Milne, R.L., Burwinkel, B., Michailidou, K. et al. (178 more authors) (2014) Common non-synonymous SNPs associated with breast cancer susceptibility: findings from the Breast Cancer Association Consortium. Human Molecular Genetics, 23 (22). pp. 6096-6111. ISSN 0964-6906
Abstract
Candidate variant association studies have been largely unsuccessful in identifying common breast cancer susceptibility variants, although most studies have been underpowered to detect associations of a realistic magnitude. We assessed 41 common non-synonymous single-nucleotide polymorphisms (nsSNPs) for which evidence of association with breast cancer risk had been previously reported. Case-control data were combined from 38 studies of white European women (46 450 cases and 42 600 controls) and analyzed using unconditional logistic regression. Strong evidence of association was observed for three nsSNPs: ATXN7-K264R at 3p21 [rs1053338, per allele OR 5 1.07, 95% confidence interval (CI) 5 1.04–1.10, P 5 2.9 3 1026 ], AKAP9-M463I at 7q21 (rs6964587, OR 5 1.05, 95% CI 5 1.03–1.07, P 5 1.7 3 1026 ) and NEK10-L513S at 3p24 (rs10510592, OR 5 1.10, 95% CI 5 1.07 –1.12, P 5 5.1 3 10217). The first two associations reached genome-wide statistical significance in a combined analysis of available data, including independent data from nine genome-wide association studies (GWASs): for ATXN7-K264R, OR 5 1.07 (95% CI 5 1.05–1.10, P 5 1.0 3 1028 ); for AKAP9-M463I, OR 5 1.05 (95% CI 5 1.04–1.07, P 5 2.0 3 10210). Further analysis of other common variants in these two regions suggested that intronic SNPs nearby are more strongly associated with disease risk. We have thus identified a novel susceptibility locus at 3p21, and confirmed previous suggestive evidence that rs6964587 at 7q21 is associated with risk. The third locus, rs10510592, is located in an established breast cancer susceptibility region; the association was substantially attenuated after adjustment for the known GWAS hit. Thus, each of the associated nsSNPs is likely to be a marker for another, non-coding, variant causally related to breast cancer risk. Further fine-mapping and functional studies are required to identify the underlying risk-modifying variants and the genes through which they act.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © The Author 2014. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/ .0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Department of Neuroscience (Sheffield) The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > The Medical School (Sheffield) > Division of Genomic Medicine (Sheffield) > Department of Oncology and Metabolism (Sheffield) The University of Sheffield > Sheffield Teaching Hospitals |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 14 Apr 2016 14:45 |
Last Modified: | 14 Apr 2016 14:45 |
Published Version: | http://dx.doi.org/10.1093/hmg/ddu311 |
Status: | Published |
Publisher: | Oxford University Press (OUP): Policy B - Oxford Open Option B |
Refereed: | Yes |
Identification Number: | 10.1093/hmg/ddu311 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:97453 |