Breast cancer risk variants at 6 q 25 display different phenotype associations and regulate ESR 1 , RMND 1 and CCDC 170

We analyzed 3,872 common genetic variants across the ESR1 locus (encoding estrogen receptor α) in 118,816 subjects from three international consortia. We found evidence for at least five independent causal variants, each associated with different phenotype sets, including estrogen receptor (ER+ or ER−) and human ERBB2 (HER2+ or HER2−) tumor subtypes, mammographic density and tumor grade. The best candidate causal variants for ER− tumors lie in four separate enhancer elements, and their risk alleles reduce expression of ESR1, RMND1 and CCDC170, whereas the risk alleles of the strongest candidates for the remaining independent causal variant disrupt a silencer element and putatively increase ESR1 and RMND1 expression. Reprints and permissions information is available online at http://www.nature.com/reprints/index.html. Correspondence should be addressed to A.M.D. (amd24@medschl.cam.ac.uk), D.F.E. (dfe20@medschl.cam.ac.uk) or S.L.E. (stacey.edwards@qimrberghofer.edu.au). 129A full list of members appears in the Supplementary Note. 198These authors contributed equally to this work. 199These authors jointly supervised this work. Accession codes. The relevant SNP genotype data underpinning these analyses can be accessed by applying to the BCAC and CIMBA consortia (see URLs). Note: Any Supplementary Information and Source Data files are available in the online version of the paper. AUTHOR CONTRIBUTIONS Manuscript writing group: A.M.D., K. Michailidou, K.B.K., D. Thompson, J.D.F., K.A.P., J. Beesley, C.S.H., G.C.-T., A.C.A., D.F.E. and S.L.E. Locus SNP selection: A.M.D., C.S.H. and E.D. iCOGS genotyping, genotype calling and quality control: A.M.D., J. Beesley, C.S.H., M.G., G.C.-T., K.A.P. and D.F.E. Imputation: K. Michailidou, K.B.K., A.C.A. and D.F.E. Statistical analyses and programming: K. Michailidou, K.B.K., A.C.A. and D.F.E. Functional analysis and bioinformatics: S.L.E., J.D.F., K.M.H., S. Kaufmann, H.S., M.M.M., J.S.L., E.L.-K., M. Hills, M.J., S.D., J. Beesley, S. Kar, N.A.S.-A., R.C.S., S.C. and S.N. COGS coordination: P.H., D.F.E., J. Beesley and A.M.D. BCAC coordination: D.F.E., G.C.-T., P.D.P.P. and J. Stone. BCAC data management: M.K.B. and Q.W. CIMBA coordination: A.C.A., G.C.-T., J. Stone and F.J.C. CIMBA data management: L.M. and D.B. MODE coordination: D. Thompson, C.V. and F.J.C. Provided participant samples and phenotype information and read and approved the manuscript: A.M.D., K. Michailidou, K.B.K., D. Thompson, J.D.F., J. Beesley, C.S.H., S. Kar, K.A.P., E.L.-K., E.D., D.B., N.A.S.A., R.C.S., K.M.H., S. Kaufmann, H.S., M.M.M., J.S.L., M. Hills, M.J., S.D., S.C., M.K.B., J.D., Q.W., J.L.H., M.C.S., A. Broeks, M.K.S., A. Lophatananon, K. Muir, M.W.B., P.A.F., I.d.-S.-S., J.P., E.J.S., I.T., B. Burwinkel, F.M., P.G., T.T., S.E.B., H.F., A.G.-N., J.I.A.P., H.A.-C., L.E., V.A., H. Brenner, A. Meindl, R.K.S., H. Brauch, U.H., K.A., C.B., H.I., K. Matsuo, N.B., T.D., A. Lindblom, S. Margolin, V.-M.K., A. Mannermaa, C.T., A.H.W., D.L., H.W., J.C.-C., A.R., P.P., P.R., J.E.O., G.G.G., R.L.M., C.A.H., B.E.H., M.S.G., S.H.T., C.H.Y., S.N., A.-L.B.-D., V.K., J. Long, W.Z., K.P., R.W., I.L.A., J.A.K., P.D., C. Seynaeve, J.F., M.E.S., K.C., H.D., A.Hollestelle, A.M.W.v.d.O., K.H., Y.-T.G., X.-O.S., A.C., S.S.C., W.B., Q.C., B.J.P., M.S., J.-Y.C., D.K., S.C.L., M. Hartman, M. Kabisch, D. Torres, A.J., J. Lubinski, P.B., S.S., C.B.A., A.E.T., C.-Y.S., P.-E.W., N.O., A.S., L.M., S.H., A. Lee, M. Kapuscinski, E.M.J., M.B.T., M.B.D., D.E.G., S.S.B., R.J., L.T., N.T., C.M.D., E.J.v.R., S.L.N., B.E., T.V.O.H., A.O., J. Benitez, R.R., J.N.W., B. Bonanni, B.P., S. Manoukian, L.P., L.O., I.K., P.A., J. Garber, M.U.R., D.F., L.I., S.E., A.K.G., N.A., D.N., K.R., N.B.-M., C. Sagne, D.S.-L., F.D., O.M.S., S. Mazoyer, C.I., K.B.M.C., K.D.L., M.d.l.H., T.C., H.N., S. Khan, A.R.M., M.J.H., M.A.R., A.K., E.O., O.D., J. Brunet, M.A.P., J. Gronwald, T.H., R.B.B., R. Laframboise, P.S., M.M., S.A., M.R.T., S.K.P., N.L., F.J.C., M. Tischkowitz, L.F., J.V., K.O., C.F.S., C.R., C.M.P., M.H.G., P.L.M., G.R., E.N.I., P.J.H., K.-A.P., M.P., A.M.M., G.G., A. Bojesen, M. Thomassen, M.A.C., S.-Y.Y., E.F., Y.L., A. Borg, A.v.W., H.E., J.R., O.I.O., P.A.G., R.L.N., S.A.G., K.L.N., S.M.D., B.K.A., G. Mitchell, B.Y.K., J. Lester, G. Maskarinec, C.W., C. Scott, J. Stone, C.A., R.T., R. Luben, K.-T.K., Å.Helland, V.H., M.D., P.D.P.P., J. Simard, P.H., M.G.-C., C.V., G.C.-T., A.C.A., D.F.E. and, S.L.E. COMPETING FINANCIAL INTERESTS The authors declare no competing financial interests. HHS Public Access Author manuscript Nat Genet. Author manuscript; available in PMC 2016 October 01. Published in final edited form as: Nat Genet. 2016 April ; 48(4): 374–386. doi:10.1038/ng.3521. A uhor M anscript