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

RL Milne; B Burwinkel; K Michailidou; JI Arias-Perez; MP Zamora; P Menendez-Rodriguez; D Hardisson; M Mendiola; A Gonzalez-Neira; G Pita; MR Alonso; J Dennis; Q (Qing) Wang; MK Bolla; A Swerdlow; A Ashworth; N Orr; M Schoemaker; YD Ko; H Brauch; U Hamann; IL Andrulis; JA Knight; G Glendon; S Tchatchou; K Matsuo; H Ito; H Iwata; K Tajima; JM Li; JS Brand; H Brenner; AK Dieffenbach; V Arndt; C Stegmaier; D Lambrechts; G Peuteman; MR Christiaens; A Smeets; A Jakubowska; J Lubinski; K Jaworska-Bieniek; K Durda; M Hartman; M Hui; WY Lim; CW Chan; F Marme; RX Yang; P Bugert; A Lindblom; S Margolin; M Garcia-Closas; SJ Chanock; J Lissowska; JD Figueroa; SE Bojesen; BG Nordestgaard; H Flyger; Maartje Hooning; Mieke Kriege; Ans van den Ouweland; Linetta Koppert; O Fletcher; N Johnson; I dos-Santos-Silva; J Peto; W Zheng; S Deming-Halverson; MJ Shrubsole; JR Long; J Chang-Claude; A Rudolph; P Seibold; D Flesch-Janys; R Winqvist; K Pylkas; A Jukkola-Vuorinen; M Grip; A Cox; SS Cross; MWR Reed; MK (Marjanka) Schmidt; A Broeks; S Cornelissen; L Braaf; D Kang; JY Choi; SK Park; DY Noh; J Simard; M Dumont; MS Goldberg; F Labreche; PA Fasching; A Hein; AB Ekici; MW Beckmann; P Radice; P Peterlongo; J Azzollini; M Barile; E Sawyer; I Tomlinson; M Kerin; N Miller; JL Hopper; DF Schmidt; E Makalic; MC Southey; SH Teo; CH Yip; K Sivanandan; WT Tay; CY Shen; CN Hsiung; JC Yu; MF Hou; P Guenel; M Sanchez; C Mulot; W Blot; QY Cai; H Nevanlinna; TA Muranen; K Aittomaki; C Blomqvist; AH Wu; CC Tseng; D van den Berg; DO Stram; N Bogdanova; T Dork; K Muir; A Lophatananon; S Stewart-Brown; P Siriwanarangsan; A Mannermaa; V Kataja; VM Kosma; JM Hartikainen; XO Shu; W Lu; YT Gao; B Zhang; FJ Couch; AE Toland; D Yannoukakos; S Sangrajrang; J Mckay; XS Wang; JE Olson; C Vachon; K Purrington; G Severi; L Baglietto; CA Haiman; BE Henderson; F Schumacher; L Le Marchand; P Devilee; RAEM Tollenaar; Caroline Seynaeve; K Czene; M Eriksson; K Humphreys; H Darabi; S (Shahana) Ahmed; M Shah; PDP Pharoah; P Hall; GG Giles; J Benitez; AM Dunning; G Chenevix-Trench; DF Easton

