Abstract
Breast cancer is the most common cancer among women. Common variants at 27 loci have been identified as associated with susceptibility to breast cancer, and these account for ∼9% of the familial risk of the disease. We report here a meta-analysis of 9 genome-wide association studies, including 10,052 breast cancer cases and 12,575 controls of European ancestry, from which we selected 29,807 SNPs for further genotyping. These SNPs were genotyped in 45,290 cases and 41,880 controls of European ancestry from 41 studies in the Breast Cancer Association Consortium (BCAC). The SNPs were genotyped as part of a collaborative genotyping experiment involving four consortia (Collaborative Oncological Gene-environment Study, COGS) and used a custom Illumina iSelect genotyping array, iCOGS, comprising more than 200,000 SNPs. We identified SNPs at 41 new breast cancer susceptibility loci at genome-wide significance (P < 5 × 10−8). Further analyses suggest that more than 1,000 additional loci are involved in breast cancer susceptibility.
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Acknowledgements
The authors wish to 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 and C1287/A12014) and by the European Community's Seventh Framework Programme under grant agreement 223175 (HEALTH-F2-2009-223175) (COGS). Meetings of BCAC have been funded by the European Union European Cooperation in Science and Technology (COST) programme (BM0606). 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 (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). Combining the GWAS data was supported in part by the US National Institutes of Health (NIH) Cancer Post-Cancer GWAS initiative grant 1 U19 CA 148065-01 (DRIVE, part of the GAME-ON initiative). A full description of funding and acknowledgments is provided in 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 BCAC. P.H. coordinated COGS. J. Benitez led the iCOGS genotyping working group. A.G.-N., G.P., M.R.A., J. Benitez, D.V., F.B., D.C.T., J. Simard, A.M.D. and C.L. coordinated genotyping of the iCOGS array. M.G.-C., 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.D., E.D., M. Ghoussaini and A. Lee provided bioinformatics support. M.K.B. and Q. Wang provided data management support for BCAC. S.C. and L.F.A.W. provided analysis of the TCGA expression data. C.T., N.R. and D.F.E. led the UK2 GWAS. O.F., J.P. and I.d.S.S. led the BBCS GWAS. H.N., T.A.M., K. Aittomäki and C.B. led the HEBCS GWAS. P.H., K.C., A.I. and J. Liu led the SASBAC GWAS. Q. Waisfisz, H.M.-H., M.A. and R.B.v.d.L. led the DFBBCS GWAS. J.C.-C., R.H., N.D. and L. Beckman led the MARIE GWAS. A. Meindl, R.K.S., B.M.-M. and P.L. led the GC-HBOC GWAS. J.L.H., M.C.S., E.M., D.F.S. and H.T. led the ABCFS GWAS. A.G.U. and A. Hofman led the genotyping in the Rotterdam study. D.J.H. and S.J.C. led the CGEMS GWAS. F.J.C. and S. Slager coordinated TNBCC. C.A.H., B.E.H., F.S. and L.L.M. coordinated MEC. P.D.P.P., D.F.E. and M. Shah coordinated SEARCH. R.L. coordinated EPIC-Norfolk. J. Brown coordinated SIBS. P.H., K.C., N.S., K.H. and J. Li coordinated SASBAC and pKARMA. S.E.B., B.G.N., S.F.N. and H.F. coordinated CGPS. F.J.C., X.W., C.V. and K.N.S. coordinated MCBCS. D.L., M.M., R.P. and M.-R.C. coordinated LMBC. J.C.-C., A.R., S.N. and D.F.-J. coordinated MARIE. N.J., L.G. and Z.A. coordinated BBCS. K. Aaltonen and T.H. coordinated HEBCS. M.K.S., A.B., L.J.V.t.V. and C.E.v.d.S. coordinated ABCS. P.G., T.T., P.L.-P. and F. Menegaux coordinated CECILE. F. Marme, A. Schneeweiss, C. Sohn and B. Burwinkel coordinated BSUCH. R.L.M., A.G.-N., M.P.Z., J.I.A.P. and J. Benitez coordinated CNIO-BCS. A.C., I.W.B., S.S.C. and M.W.R.R. coordinated SBCS. E.J.S., I.T., M.J.K. and N.M. coordinated BIGGS. I.L.A., J.A.K., G.G. and A.M.M. coordinated OFBCR. A. Lindblom and S. Margolin coordinated KARBAC. M.J.H., A. Hollestelle, A.M.W.v.d.O. and A. Jager coordinated RBCS. J.L.H., M.C.S., Q.M.B., J. Stone, G.S.D. and C.A. coordinated ABCFS. J.L.H., M.C.S., G.G.G., G.S. and L. Baglietto coordinated MCCS. P.A.F., L.H., A.B.E. and M.W.B. coordinated BBCC. H. Brenner, H. Müller, V.A. and C. Stegmaier coordinated ESTHER. A. Swerdlow, A.A., N.O., M.J. and M.G.-C. coordinated UKBGS. M.G.-C., J.F., J. Lissowska and L. Brinton coordinated PBCS. M.S.G., F.L., M.D. and J. Simard coordinated MTLGEBCS. R.W., K.P., A.J.-V. and M. Grip coordinated OBCS. H. Brauch, U.H. and T.B. coordinated GENICA. P.R., P.P., S. Manoukian and B. Bonanni coordinated MBCSG. P.D., R.A.E.M.T., C. Seynaeve and C.J.v.A. coordinated ORIGO. A. Jakubowska, J. Lubinski, K.J. and K.D. coordinated SZBCS. A. Mannermaa, V.K., V.-M.K. and J.M.H. coordinated KBCP. N.V.B., N.N.A. and T.D. coordinated HMBCS. V.N.K. coordinated NBCS. H.A.-C. coordinated UCIBCS. A.E.T. coordinated OSU. S.E. coordinated RPCI. F.F. coordinated DEMOKRITOS. D.K., K.-Y.Y. and D.-Y.N. coordinated SEBCS. K. Matsuo, H. Ito, H. Iwata and A. Sueta coordinated HERPACC. A.H.W., C.-C.T., D.V.D.B. and D.O.S. coordinated LAABC. W.Z., X.-O.S., W.L., Y.-T.G. and H.C. coordinated SGBCS. S.H.T., C.H.Y., S.Y.P. and B.K.C. coordinated MYBRCA. M.H., H. Miao, W.Y.L. and J.-H.S. coordinated SGBCC. K. Muir, A. Lophatananon, S.S.-B. and P.S. coordinated ACP. C.-Y.S., C.-N.H., P.-E.W. and S.-L.D. coordinated TWBCS. S. Sangrajrang, V.G., P.B. and J.M. coordinated TBCS. W.J.B., L.B.S., Q.C. and W.Z. coordinated SCCS. W.Z., S.D.-H., M. Shrubsole and J. Long coordinated NBHS. G.C.-T. coordinated the genotyping component of kConFab. All authors provided critical review of the manuscript.
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A list of members is provided in the Supplementary Note.
A list of members is provided in the Supplementary Note.
A list of members is provided in the Supplementary Note.
A list of members is provided in the Supplementary Note.
A list of members is provided in the Supplementary Note.
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Michailidou, K., Hall, P., Gonzalez-Neira, A. et al. Large-scale genotyping identifies 41 new loci associated with breast cancer risk. Nat Genet 45, 353–361 (2013). https://doi.org/10.1038/ng.2563
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DOI: https://doi.org/10.1038/ng.2563
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