Genome-wide association analysis of more than 120,000 individuals identifies 15 new susceptibility loci for breast cancer

Abstract

Genome-wide association studies (GWAS) and large-scale replication studies have identified common variants in 79 loci associated with breast cancer, explaining 14% of the familial risk of the disease. To identify new susceptibility loci, we performed a meta-analysis of 11 GWAS, comprising 15,748 breast cancer cases and 18,084 controls together with 46,785 cases and 42,892 controls from 41 studies genotyped on a 211,155-marker custom array (iCOGS). Analyses were restricted to women of European ancestry. We generated genotypes for more than 11 million SNPs by imputation using the 1000 Genomes Project reference panel, and we identified 15 new loci associated with breast cancer at P < 5 × 10−8. Combining association analysis with ChIP-seq chromatin binding data in mammary cell lines and ChIA-PET chromatin interaction data from ENCODE, we identified likely target genes in two regions: SETBP1 at 18q12.3 and RNF115 and PDZK1 at 1q21.1. One association appears to be driven by an amino acid substitution encoded in EXO1.

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Figure 1: Histograms of imputation r2.
Figure 2: The chromosome 1 locus tagged by rs12405132.

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Acknowledgements

The authors thank all the individuals who took part in these studies and all the researchers, clinicians, technicians and administrative staff who have enabled this work to be carried out.

BCAC is funded by Cancer Research UK (C1287/A10118, C1287/A12014) and by the European Community's Seventh Framework Programme under grant agreement 223175 (HEALTH-F2-2009-223175) (COGS). Meetings of the BCAC have been funded by the European Union COST programme (BM0606). Genotyping on the iCOGS array was funded by the European Union (HEALTH-F2-2009-223175), Cancer Research UK (C1287/A10710, C8197/A16565), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer program and the Ministry of Economic Development, Innovation and Export Trade of Quebec, grant PSR-SIIRI-701. Combination of the GWAS data was supported in part by the US National Institutes of Health (NIH) Cancer Post-Cancer GWAS initiative, grant 1 U19 CA148065-01 (DRIVE, part of the GAME-ON initiative). For a full description of funding and acknowledgments, see the Supplementary Note.

