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

The GENICA Network

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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

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Single Nucleotide Polymorphism
Confidence Intervals
Breast Neoplasms
Genome-Wide Association Study
Logistic Models
Alleles
Genome
Genes
Neoplasms

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Common non-synonymous SNPs associated with breast cancer susceptibility : Findings from the Breast Cancer Association Consortium. / The GENICA Network.

In: Human Molecular Genetics, Vol. 23, No. 22, 15.11.2014, p. 6096-6111.

Research output: Contribution to journalArticle

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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.",
author = "{The GENICA Network} and Milne, {Roger L.} and Barbara Burwinkel and Kyriaki Michailidou and {Arias Perez}, {Jose Ignacio} and {Pilar Zamora}, M. and Primitiva Men{\'e}ndez-Rodr{\'i}guez and David Hardisson and Marta Mendiola and Anna Gonz{\'a}lez-Neira and Guillermo Pita and {Rosario Alonso}, M. and Joe Dennis and Qin Wang and Bolla, {Manjeet K.} and Anthony Swerdlow and Alan Ashworth and Nick Orr and Minouk Schoemaker and Ko, {Yon Dschun} and Hiltrud Brauch and Ute Hamann and Andrulis, {Irene L.} and Knight, {Julia A.} and Gord Glendon and Sandrine Tchatchou and Keitaro Matsuo and Hidemi Ito and Hiroji Iwata and Kazuo Tajima and Jingmei Li and Brand, {Judith S.} and Hermann Brenner and Dieffenbach, {Aida Karina} and Volker Arndt and Christa Stegmaier and Diether Lambrechts and Gilian Peuteman and Christiaens, {Marie Rose} and Ann Smeets and Anna Jakubowska and Jan Lubinski and Katarzyna Jaworska-Bieniek and Katazyna Durda and Mikael Hartman and Miao Hui and Lim, {Wei Yen} and Chan, {Ching Wan} and Couch, {Fergus J} and Olson, {Janet E} and Vachon, {Celine M}",
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T1 - Common non-synonymous SNPs associated with breast cancer susceptibility

T2 - Findings from the Breast Cancer Association Consortium

AU - The GENICA Network

AU - Milne, Roger L.

AU - Burwinkel, Barbara

AU - Michailidou, Kyriaki

AU - Arias Perez, Jose Ignacio

AU - Pilar Zamora, M.

AU - Menéndez-Rodríguez, Primitiva

AU - Hardisson, David

AU - Mendiola, Marta

AU - González-Neira, Anna

AU - Pita, Guillermo

AU - Rosario Alonso, M.

AU - Dennis, Joe

AU - Wang, Qin

AU - Bolla, Manjeet K.

AU - Swerdlow, Anthony

AU - Ashworth, Alan

AU - Orr, Nick

AU - Schoemaker, Minouk

AU - Ko, Yon Dschun

AU - Brauch, Hiltrud

AU - Hamann, Ute

AU - Andrulis, Irene L.

AU - Knight, Julia A.

AU - Glendon, Gord

AU - Tchatchou, Sandrine

AU - Matsuo, Keitaro

AU - Ito, Hidemi

AU - Iwata, Hiroji

AU - Tajima, Kazuo

AU - Li, Jingmei

AU - Brand, Judith S.

AU - Brenner, Hermann

AU - Dieffenbach, Aida Karina

AU - Arndt, Volker

AU - Stegmaier, Christa

AU - Lambrechts, Diether

AU - Peuteman, Gilian

AU - Christiaens, Marie Rose

AU - Smeets, Ann

AU - Jakubowska, Anna

AU - Lubinski, Jan

AU - Jaworska-Bieniek, Katarzyna

AU - Durda, Katazyna

AU - Hartman, Mikael

AU - Hui, Miao

AU - Lim, Wei Yen

AU - Chan, Ching Wan

AU - Couch, Fergus J

AU - Olson, Janet E

AU - Vachon, Celine M

PY - 2014/11/15

Y1 - 2014/11/15

N2 - 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.

AB - 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.

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