doi:10.1093/hmg/ddu311

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

RL Milne, B Burwinkel, K Michailidou, JI Arias-Perez, MP Zamora, P Menendez-Rodriguez, D Hardisson, M Mendiola, A Gonzalez-Neira, G Pita, MR Alonso, J Dennis, Q (Qing) Wang, MK Bolla, A Swerdlow, A Ashworth, N Orr, M Schoemaker, YD Ko, H BrauchU Hamann, IL Andrulis, JA Knight, G Glendon, S Tchatchou, K Matsuo, H Ito, H Iwata, K Tajima, JM Li, JS Brand, H Brenner, AK Dieffenbach, V Arndt, C Stegmaier, D Lambrechts, G Peuteman, MR Christiaens, A Smeets, A Jakubowska, J Lubinski, K Jaworska-Bieniek, K Durda, M Hartman, M Hui, WY Lim, CW Chan, F Marme, RX Yang, P Bugert, A Lindblom, S Margolin, M Garcia-Closas, SJ Chanock, J Lissowska, JD Figueroa, SE Bojesen, BG Nordestgaard, H Flyger, Maartje Hooning, Mieke Kriege, Ans van den Ouweland, Linetta Koppert, O Fletcher, N Johnson, I dos-Santos-Silva, J Peto, W Zheng, S Deming-Halverson, MJ Shrubsole, JR Long, J Chang-Claude, A Rudolph, P Seibold, D Flesch-Janys, R Winqvist, K Pylkas, A Jukkola-Vuorinen, M Grip, A Cox, SS Cross, MWR Reed, MK (Marjanka) Schmidt, A Broeks, S Cornelissen, L Braaf, D Kang, JY Choi, SK Park, DY Noh, J Simard, M Dumont, MS Goldberg, F Labreche, PA Fasching, A Hein, AB Ekici, MW Beckmann, P Radice, P Peterlongo, J Azzollini, M Barile, E Sawyer, I Tomlinson, M Kerin, N Miller, JL Hopper, DF Schmidt, E Makalic, MC Southey, SH Teo, CH Yip, K Sivanandan, WT Tay, CY Shen, CN Hsiung, JC Yu, MF Hou, P Guenel, M Sanchez, C Mulot, W Blot, QY Cai, H Nevanlinna, TA Muranen, K Aittomaki, C Blomqvist, AH Wu, CC Tseng, D van den Berg, DO Stram, N Bogdanova, T Dork, K Muir, A Lophatananon, S Stewart-Brown, P Siriwanarangsan, A Mannermaa, V Kataja, VM Kosma, JM Hartikainen, XO Shu, W Lu, YT Gao, B Zhang, FJ Couch, AE Toland, D Yannoukakos, S Sangrajrang, J Mckay, XS Wang, JE Olson, C Vachon, K Purrington, G Severi, L Baglietto, CA Haiman, BE Henderson, F Schumacher, L Le Marchand, P Devilee, RAEM Tollenaar, Caroline Seynaeve, K Czene, M Eriksson, K Humphreys, H Darabi, S (Shahana) Ahmed, M Shah, PDP Pharoah, P Hall, GG Giles, J Benitez, AM Dunning, G Chenevix-Trench, DF Easton

Research output: Contribution to journal › Article › Academic › peer-review

49 Citations (Scopus)

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 = 1.07, 95% confidence interval (CI) = 1.04-1.10, P = 2.9 x 10 26], AKAP9-M463I at 7q21 (rs6964587, OR = 1.05, 95% CI = 1.03-1.07, P = 1.7 x 10(-6)) and NEK10-L513S at 3p24 (rs10510592, OR = 1.10, 95% CI = 1.07-1.12, P = 5.1 x 10(-17)). 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 = 1.07 (95% CI = 1.05-1.10, P = 1.0 x 10(-8)); for AKAP9-M463I, OR = 1.05 (95% CI = 1.04-1.07, P = 2.0 x 10(-10)). 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.

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

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EMC MM-03-86-01

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10.1093/hmg/ddu311

Cite this

Milne, RL., Burwinkel, B., Michailidou, K., Arias-Perez, JI., Zamora, MP., Menendez-Rodriguez, P., Hardisson, D., Mendiola, M., Gonzalez-Neira, A., Pita, G., Alonso, MR., Dennis, J., Wang, Q., Bolla, MK., Swerdlow, A., Ashworth, A., Orr, N., Schoemaker, M., Ko, YD., ... Easton, DF. (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

@article{57954dd3969d4108998166d48696ce20,

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

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 = 1.07, 95% confidence interval (CI) = 1.04-1.10, P = 2.9 x 10 26], AKAP9-M463I at 7q21 (rs6964587, OR = 1.05, 95% CI = 1.03-1.07, P = 1.7 x 10(-6)) and NEK10-L513S at 3p24 (rs10510592, OR = 1.10, 95% CI = 1.07-1.12, P = 5.1 x 10(-17)). 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 = 1.07 (95% CI = 1.05-1.10, P = 1.0 x 10(-8)); for AKAP9-M463I, OR = 1.05 (95% CI = 1.04-1.07, P = 2.0 x 10(-10)). 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.",

