Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation

M Ghoussaini; SL Edwards; K Michailidou; S Nord; RCS Lari; K Desai; S Kar; KM Hillman; S Kaufmann; DM Glubb; J Beesley; J Dennis; MK Bolla; Q (Qing) Wang; E Dicks; Q Guo; MK (Marjanka) Schmidt; M Shah; R Luben; J Brown; K Czene; H Darabi; M Eriksson; D Klevebring; SE Bojesen; BG Nordestgaard; SF Nielsen; H Flyger; D Lambrechts; B Thienpont; P Neven; H Wildiers; A Broeks; LJ (Laura) van 't Veer; EJT Rutgers; FJ Couch; JE Olson; E Hallberg; C Vachon; J Chang-Claude; A Rudolph; P Seibold; D Flesch-Janys; J Peto; I dos-Santos-Silva; L Gibson; H Nevanlinna; TA Muranen; K Aittomaki; C Blomqvist; P Hall; JM Li; JJ Liu; K Humphreys; D Kang; JY Choi; SK Park; DY Noh; K Matsuo; H Ito; H Iwata; Y Yatabe; P Guenel; F Menegaux; M Sanchez; B Burwinkel; F Marme; A Schneeweiss; C Sohn; AH Wu; CC Tseng; D van den Berg; DO Stram; J Benitez; MP Zamora; JIA Perez; P Menendez; XO Shu; W Lu; YT Gao; QY Cai; A Cox; SS Cross; MWR Reed; IL Andrulis; JA Knight; G Glendon; S Tchatchou; EJ Sawyer; I Tomlinson; MJ Kerin; N Miller; CA Haiman; BE Henderson; F Schumacher; L Le Marchand; A Lindblom; S Margolin; SH Teo; CH Yip; DSC Lee; TY (Tien Yin) Wong; Maartje Hooning; John Martens; Margriet Collee; Carolien van Deurzen; JL Hopper; MC Southey; H Tsimiklis; MK Kapuscinski; CY Shen; PE Wu; JC Yu; ST Chen; GG Alnaes; AL Borresen-Dale; GG Giles; RL Milne; C McLean; K Muir; A Lophatananon; S Stewart-Brown; P Siriwanarangsan; M Hartman; H Miao; SAB Buhari; YY Teo; PA Fasching; L Haeberle; AB Ekici; MW Beckmann; H Brenner; AK Dieffenbach; V Arndt; C Stegmaier; A Swerdlow; A Ashworth; N Orr; MJ Schoemaker; M Garcia-Closas; J Figueroa; SJ Chanock; J Lissowska; J Simard; MS Goldberg; F Labreche; M Dumont; R Winqvist; K Pylkas; A Jukkola-Vuorinen; H Brauch; T Bruning; YD Koto; P Radice; P Peterlongo; B Bonanni; S Volorio; T Dork; NV Bogdanova; S Helbig; A Mannermaa; V Kataja; VM Kosma; JM Hartikainen; P Devilee; RAEM Tollenaar; Caroline Seynaeve; CJ van Asperen; A Jakubowska; J Lubinski; K Jaworska-Bieniek; K Durda; S Slager; AE Toland; CB Ambrosone; D Yannoukakos; S Sangrajrang; V Gaborieau; P Brennan; J Mckay; U Hamann; D Torres; W Zheng; JR Long; H Anton-Culver; SL Neuhausen; C Luccarini; C Baynes; S (Shahana) Ahmed; M Maranian; CS Healey; A Gonzalez-Neira; G Pita; MR Alonso; N Alvarez; D Herrero; DC Tessier; D Vincent; F Bacot; I de Santiago; J Carroll; C Caldas; MA Brown; M Lupien; VN Kristensen; PDP Pharoah; G Chenevix-Trench; JD French; DF Easton; AM Dunning; Thanh Dam Truong