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K. Michailidou and D.F.E. performed the statistical analysis and drafted the manuscript. D.F.E. conceived and coordinated the synthesis of the iCOGS array and led the BCAC. P.H. coordinated COGS. J. Benitez led the iCOGS genotyping working group. A.G.-N., G.P., M.R.A., N.Á., D.H., J. Benitez, D.V., F.B., D.C.T., J.S., A.M.D., C.L., C. Baynes, S.A., C.S.H. and M.J.M. coordinated genotyping of the iCOGS array. M.G.-C., P.P.D.P.P. and M.K.S. led the BCAC pathology and survival working group. J.C.-C. led the BCAC risk factor working group. A.M.D. and G.C.-T. led the iCOGS quality control working group. J. Beesley, J.D. and M.J.L. provided bioinformatics support. M.K.B. and Q. Wang provided data management support for BCAC. S. Canisius provided analysis of the TCGA expression data. J.L.H., M.C.S., H.T. and C.A. coordinated ABCFS. M.K.S., A.B., S.V. and S. Cornelissen coordinated ABCS. K. Muir, A. Lophatananon, S.S.-B. and P.S. coordinated ACP. P.A.F., A. Hein, M.W.B. and L.H. coordinated BBCC. J.P., I.d.-S.-S., O.F. and L.G. coordinated BBCS. E.J.S., I.T., M.J.K. and N.M. coordinated BIGGS. P.K., D.J.H., S.L., S.M.G., M.M.G., W.R.D., C.A.H., F.S., B.E.H., L.L.M., C.D.B., S.J.C., J.F. and R.N.H. coordinated BPC3. B.B., F.M., H.S. and C. Sohn coordinated BSUCH. N.R. and C. Turnbull coordinated BOCS. P.G., T.T., C. Mulot and M. Sanchez coordinated CECILE. S.E.B., B.G.N., H.F. and S.F.N. coordinated CGPS. A.G.-N., J. Benitez, M.P.Z. and J.I.A.P. coordinated CNIO-BCS. H.A.-C. and S.L.N. coordinated CTS. H. Brenner, A.K.D., V.A. and C. Stegmaier coordinated ESTHER. A. Meindl, R.K.S., C. Sutter and R.Y. coordinated GC-HBOC. H. Brauch, U.H. and T.B. coordinated GENICA. H.N., T.A.M., K. Aittomäki, C. Blomqvist, K. Aaltonen and S.K. coordinated HEBCS. K. Matsuo, H. Ito, H. Iwata and K.T. coordinated HERPACC. T.D. and N.V.B. coordinated HMBCS. A. Lindblom and S. Margolin coordinated KARBAC. A. Mannermaa, V.K., V.-M.K. and J.M.H. coordinated KBCP. G.C.-T. and J. Beesley coordinated kConFab/AOCS. A.H.W., C. Tseng, D.V.D.B. and D.O.S. coordinated LAABC. D.L., P.N., H.W. and E.v.L. coordinated LMBC. J.C.-C., D.F.-J., U.E., S.B. and A.R. coordinated MARIE. P.R., P. Peterlongo, S. Manoukian and L. Bernard coordinated MBCSG. F.J.C., J.E.O., E.H. and C.V. coordinated MCBCS. G.G.G., R.L.M. and C. McLean coordinated MCCS. C.A.H., B.E.H., F.S. and L.L.M. coordinated MEC. J.S., M.S.G., F.L. and M.D. coordinated MTLGEBCS. S.H.T., C.H.Y., N.A.M.T. and G.-H.T. coordinated MYBRCA. V.N.K., G.I.G.A. and S.N. coordinated NBCS. W.Z., S.L.H., M. Shrubsole and J. Long coordinated NBHS. R.W., K.P., A.J.-V. and M.G. coordinated OBCS. I.L.A., J.A.K., G.G. and A.M.M. coordinated OFBCR. P.D., R.A.E.M.T., C. Seynaeve and C.J.V.A. coordinated ORIGO. M.G.-C., J.F., S.J.C. and L. Brinton coordinated PBCS. K.C., H.D., M.E. and J.S.B. coordinated pKARMA. M.J.H., A. Hollestelle, J.W.M.M. and J.M.C. coordinated RBCS. P.H., J. Li, J. Liu and K.H. coordinated SASBAC. X.-O.S., W.L., Y.-T.G. and H.C. coordinated SBCGS. A.C., S.S.C. and M.W.R.R. coordinated SBCS. W.B., L.B.S. and Q.C. coordinated SCCS. M. Shah and B.J.P. coordinated SEARCH. D.K., J.-Y.C., S.K.P. and K.-Y.Y. coordinated SEBCS. M.H., H.M., K.S.C. and C.W.C. coordinated SGBCC. U.H., M.K. and D. Torres coordinated SKKDKFZS. A.J., J. Lubinski, K.J. and T.H. coordinated SZBCS. S. Sangrajrang, V.G., P.B. and J.M. coordinated TBCS. F.J.C., S. Slager, A.E.T., C.B.A. and D.Y. coordinated the TNBCC. C.-Y.S., C.-N.H., P.-E.W. and M.-F.H. coordinated TWBCS. A.J.S.,A.A., N.O. and M.J.S. coordinated UKBGS. H.A., M.G.K., A.S.W., E.M.J., K.E.M., M.D.G., R.M.S., G.U., E.M., D.F.S. and G.C. coordinated EBCG GWAS. Q. Waisfisz, H.M.-H., M.A.A. and R.B.v.d.L. coordinated DFBBCS GWAS. D.F.E., N.R. and C. Turnbull coordinated UK2 GWAS. F.C., D. Trichopoulos, P. Peeters, E.L., M. Sund, K.-T.K., M.J.G., D.P., L.D., J.-M.H. and L.M.M. coordinated EPIC. All authors provided critical review of the manuscript.

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Correspondence to Douglas F Easton.

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The authors declare no competing financial interests.

Additional information

A full list of members and affiliations appears in the Supplementary Note.

A full list of members and affiliations appears in the Supplementary Note.

A full list of members and affiliations appears in the Supplementary Note.

A full list of members and affiliations appears in the Supplementary Note.

A full list of members and affiliations appears in the Supplementary Note.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–6, Supplementary Tables 1–9 and Supplementary Note. (PDF 5459 kb)

Supplementary Table 10

Set of all 522 SNPs correlated with 1 of the 15 lead SNPs and that could not be ruled out as potentially causal (based on a likelihood ratio of 100:1). (XLS 92 kb)

Supplementary Table 11

Associations between the 15 new susceptibility variants and expression of neighboring genes in breast tumors and normal breast tissue, from the TCGA data set. (XLS 78 kb)

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Michailidou, K., Beesley, J., Lindstrom, S. et al. Genome-wide association analysis of more than 120,000 individuals identifies 15 new susceptibility loci for breast cancer. Nat Genet 47, 373–380 (2015). https://doi.org/10.1038/ng.3242

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