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A transcriptome-wide association study of 229,000 women identifies new candidate susceptibility genes for breast cancer

Abstract

The breast cancer risk variants identified in genome-wide association studies explain only a small fraction of the familial relative risk, and the genes responsible for these associations remain largely unknown. To identify novel risk loci and likely causal genes, we performed a transcriptome-wide association study evaluating associations of genetically predicted gene expression with breast cancer risk in 122,977 cases and 105,974 controls of European ancestry. We used data from the Genotype-Tissue Expression Project to establish genetic models to predict gene expression in breast tissue and evaluated model performance using data from The Cancer Genome Atlas. Of the 8,597 genes evaluated, significant associations were identified for 48 at a Bonferroni-corrected threshold of P < 5.82 × 10−6, including 14 genes at loci not yet reported for breast cancer. We silenced 13 genes and showed an effect for 11 on cell proliferation and/or colony-forming efficiency. Our study provides new insights into breast cancer genetics and biology.

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Acknowledgements

The authors thank J. He, W. Wen, A. Giri and T. Edwards of Vanderbilt Epidemiology Center and R. Tao of the Department of Biostatistics, Vanderbilt University Medical Center for their help with the data analysis of this study. The authors would also like to thank all of the individuals for their participation in the parent studies and all of the researchers, clinicians, technicians and administrative staff for their contribution to the studies. We are also grateful to H. K. Im of University of Chicago for her help. The data analyses were conducted using the Advanced Computing Center for Research and Education (ACCRE) at Vanderbilt University. This project at Vanderbilt University Medical Center was supported in part by grants R01CA158473 and R01CA148677 from the US National Institutes of Health as well as funds from Anne Potter Wilson endowment. L.W. is supported by NCI K99 CA218892 and the Vanderbilt Molecular and Genetic Epidemiology of Cancer (MAGEC) training program (US NCI grant R25 CA160056 awarded to X.-O.S.). Genotyping of the OncoArray was principally funded from three sources: the PERSPECTIVE project, funded by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the Ministère de l’Économie, de la Science et de l’Innovation du Québec through Genome Québec and the Quebec Breast Cancer Foundation; the NCI Genetic Associations and Mechanisms in Oncology (GAME-ON) initiative and the Discovery, Biology and Risk of Inherited Variants in Breast Cancer (DRIVE) project (National Institutes of Health (NIH) grants U19 CA148065 and X01HG007492); and Cancer Research UK (C1287/A10118 and C1287/A16563). BCAC is funded by Cancer Research UK (C1287/A16563), by the European Community’s Seventh Framework Programme under grant agreement 223175 (HEALTH-F2-2009-223175) (COGS) and by the European Union’s Horizon 2020 Research and Innovation Programme under grant agreements 633784 (B-CAST) and 634935 (BRIDGES). Genotyping of the iCOGS array was funded by the European Union (HEALTH-F2-2009-223175), Cancer Research UK (C1287/A10710), the Canadian Institutes of Health Research for the ‘CIHR Team in Familial Risks of Breast Cancer’ program, and the Ministry of Economic Development, Innovation and Export Trade of Quebec—grant no. PSR-SIIRI-701. Combining of the GWAS data was supported in part by the NIH Cancer Post-Cancer GWAS initiative grant U19 CA 148065 (DRIVE, part of the GAME-ON initiative). A full description of funding and acknowledgments for BCAC studies, along with consortium membership, are included in the Supplementary Note.

Author information

W.Z. and J. Long conceived the study. L.W. contributed to the study design and performed statistical analyses. L.W., W.Z. and G.C.-T. wrote the manuscript with significant contributions from W.S., J. Long, X.G. and S.L.E. W.S. performed the in vitro experiments. G.C.-T. directed the in vitro experiments. X.G. contributed to the model building and pathway analyses. J.B. contributed to the bioinformatics analyses. F.A.-E., E.R. and S.L.E. contributed to the in vitro experiments. Y.L. and C.Z. contributed to the model building. K.M., M.K.B., X.-O.S., Q.W., J.D., B.L., C.Z., H.F., A.G., R.T.B., A.M.D., P.D.P.P., J.S., R.L.M., P.K. and D.F.E. contributed to manuscript revision, statistical analyses and/or BCAC data management. I.L.A., H.A.-C., V.A., K.J.A., P.L.A., M. Barrdahl, C.B., M.W.B., J.B., M. Bermisheva, C.B., N.V.B., S.E.B., H. Brauch, H. Brenner, L.B., P.B., S.Y.B., B.B., Q.C., T.C., F.C., B.D.C., J.E.C., J.C.-C., X.C., T.-Y.D.C., H.C., C.L.C., NBCS Collaborators, M.C., S.C., F.J.C., D.C., A.C., S.S.C., J.M.C., K.C., M.B.D., P.D., K.F.D., T.D., I.d.S.S., M. Dumont, M. Dwek, D.M.E., U.E., H.E., C.E., M.E., L.F., P.A.F., J.F., D.F.-J., O.F., H.F., L.F., M. Gabrielson, M.G.-D., S.M.G., M.G.-C., M.M.G., M. Ghoussaini, G.G.G., M.S.G., D.E.G., A.G.-N., P.G., E. Hahnen, C.A.H., N.H., P. Hall, E. Hallberg, U.H., P. Harrington, A. Hein, B.H., P. Hillemanns, A. Hollestelle, R.N.H., J.L.H., G.H., K.H., D.J.H., A.J., W.J., E.M.J., N.J., K.J., M.E.J., A. Jung, R.K., M.J.K., E.K., V.-M.K., V.N.K., D.L., L.L.M., J. Li, S.L., J. Lissowska, W.-Y.L., S. Loibl, J. Lubinski, C.L., M.P.L., R.J.M., T.M., I.M.K., A. Mannermaa, J.E.M., S.M., D.M., H.M.-H., A. Meindl, U.M., J.M., A.M.M., S.L.N., H.N., P.N., S.F.N., B.G.N., O.I.O., J.E.O., H.O., P.P., J.P., D.P.-K., R.P., N.P., K.P., B.R., P.R., N.R., G.R., H.S.R., V.R., A. Romero, J.R., A. Rudolph, E.S., D.P.S., E.J.S., M.K.S., R.K.S., A.S., R.J.S., C.G.S., S.S., M.S., M.J.S., A.S., M.C.S., J.J.S., J.S., H.S., A.J.S., R.T., W.T., J.A.T., M.B.T., D.C.T., A.T., K.T., R.A.E.M.T., D.T., T.T., M.U., C.V., D.V.D.B., D.V., Q.W., C.R.W., C.W., A.S.W., H.W., W.C.W., R.W., A.W., L.X., X.R.Y., A.Z., E.Z. and kConFab/AOCS Investigators contributed to the collection of the data and biological samples for the original BCAC studies. All authors have reviewed and approved the final manuscript.