author = "RL Milne and B Burwinkel and K Michailidou and JI Arias-Perez and MP Zamora and P Menendez-Rodriguez and D Hardisson and M Mendiola and A Gonzalez-Neira and G Pita and MR Alonso and J Dennis and Wang, {Q (Qing)} and MK Bolla and A Swerdlow and A Ashworth and N Orr and M Schoemaker and YD Ko and H Brauch and U Hamann and IL Andrulis and JA Knight and G Glendon and S Tchatchou and K Matsuo and H Ito and H Iwata and K Tajima and JM Li and JS Brand and H Brenner and AK Dieffenbach and V Arndt and C Stegmaier and D Lambrechts and G Peuteman and MR Christiaens and A Smeets and A Jakubowska and J Lubinski and K Jaworska-Bieniek and K Durda and M Hartman and M Hui and WY Lim and CW Chan and F Marme and RX Yang and P Bugert and A Lindblom and S Margolin and M Garcia-Closas and SJ Chanock and J Lissowska and JD Figueroa and SE Bojesen and BG Nordestgaard and H Flyger and Maartje Hooning and Mieke Kriege and {van den Ouweland}, Ans and Linetta Koppert and O Fletcher and N Johnson and I dos-Santos-Silva and J Peto and W Zheng and S Deming-Halverson and MJ Shrubsole and JR Long and J Chang-Claude and A Rudolph and P Seibold and D Flesch-Janys and R Winqvist and K Pylkas and A Jukkola-Vuorinen and M Grip and A Cox and SS Cross and MWR Reed and Schmidt, {MK (Marjanka)} and A Broeks and S Cornelissen and L Braaf and D Kang and JY Choi and SK Park and DY Noh and J Simard and M Dumont and MS Goldberg and F Labreche and PA Fasching and A Hein and AB Ekici and MW Beckmann and P Radice and P Peterlongo and J Azzollini and M Barile and E Sawyer and I Tomlinson and M Kerin and N Miller and JL Hopper and DF Schmidt and E Makalic and MC Southey and SH Teo and CH Yip and K Sivanandan and WT Tay and CY Shen and CN Hsiung and JC Yu and MF Hou and P Guenel and M Sanchez and C Mulot and W Blot and QY Cai and H Nevanlinna and TA Muranen and K Aittomaki and C Blomqvist and AH Wu and CC Tseng and {van den Berg}, D and DO Stram and N Bogdanova and T Dork and K Muir and A Lophatananon and S Stewart-Brown and P Siriwanarangsan and A Mannermaa and V Kataja and VM Kosma and JM Hartikainen and XO Shu and W Lu and YT Gao and B Zhang and FJ Couch and AE Toland and D Yannoukakos and S Sangrajrang and J Mckay and XS Wang and JE Olson and C Vachon and K Purrington and G Severi and L Baglietto and CA Haiman and BE Henderson and F Schumacher and {Le Marchand}, L and P Devilee and RAEM Tollenaar and Caroline Seynaeve and K Czene and M Eriksson and K Humphreys and H Darabi and Ahmed, {S (Shahana)} and M Shah and PDP Pharoah and P Hall and GG Giles and J Benitez and AM Dunning and G Chenevix-Trench and DF Easton",

year = "2014",

doi = "10.1093/hmg/ddu311",

language = "Undefined/Unknown",

volume = "23",

pages = "6096--6111",

journal = "Human Molecular Genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

