Abstract
We performed genome-wide association studies of breast cancer including 18,034 cases and 22,104 controls of African ancestry. Genetic variants at 12 loci were associated with breast cancer risk (P < 5 × 10−8), including associations of a low-frequency missense variant rs61751053 in ARHGEF38 with overall breast cancer (odds ratio (OR) = 1.48) and a common variant rs76664032 at chromosome 2q14.2 with triple-negative breast cancer (TNBC) (OR = 1.30). Approximately 15.4% of cases with TNBC carried six risk alleles in three genome-wide association study-identified TNBC risk variants, with an OR of 4.21 (95% confidence interval = 2.66–7.03) compared with those carrying fewer than two risk alleles. A polygenic risk score (PRS) showed an area under the receiver operating characteristic curve of 0.60 for the prediction of breast cancer risk, which outperformed PRS derived using data from females of European ancestry. Our study markedly increases the population diversity in genetic studies for breast cancer and demonstrates the utility of PRS for risk prediction in females of African ancestry.
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Data availability
Summary-level statistics data have been uploaded to the GWAS Catalog (GCST90296719 for overall breast cancer, GCST90296720 for ER+ breast cancer, GCST90296721 for ER− breast cancer and GCST90296722 for TNBC). Data from the 1000 Genomes Project can be obtained from www.internationalgenome.org/data/. The GENCODE datasets are available from www.gencodegenes.org/human/. The genomic and transcriptomic data generated from the Komen Tissue Bank samples have been uploaded to the database of Genotypes and Phenotypes (accession no. phs003535).
Code availability
The analysis code can be accessed at the GitHub repository (github.com/Damon0212/AABCG_GWAS_breast_cancer). The code has also been uploaded to Zenodo60 (https://doi.org/10.5281/zenodo.10372821).
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Acknowledgements
This research was supported in part by National Institutes of Health grant nos. R01 CA202981 (to W.Z., C.A.H. and J.R.P.) and R01 CA235553 (to W.Z. and J. L.). Sample preparation and genotyping assays at Vanderbilt were conducted at the Survey and Biospecimen Shared Resources and Vanderbilt Technologies for Advanced Genomics, which are supported in part by the Vanderbilt-Ingram Cancer Center (no. P30CA068485 to B. H. Park). Data analyses were conducted using the Advanced Computing Center for Research and Education at Vanderbilt University. Additional information is provided in the Supplementary Note. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agents. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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G.J. and W.Z. conceived and designed the study. S.A., M.E.B., Y.C., M.G.-C., J.G., J.J.H., D.H., E.M.J., C.I.L., K.L.N., B.N., O.I.O., T.P., M.F.P., M.S., D.P.S., X.-O.S., M.A.T., S.Y., P.O.A., T.A., A.M.B., A.J.M.H., T.M., P.N., K.M.O., A.F.O., M.M.O., S.R., E.N.B., M.H., A.N., C.B.A., Q.C., J.L., J.R.P., C.A.H. and W.Z. recruited the study participants, and collected the data and specimens. G.J., J.P., X.G., Y.Y., M.G., J.G., D.H., E.M.J., M.A.T., S.Y., T.A., A.F.O., E.N.B., M.H., C.B.A. and Q.C. managed sample and data preparation, or carried out quality control. G.J., J.P., X.G., Y.Y., R.T., J.L.L., H.Q. and H.Z. analyzed the data. G.J., J.P., Y.Y., B.L., J.L.L., T.P., X.-O.S., A.J.M.H., S.R., H.Z. and W.Z. interpreted the findings. G.J., X.G., R.T., M.E.B., M.G., D.H., C.I.L., J.L.L., O.I.O., T.P., M.F.P., P.O.A., T.A., A.J.M.H., T.M., P.N., M.M.O., S.R., A.N., J.L., J.R.P., C.A.H. and W.Z. drafted or substantively revised the paper. J.R.P., C.A.H. and W.Z. supervised the project.
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O.I.O. is a cofounder of CancerIQ, serves as scientific adviser at Tempus and is on the board of 54gene. A.N. has received research support from Roche. The other authors declare no competing interests.
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Extended data
Extended Data Fig. 1 Genome-wide association with overall breast cancer and subtypes.
(a) Overall breast cancer, (b) ER-positive breast cancer, (c) ER-negative breast cancer, (d) triple-negative breast cancer. Associations were estimated in each dataset and meta-analyzed with fixed effects model. Logistic regression was used for genome-wide association analyses, with two-sided tests, using 5 × 10−8 as genome-wide significance level (dashed lines).
Extended Data Fig. 2 Forest plot for risk estimates of selected variants.
(a) missense variant rs61751053 at locus 4q24 in association with overall breast cancer, T allele as effect allele; (b) novel variant rs10853615 at locus 18q11.2 in association with ER-positive breast cancer, A allele as effect allele; (c) novel risk variant rs76664032 at locus 2q14.2 in association with ER-negative breast cancer, A allele as effect allele; (d) novel risk variant rs76664032 at locus 2q14.2 in association with TNBC, A allele as effect allele. r2, imputation quality score. a. Studies for each dataset are described in Supplementary Note and Supplementary Table 1. EAF, effect allele frequency. CI, confidence interval. Logistic regression was used for association analyses with two-sided tests. The sample size (n) was shown for each participating study/dataset. In the bar plot, the log odds ratios (beta) are presented as mean ±1.96*standard error, with mean value as the center and 95% CI as the minimum and maximum.
Extended Data Fig. 3 Distribution of PRS in the testing set of samples.
(a) The PRSAFR was calculated using 94 selected variants with weights derived from the training samples; (b) The PRSEUR constructed with previously reported weight derived from European-ancestry women. Both PRSs were divided by the standard deviation in controls and centered at the mean in controls.
Supplementary information
Supplementary Information
Supplementary Figs. 1–10, Methods and Acknowledgements.
Supplementary Tables
Supplementary Tables 1–12
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Jia, G., Ping, J., Guo, X. et al. Genome-wide association analyses of breast cancer in women of African ancestry identify new susceptibility loci and improve risk prediction. Nat Genet 56, 819–826 (2024). https://doi.org/10.1038/s41588-024-01736-4
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DOI: https://doi.org/10.1038/s41588-024-01736-4