Competing interests

The authors declare no competing interests.

Correspondence to Georgia Chenevix-Trench or Wei Zheng.

Integrated Supplementary Information

Supplementary Figure 1

Study design flow chart

Supplementary Figure 2 Performance of expression prediction models in GTEx and TCGA datasets for genes with at least 10% correlation in GTEx data.

The x axis represents the prediction performance (R2) in the GTEx dataset (n = 67). The y axis represents the prediction performance in the TCGA dataset (n = 86). Each dot represents the expression prediction model for one gene. There is a trend that genes with high internal prediction performance in GTEx data also have high external prediction performance in TCGA data (Pearson's correlation coefficient: 0.55).

Supplementary Figure 3 Quantile–quantile plots.

a, Quantile–quantile plot of P values in –log scale of associations between the genetically predicted expression levels of 8,597 genes and breast cancer risk. b, Quantile–quantile plot of P values in –log scale of associations between all 11.8 million SNPs and breast cancer risk in BCAC. c, Quantile–quantile plot of P values in –log scale of associations between the over 250,000 SNPs predicting expression levels of the 8,597 genes and breast cancer risk in BCAC.

Supplementary Figure 4 Heatmap of log fold change (FC) of selected genes normalized to expression levels in 184A1 breast cells.

Two or three primer sets were designed for each gene (y axis), and mRNA levels were quantified by qPCR in the indicated cells lines (x axis), including 184A1. The FC of genes normalized to that in 184A1 equals the mRNA level in the indicated cells divided by the mRNA level in 184A1. The log2 (FC) over 184A1 is depicted as a heatmap. An X represents ‘not detectable’ with all primer sets. The experiment was repeated independently twice with similar results.

Supplementary Figure 5 Validation of knockdown.

184A1, MCF7 and T47D cells, transfected with the indicated siRNAs, were harvested after 36 h for qPCR analysis to assess knockdown efficiency. The fold changes over NTCsi-transfected parental cells are plotted. The experiment was repeated three times independently with similar results.

Supplementary Figure 6 Proliferation in breast cells using two independent siRNAs.

ac, 184A1 (a), MCF7 (b) and T47D (c) cells were transfected with the indicated siRNAs over 7 d, and phase-contrast images were collected using an IncuCyte ZOOM. Each cell proliferation time course was normalized to the baseline confluency and analyzed in GraphPad Prism. Corrected proliferation % = 100 ± (relative proliferation in indicated siRNA – proliferation in control siRNA (consi))/knockdown efficiency. Related to Fig. 2a.

Supplementary Figure 7 Colony formation efficiency in MCF7 cells using two independent siRNAs.

MCF7 cells were transfected with the indicated siRNAs and then reseeded after 16 h for colony formation (CF) assays. At day 14, colonies were fixed with methanol, stained with crystal violet, scanned and batch analyzed by ImageJ. Corrected CF efficiency (CFE) % = 100 ± (relative CFE in indicated siRNA – CFE in control siRNA (consi))/knockdown efficiency. Error bars, s.d. (n = 4). P values were determined by one-way ANOVA followed by Dunnett’s multiple-comparisons test: *P < 0.05. Related to Fig. 2b.

Supplementary Figure 8 Power calculation of the TWAS analysis.

The simulation analysis is based on 122,977 cases and 105,974 controls. Gene expression was generated from the empirical distribution of predicted gene expression levels in the BCAC. Statistical power was calculated at P < 5.82 × 10–6 (the significance level used in the main TWAS analyses) according for cis-heritability (h2), which we aim to capture using gene expression prediction models (R2). The figure shows results per 1 s.d. increase (or decrease) in the gene expression based on 1,000 replicates.

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Supplementary Figures 1–8, Supplementary Tables 1, 5, 6, 8–11 and 13, and Supplementary Note

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    •  & Georgia Chenevix-Trench

    Nature Communications (2019)

Fig. 1: A Manhattan plot of the association results from the breast cancer transcriptome-wide association study.
Fig. 2: Heat maps of proliferation and CFE in breast cells.
Supplementary Figure 1
Supplementary Figure 2: Performance of expression prediction models in GTEx and TCGA datasets for genes with at least 10% correlation in GTEx data.
Supplementary Figure 3: Quantile–quantile plots.
Supplementary Figure 4: Heatmap of log fold change (FC) of selected genes normalized to expression levels in 184A1 breast cells.
Supplementary Figure 5: Validation of knockdown.
Supplementary Figure 6: Proliferation in breast cells using two independent siRNAs.
Supplementary Figure 7: Colony formation efficiency in MCF7 cells using two independent siRNAs.
Supplementary Figure 8: Power calculation of the TWAS analysis.