number = "22",

}

Milne, RL, Burwinkel, B, Michailidou, K, Arias-Perez, JI, Zamora, MP, Menendez-Rodriguez, P, Hardisson, D, Mendiola, M, Gonzalez-Neira, A, Pita, G, Alonso, MR, Dennis, J, Wang, Q, Bolla, MK, Swerdlow, A, Ashworth, A, Orr, N, Schoemaker, M, Ko, YD, Brauch, H, Hamann, U, Andrulis, IL, Knight, JA, Glendon, G, Tchatchou, S, Matsuo, K, Ito, H, Iwata, H, Tajima, K, Li, JM, Brand, JS, Brenner, H, Dieffenbach, AK, Arndt, V, Stegmaier, C, Lambrechts, D, Peuteman, G, Christiaens, MR, Smeets, A, Jakubowska, A, Lubinski, J, Jaworska-Bieniek, K, Durda, K, Hartman, M, Hui, M, Lim, WY, Chan, CW, Marme, F, Yang, RX, Bugert, P, Lindblom, A, Margolin, S, Garcia-Closas, M, Chanock, SJ, Lissowska, J, Figueroa, JD, Bojesen, SE, Nordestgaard, BG, Flyger, H, Hooning, M, Kriege, M, van den Ouweland, A, Koppert, L, Fletcher, O, Johnson, N, dos-Santos-Silva, I, Peto, J, Zheng, W, Deming-Halverson, S, Shrubsole, MJ, Long, JR, Chang-Claude, J, Rudolph, A, Seibold, P, Flesch-Janys, D, Winqvist, R, Pylkas, K, Jukkola-Vuorinen, A, Grip, M, Cox, A, Cross, SS, Reed, MWR, Schmidt, MK, Broeks, A, Cornelissen, S, Braaf, L, Kang, D, Choi, JY, Park, SK, Noh, DY, Simard, J, Dumont, M, Goldberg, MS, Labreche, F, Fasching, PA, Hein, A, Ekici, AB, Beckmann, MW, Radice, P, Peterlongo, P, Azzollini, J, Barile, M, Sawyer, E, Tomlinson, I, Kerin, M, Miller, N, Hopper, JL, Schmidt, DF, Makalic, E, Southey, MC, Teo, SH, Yip, CH, Sivanandan, K, Tay, WT, Shen, CY, Hsiung, CN, Yu, JC, Hou, MF, Guenel, P, Sanchez, M, Mulot, C, Blot, W, Cai, QY, Nevanlinna, H, Muranen, TA, Aittomaki, K, Blomqvist, C, Wu, AH, Tseng, CC, van den Berg, D, Stram, DO, Bogdanova, N, Dork, T, Muir, K, Lophatananon, A, Stewart-Brown, S, Siriwanarangsan, P, Mannermaa, A, Kataja, V, Kosma, VM, Hartikainen, JM, Shu, XO, Lu, W, Gao, YT, Zhang, B, Couch, FJ, Toland, AE, Yannoukakos, D, Sangrajrang, S, Mckay, J, Wang, XS, Olson, JE, Vachon, C, Purrington, K, Severi, G, Baglietto, L, Haiman, CA, Henderson, BE, Schumacher, F, Le Marchand, L, Devilee, P, Tollenaar, RAEM, Seynaeve, C, Czene, K, Eriksson, M, Humphreys, K, Darabi, H, Ahmed, S, Shah, M, Pharoah, PDP, Hall, P, Giles, GG, Benitez, J, Dunning, AM, Chenevix-Trench, G & Easton, DF 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

TY - JOUR

T1 - Common non-synonymous SNPs associated with breast cancer susceptibility: findings from the Breast Cancer Association Consortium

AU - Milne, RL

AU - Burwinkel, B

AU - Michailidou, K

AU - Arias-Perez, JI

AU - Zamora, MP

AU - Menendez-Rodriguez, P

AU - Hardisson, D

AU - Mendiola, M

AU - Gonzalez-Neira, A

AU - Pita, G

AU - Alonso, MR

AU - Dennis, J

AU - Wang, Q (Qing)

AU - Bolla, MK

AU - Swerdlow, A

AU - Ashworth, A

AU - Orr, N

AU - Schoemaker, M

AU - Ko, YD

AU - Brauch, H

AU - Hamann, U

AU - Andrulis, IL

AU - Knight, JA

AU - Glendon, G

AU - Tchatchou, S

AU - Matsuo, K

AU - Ito, H

AU - Iwata, H

AU - Tajima, K

AU - Li, JM

AU - Brand, JS

AU - Brenner, H

AU - Dieffenbach, AK

AU - Arndt, V

AU - Stegmaier, C

AU - Lambrechts, D

AU - Peuteman, G

AU - Christiaens, MR

AU - Smeets, A

AU - Jakubowska, A

AU - Lubinski, J

AU - Jaworska-Bieniek, K

AU - Durda, K

AU - Hartman, M

AU - Hui, M

AU - Lim, WY

AU - Chan, CW

AU - Marme, F

AU - Yang, RX

AU - Bugert, P

AU - Lindblom, A

AU - Margolin, S

AU - Garcia-Closas, M

AU - Chanock, SJ

AU - Lissowska, J

AU - Figueroa, JD

AU - Bojesen, SE

AU - Nordestgaard, BG

AU - Flyger, H

AU - Hooning, Maartje

AU - Kriege, Mieke

AU - van den Ouweland, Ans

AU - Koppert, Linetta

AU - Fletcher, O

AU - Johnson, N

AU - dos-Santos-Silva, I

AU - Peto, J

AU - Zheng, W

AU - Deming-Halverson, S

AU - Shrubsole, MJ

AU - Long, JR

AU - Chang-Claude, J

AU - Rudolph, A

AU - Seibold, P

AU - Flesch-Janys, D

AU - Winqvist, R

AU - Pylkas, K

AU - Jukkola-Vuorinen, A

AU - Grip, M

AU - Cox, A

AU - Cross, SS

AU - Reed, MWR

AU - Schmidt, MK (Marjanka)

