Breast cancer exhibits familial aggregation, consistent with variation in genetic susceptibility to the disease. Known susceptibility genes account for less than 25% of the familial risk of breast cancer, and the residual genetic variance is likely to be due to variants conferring more moderate risks. To identify further susceptibility alleles, we conducted a two-stage genome-wide association study in 4,398 breast cancer cases and 4,316 controls, followed by a third stage in which 30 single nucleotide polymorphisms (SNPs) were tested for confirmation in 21,860 cases and 22,578 controls from 22 studies. We used 227,876 SNPs that were estimated to correlate with 77% of known common SNPs in Europeans at r2 > 0.5. SNPs in five novel independent loci exhibited strong and consistent evidence of association with breast cancer (P < 10-7). Four of these contain plausible causative genes (FGFR2, TNRC9, MAP3K1 and LSP1). At the second stage, 1,792 SNPs were significant at the P < 0.05 level compared with an estimated 1,343 that would be expected by chance, indicating that many additional common susceptibility alleles may be identifiable by this approach.
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The authors thank the women who took part in this research, and all the funders and support staff who made this study possible. The principal funding for this study was provided by Cancer Research UK. Detailed acknowledgements are provided in Supplementary Information.
Author Contributions D.F.E., A.M.D., P.D.P.P., D.R.C. and B.A.J.P. designed the study and obtained financial support. D.G.B. and D.R.C. directed the genotyping of stages 1 and 2. D.F.E. and D.T. conducted the statistical analysis. K.A.P. and A.M.D. coordinated the genotyping for stage 3 and the fine-scale mapping of the FGFR2 and TNRC9 loci. J.P.S. and J.Z. performed resequencing and analysis of the FGFR2 locus. K.A.P., S.A., C.S.H., R.B., C.A.H., L.K.K., B.E.H., L.L.M., P.B., S.S., V.G., F.O., C-Y. S., P-E.W. and H-C.W. conducted genotyping for the fine-scale mapping. R.L., J.M., H.F. and K.B.M. provided bioinformatics support. D.E., D.G.E., J.P., O.F., N.J., S.S., M.R.S. and N.R. coordinated the studies used in stage 1. N.W. and N.E.D. coordinated the EPIC study used in stages 1 and 2. The remaining authors coordinated the studies in stage 3 and undertook genotyping in those studies. D.F.E. drafted the manuscript, with substantial contributions from K.A.P., A.M.D., P.D.P.P. and B.A.J.P. All authors contributed to the final paper.
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Biomedicine & Pharmacotherapy (2019)