRS and was optimized for women with Latinx ancestry.
Figure 2.
Figure 2.. The Association of Polygenic Risk Scores (PRSs) With Overall Breast Cancer Risk in Women With European Ancestry Relative to the Middle Quantile
Odds ratios (ORs) are adjusted for the first 3 ancestry-specific principal components, age, family history, and study site. BCAC-L indicates Breast Cancer Association Consortium with large variant total; BCAC-S, Breast Cancer Association Consortium with small variant total; UKBB, UKBiobank.
Figure 3.
Figure 3.. Cumulative Risk of Breast Cancer From Birth Estimated Using UKBB Polygenic Risk Score Model in Women With European, African, and Latinx Ancestry
See this image and copyright information in PMC

Comment in

References

    1. Yanes T, Young M-A, Meiser B, James PA. Clinical applications of polygenic breast cancer risk: a critical review and perspectives of an emerging field. Breast Cancer Res. 2020;22(1):21. doi:10.1186/s13058-020-01260-3 - DOI - PMC - PubMed
    1. Mavaddat N, Michailidou K, Dennis J, et al. ; ABCTB Investigators; kConFab/AOCS Investigators; NBCS Collaborators . Polygenic risk scores for prediction of breast cancer and breast cancer subtypes. Am J Hum Genet. 2019;104(1):21-34. doi:10.1016/j.ajhg.2018.11.002 - DOI - PMC - PubMed
    1. Lakeman IMM, Rodríguez-Girondo M, Lee A, et al. . Validation of the BOADICEA model and a 313-variant polygenic risk score for breast cancer risk prediction in a Dutch prospective cohort. Genet Med. 2020;22(11):1803-1811. doi:10.1038/s41436-020-0884-4 - DOI - PMC - PubMed
    1. Jia G, Lu Y, Wen W, et al. . Evaluating the utility of polygenic risk scores in identifying high-risk individuals for eight common cancers. JNCI Cancer Spectr. 2020;4(3):pkaa021. doi:10.1093/jncics/pkaa021 - DOI - PMC - PubMed
    1. Lambert SA, Abraham G, Inouye M. Towards clinical utility of polygenic risk scores. Hum Mol Genet. 2019;28(R2):R133-R142. doi:10.1093/hmg/ddz187 - DOI - PubMed

Publication types