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

Cong Liu,Gail P Jarvik,David Fasel,Georgia L Wiesner,Ali G Gharavi,Atlas Khan,Ann E Justice,Eric B Larson,Teri A Manolio,Ning Shang,Krzysztof Kiryluk,George Hripcsak,Alanna Kulchak Rahm ,Ozan Dikilitas,Alexander Bick ,Paul K Crane,Mary Beth Terry,Wendy K Chung,Nur Zeinomar,Stephanie M Fullerton,Jordan W Smoller,Katherine D Crew,Robb Rowley,Chunhua Weng

doi:10.1001/jamanetworkopen.2021.19084

Abstract

Multiple polygenic risk scores (PRSs) for breast cancer have been developed from large research consortia; however, their generalizability to diverse clinical settings is unknown. To examine the performance of previously developed breast cancer PRSs in a clinical setting for women of European, African, and Latinx ancestry. 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. 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. 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. 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.

Highlights

Polygenic risk scores (PRSs) have consistently shown the ability to stratify the risk of breast cancer among women with European ancestry,[1] but their generalizability to other race/ethnic groups is more limited
polygenic risk scores (PRSs) derived from women with European ancestry were associated with breast cancer risk in women with European ancestry, women with Latinx ancestry, and women with African ancestry (OR, 1.19; 95% CI, 1.05-1.35)
Among women with Latinx and African ancestries at the extremes of the PRS distribution, there were no statistically significant associations. 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, the effect sizes for women with African ancestry were smaller, likely because of differences in risk allele frequencies and linkage disequilibrium patterns

Summary

Introduction

Polygenic risk scores (PRSs) have consistently shown the ability to stratify the risk of breast cancer among women with European ancestry,[1] but their generalizability to other race/ethnic groups is more limited. Using large consortia of women with European ancestry, a PRS developed in the Breast Cancer Association Consortium (BCAC), reported approximately 2-fold and 4-fold increases in breast cancer risk for women in the top 10% and 1% of the PRS respectively; compared with women in the middle quantiles of risk (40% to 60%).[2] This association has been replicated in validation studies using large cohorts of women with European ancestry.[3,4]. Understanding the performance of these PRSs in diverse populations is crucial as we move toward clinical implementation of the PRS. In order to incorporate PRSs into clinical practice, models will need to be integrated with other clinical covariates like family history in the electronical medical records (EMR).[5] With few exceptions,[6] studies have not yet evaluated the performance of breast cancer PRSs using clinical data extracted from the EMR

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