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

Roger L Milne; Barbara Burwinkel; Kyriaki Michailidou; Jose-Ignacio Arias-Perez; M Pilar Zamora; Primitiva Menéndez-Rodríguez; David Hardisson; Marta Mendiola; Anna González-Neira; Guillermo Pita; M Rosario Alonso; Joe Dennis; Qin Wang; Manjeet K Bolla; Anthony Swerdlow; Alan Ashworth; Nick Orr; Minouk Schoemaker; Yon-Dschun Ko; Hiltrud Brauch; Ute Hamann; Irene L Andrulis; Julia A Knight; Gord Glendon; Sandrine Tchatchou; Keitaro Matsuo; Hidemi Ito; Hiroji Iwata; Kazuo Tajima; Jingmei Li; Judith S Brand; Hermann Brenner; Aida Karina Dieffenbach; Volker Arndt; Christa Stegmaier; Diether Lambrechts; Gilian Peuteman; Marie-Rose Christiaens; Ann Smeets; Anna Jakubowska; Jan Lubinski; Katarzyna Jaworska-Bieniek; Katazyna Durda; Mikael Hartman; Miao Hui; Wei Yen Lim; Ching Wan Chan; Federick Marme; Stig E Bojesen; Børge G Nordestgaard; GENICA Network

doi:10.1093/hmg/ddu311

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

Roger L Milne, Barbara Burwinkel, Kyriaki Michailidou, Jose-Ignacio Arias-Perez, M Pilar Zamora, Primitiva Menéndez-Rodríguez, David Hardisson, Marta Mendiola, Anna González-Neira, Guillermo Pita, M Rosario Alonso, Joe Dennis, Qin Wang, Manjeet K Bolla, Anthony Swerdlow, Alan Ashworth, Nick Orr, Minouk Schoemaker, Yon-Dschun Ko, Hiltrud BrauchUte Hamann, Irene L Andrulis, Julia A Knight, Gord Glendon, Sandrine Tchatchou, Keitaro Matsuo, Hidemi Ito, Hiroji Iwata, Kazuo Tajima, Jingmei Li, Judith S Brand, Hermann Brenner, Aida Karina Dieffenbach, Volker Arndt, Christa Stegmaier, Diether Lambrechts, Gilian Peuteman, Marie-Rose Christiaens, Ann Smeets, Anna Jakubowska, Jan Lubinski, Katarzyna Jaworska-Bieniek, Katazyna Durda, Mikael Hartman, Miao Hui, Wei Yen Lim, Ching Wan Chan, Federick Marme, Stig E Bojesen, Børge G Nordestgaard, GENICA Network

Department of Clinical Medicine

44 Citations (Scopus)

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 language	English
Journal	Human Molecular Genetics
Volume	23
Issue number	22
Pages (from-to)	6096-6111
Number of pages	16
ISSN	0964-6906
DOIs	https://doi.org/10.1093/hmg/ddu311
Publication status	Published - 15 Nov 2014

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Milne, R. L., Burwinkel, B., Michailidou, K., Arias-Perez, J-I., Zamora, M. P., Menéndez-Rodríguez, P., Hardisson, D., Mendiola, M., González-Neira, A., Pita, G., Alonso, M. R., Dennis, J., Wang, Q., Bolla, M. K., Swerdlow, A., Ashworth, A., Orr, N., Schoemaker, M., Ko, Y-D., ... GENICA Network (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

Milne, RL, Burwinkel, B, Michailidou, K, Arias-Perez, J-I, Zamora, MP, Menéndez-Rodríguez, P, Hardisson, D, Mendiola, M, González-Neira, A, Pita, G, Alonso, MR, Dennis, J, Wang, Q, Bolla, MK, Swerdlow, A, Ashworth, A, Orr, N, Schoemaker, M, Ko, Y-D, Brauch, H, Hamann, U, Andrulis, IL, Knight, JA, Glendon, G, Tchatchou, S, Matsuo, K, Ito, H, Iwata, H, Tajima, K, Li, J, Brand, JS, Brenner, H, Dieffenbach, AK, Arndt, V, Stegmaier, C, Lambrechts, D, Peuteman, G, Christiaens, M-R, Smeets, A, Jakubowska, A, Lubinski, J, Jaworska-Bieniek, K, Durda, K, Hartman, M, Hui, M, Yen Lim, W, Wan Chan, C, Marme, F, Bojesen, SE , Nordestgaard, BG & GENICA Network 2014, 'Common non-synonymous SNPs associated with breast cancer susceptibility: findings from the Breast Cancer Association Consortium', Human Molecular Genetics, vol. 23, no. 22, pp. 6096-6111. https://doi.org/10.1093/hmg/ddu311

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title = "Common non-synonymous SNPs associated with breast cancer susceptibility: findings from the Breast Cancer Association Consortium",

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 = "Milne, {Roger L} and Barbara Burwinkel and Kyriaki Michailidou and Jose-Ignacio Arias-Perez and Zamora, {M Pilar} and Primitiva Men{\'e}ndez-Rodr{\'i}guez and David Hardisson and Marta Mendiola and Anna Gonz{\'a}lez-Neira and Guillermo Pita and Alonso, {M Rosario} and Joe Dennis and Qin Wang and Bolla, {Manjeet K} and Anthony Swerdlow and Alan Ashworth and Nick Orr and Minouk Schoemaker and Yon-Dschun Ko 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 Marie-Rose Christiaens and Ann Smeets and Anna Jakubowska and Jan Lubinski and Katarzyna Jaworska-Bieniek and Katazyna Durda and Mikael Hartman and Miao Hui and {Yen Lim}, Wei and {Wan Chan}, Ching and Federick Marme and Bojesen, {Stig E} and Nordestgaard, {B{\o}rge G} and {GENICA Network}",

note = "{\textcopyright} The Author 2014. Published by Oxford University Press.",

year = "2014",

month = nov,

day = "15",

doi = "10.1093/hmg/ddu311",

language = "English",

volume = "23",

pages = "6096--6111",

journal = "Human Molecular Genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

number = "22",

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TY - JOUR

T1 - Common non-synonymous SNPs associated with breast cancer susceptibility

T2 - findings from the Breast Cancer Association Consortium

AU - Milne, Roger L

AU - Burwinkel, Barbara

AU - Michailidou, Kyriaki

AU - Arias-Perez, Jose-Ignacio

AU - Zamora, M Pilar

AU - Menéndez-Rodríguez, Primitiva

AU - Hardisson, David

AU - Mendiola, Marta

AU - González-Neira, Anna

AU - Pita, Guillermo

AU - Alonso, M Rosario

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 - Yen Lim, Wei

AU - Wan Chan, Ching

AU - Marme, Federick

AU - Bojesen, Stig E

AU - Nordestgaard, Børge G

AU - GENICA Network

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.

U2 - 10.1093/hmg/ddu311

DO - 10.1093/hmg/ddu311

M3 - Journal article

C2 - 24943594

SN - 0964-6906

VL - 23

SP - 6096

EP - 6111

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 22

ER -

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

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