Common non-synonymous SNPs associated with breast cancer susceptibility: Findings from the Breast Cancer Association Consortium

The GENICA Network, The GENICA Network, The GENICA Network, The GENICA Network, The GENICA Network, The GENICA Network, The GENICA Network, Australian Ovarian Cancer Study Group, KConFab investigators, Australian Ovarian Cancer Study Group, TNBCC

Research output: Contribution to journalArticle

41 Scopus citations

Abstract

Candidate variant association studies havebeenlargely unsuccessful in identifyingcommonbreast 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 werecombined 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 acombined 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 SNPsnearby are more strongly associated with disease risk.Wehave 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.

Original languageEnglish (US)
Pages (from-to)6096-6111
Number of pages16
JournalHuman molecular genetics
Volume23
Issue number22
DOIs
StatePublished - Nov 15 2014

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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    The GENICA Network, The GENICA Network, The GENICA Network, The GENICA Network, The GENICA Network, The GENICA Network, The GENICA Network, Australian Ovarian Cancer Study Group, KConFab investigators, Australian Ovarian Cancer Study Group, & TNBCC (2014). Common non-synonymous SNPs associated with breast cancer susceptibility: Findings from the Breast Cancer Association Consortium. Human molecular genetics, 23(22), 6096-6111. https://doi.org/10.1093/hmg/ddu311