AU - Broeks, A

AU - Cornelissen, S

AU - Braaf, L

AU - Kang, D

AU - Choi, JY

AU - Park, SK

AU - Noh, DY

AU - Simard, J

AU - Dumont, M

AU - Goldberg, MS

AU - Labreche, F

AU - Fasching, PA

AU - Hein, A

AU - Ekici, AB

AU - Beckmann, MW

AU - Radice, P

AU - Peterlongo, P

AU - Azzollini, J

AU - Barile, M

AU - Sawyer, E

AU - Tomlinson, I

AU - Kerin, M

AU - Miller, N

AU - Hopper, JL

AU - Schmidt, DF

AU - Makalic, E

AU - Southey, MC

AU - Teo, SH

AU - Yip, CH

AU - Sivanandan, K

AU - Tay, WT

AU - Shen, CY

AU - Hsiung, CN

AU - Yu, JC

AU - Hou, MF

AU - Guenel, P

AU - Sanchez, M

AU - Mulot, C

AU - Blot, W

AU - Cai, QY

AU - Nevanlinna, H

AU - Muranen, TA

AU - Aittomaki, K

AU - Blomqvist, C

AU - Wu, AH

AU - Tseng, CC

AU - van den Berg, D

AU - Stram, DO

AU - Bogdanova, N

AU - Dork, T

AU - Muir, K

AU - Lophatananon, A

AU - Stewart-Brown, S

AU - Siriwanarangsan, P

AU - Mannermaa, A

AU - Kataja, V

AU - Kosma, VM

AU - Hartikainen, JM

AU - Shu, XO

AU - Lu, W

AU - Gao, YT

AU - Zhang, B

AU - Couch, FJ

AU - Toland, AE

AU - Yannoukakos, D

AU - Sangrajrang, S

AU - Mckay, J

AU - Wang, XS

AU - Olson, JE

AU - Vachon, C

AU - Purrington, K

AU - Severi, G

AU - Baglietto, L

AU - Haiman, CA

AU - Henderson, BE

AU - Schumacher, F

AU - Le Marchand, L

AU - Devilee, P

AU - Tollenaar, RAEM

AU - Seynaeve, Caroline

AU - Czene, K

AU - Eriksson, M

AU - Humphreys, K

AU - Darabi, H

AU - Ahmed, S (Shahana)

AU - Shah, M

AU - Pharoah, PDP

AU - Hall, P

AU - Giles, GG

AU - Benitez, J

AU - Dunning, AM

AU - Chenevix-Trench, G

AU - Easton, DF

PY - 2014

Y1 - 2014

N2 - 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 = 1.07, 95% confidence interval (CI) = 1.04-1.10, P = 2.9 x 10 26], AKAP9-M463I at 7q21 (rs6964587, OR = 1.05, 95% CI = 1.03-1.07, P = 1.7 x 10(-6)) and NEK10-L513S at 3p24 (rs10510592, OR = 1.10, 95% CI = 1.07-1.12, P = 5.1 x 10(-17)). 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 = 1.07 (95% CI = 1.05-1.10, P = 1.0 x 10(-8)); for AKAP9-M463I, OR = 1.05 (95% CI = 1.04-1.07, P = 2.0 x 10(-10)). 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.

AB - 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 = 1.07, 95% confidence interval (CI) = 1.04-1.10, P = 2.9 x 10 26], AKAP9-M463I at 7q21 (rs6964587, OR = 1.05, 95% CI = 1.03-1.07, P = 1.7 x 10(-6)) and NEK10-L513S at 3p24 (rs10510592, OR = 1.10, 95% CI = 1.07-1.12, P = 5.1 x 10(-17)). 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 = 1.07 (95% CI = 1.05-1.10, P = 1.0 x 10(-8)); for AKAP9-M463I, OR = 1.05 (95% CI = 1.04-1.07, P = 2.0 x 10(-10)). 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.

U2 - 10.1093/hmg/ddu311

DO - 10.1093/hmg/ddu311

M3 - Article

C2 - 24943594

SN - 0964-6906

VL - 23

SP - 6096

EP - 6111

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 22

ER -