doi:10.1038/ncomms5999

Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation

M Ghoussaini, SL Edwards, K Michailidou, S Nord, RCS Lari, K Desai, S Kar, KM Hillman, S Kaufmann, DM Glubb, J Beesley, J Dennis, MK Bolla, Q (Qing) Wang, E Dicks, Q Guo, MK (Marjanka) Schmidt, M Shah, R Luben, J BrownK Czene, H Darabi, M Eriksson, D Klevebring, SE Bojesen, BG Nordestgaard, SF Nielsen, H Flyger, D Lambrechts, B Thienpont, P Neven, H Wildiers, A Broeks, LJ (Laura) van 't Veer, EJT Rutgers, FJ Couch, JE Olson, E Hallberg, C Vachon, J Chang-Claude, A Rudolph, P Seibold, D Flesch-Janys, J Peto, I dos-Santos-Silva, L Gibson, H Nevanlinna, TA Muranen, K Aittomaki, C Blomqvist, P Hall, JM Li, JJ Liu, K Humphreys, D Kang, JY Choi, SK Park, DY Noh, K Matsuo, H Ito, H Iwata, Y Yatabe, P Guenel, F Menegaux, M Sanchez, B Burwinkel, F Marme, A Schneeweiss, C Sohn, AH Wu, CC Tseng, D van den Berg, DO Stram, J Benitez, MP Zamora, JIA Perez, P Menendez, XO Shu, W Lu, YT Gao, QY Cai, A Cox, SS Cross, MWR Reed, IL Andrulis, JA Knight, G Glendon, S Tchatchou, EJ Sawyer, I Tomlinson, MJ Kerin, N Miller, CA Haiman, BE Henderson, F Schumacher, L Le Marchand, A Lindblom, S Margolin, SH Teo, CH Yip, DSC Lee, TY (Tien Yin) Wong, Maartje Hooning, John Martens, Margriet Collee, Carolien van Deurzen, JL Hopper, MC Southey, H Tsimiklis, MK Kapuscinski, CY Shen, PE Wu, JC Yu, ST Chen, GG Alnaes, AL Borresen-Dale, GG Giles, RL Milne, C McLean, K Muir, A Lophatananon, S Stewart-Brown, P Siriwanarangsan, M Hartman, H Miao, SAB Buhari, YY Teo, PA Fasching, L Haeberle, AB Ekici, MW Beckmann, H Brenner, AK Dieffenbach, V Arndt, C Stegmaier, A Swerdlow, A Ashworth, N Orr, MJ Schoemaker, M Garcia-Closas, J Figueroa, SJ Chanock, J Lissowska, J Simard, MS Goldberg, F Labreche, M Dumont, R Winqvist, K Pylkas, A Jukkola-Vuorinen, H Brauch, T Bruning, YD Koto, P Radice, P Peterlongo, B Bonanni, S Volorio, T Dork, NV Bogdanova, S Helbig, A Mannermaa, V Kataja, VM Kosma, JM Hartikainen, P Devilee, RAEM Tollenaar, Caroline Seynaeve, CJ van Asperen, A Jakubowska, J Lubinski, K Jaworska-Bieniek, K Durda, S Slager, AE Toland, CB Ambrosone, D Yannoukakos, S Sangrajrang, V Gaborieau, P Brennan, J Mckay, U Hamann, D Torres, W Zheng, JR Long, H Anton-Culver, SL Neuhausen, C Luccarini, C Baynes, S (Shahana) Ahmed, M Maranian, CS Healey, A Gonzalez-Neira, G Pita, MR Alonso, N Alvarez, D Herrero, DC Tessier, D Vincent, F Bacot, I de Santiago, J Carroll, C Caldas, MA Brown, M Lupien, VN Kristensen, PDP Pharoah, G Chenevix-Trench, JD French, DF Easton, AM Dunning, Thanh Dam Truong

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

91 Citations (Scopus)

Abstract

GWAS have identified a breast cancer susceptibility locus on 2q35. Here we report the fine mapping of this locus using data from 101,943 subjects from 50 case-control studies. We genotype 276 SNPs using the 'iCOGS' genotyping array and impute genotypes for a further 1,284 using 1000 Genomes Project data. All but two, strongly correlated SNPs (rs4442975 G/T and rs6721996 G/A) are excluded as candidate causal variants at odds against >100:1. The best functional candidate, rs4442975, is associated with oestrogen receptor positive (ER+) disease with an odds ratio (OR) in Europeans of 0.85 (95% confidence interval = 0.84 - 0.87; P = 1.7 x 10(-43)) per t-allele. This SNP flanks a transcriptional enhancer that physically interacts with the promoter of IGFBP5 (encoding insulin-like growth factor-binding protein 5) and displays allele-specific gene expression, FOXA1 binding and chromatin looping. Evidence suggests that the g-allele confers increased breast cancer susceptibility through relative downregulation of IGFBP5, a gene with known roles in breast cell biology.

Original language	Undefined/Unknown
Journal	Nature Communications
Volume	5
DOIs	https://doi.org/10.1038/ncomms5999
Publication status	Published - 2014

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EMC MM-03-24-01
EMC MM-03-86-01

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10.1038/ncomms5999

Cite this

Ghoussaini, M., Edwards, SL., Michailidou, K., Nord, S., Lari, RCS., Desai, K., Kar, S., Hillman, KM., Kaufmann, S., Glubb, DM., Beesley, J., Dennis, J., Bolla, MK., Wang, Q., Dicks, E., Guo, Q., Schmidt, MK., Shah, M., Luben, R., ... Truong, T. D. (2014). Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation. Nature Communications, 5. https://doi.org/10.1038/ncomms5999

@article{b4f9c64216ea4576813263d88a76e422,

title = "Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation",

abstract = "GWAS have identified a breast cancer susceptibility locus on 2q35. Here we report the fine mapping of this locus using data from 101,943 subjects from 50 case-control studies. We genotype 276 SNPs using the 'iCOGS' genotyping array and impute genotypes for a further 1,284 using 1000 Genomes Project data. All but two, strongly correlated SNPs (rs4442975 G/T and rs6721996 G/A) are excluded as candidate causal variants at odds against >100:1. The best functional candidate, rs4442975, is associated with oestrogen receptor positive (ER+) disease with an odds ratio (OR) in Europeans of 0.85 (95% confidence interval = 0.84 - 0.87; P = 1.7 x 10(-43)) per t-allele. This SNP flanks a transcriptional enhancer that physically interacts with the promoter of IGFBP5 (encoding insulin-like growth factor-binding protein 5) and displays allele-specific gene expression, FOXA1 binding and chromatin looping. Evidence suggests that the g-allele confers increased breast cancer susceptibility through relative downregulation of IGFBP5, a gene with known roles in breast cell biology.",

author = "M Ghoussaini and SL Edwards and K Michailidou and S Nord and RCS Lari and K Desai and S Kar and KM Hillman and S Kaufmann and DM Glubb and J Beesley and J Dennis and MK Bolla and Wang, {Q (Qing)} and E Dicks and Q Guo and Schmidt, {MK (Marjanka)} and M Shah and R Luben and J Brown and K Czene and H Darabi and M Eriksson and D Klevebring and SE Bojesen and BG Nordestgaard and SF Nielsen and H Flyger and D Lambrechts and B Thienpont and P Neven and H Wildiers and A Broeks and {van 't Veer}, {LJ (Laura)} and EJT Rutgers and FJ Couch and JE Olson and E Hallberg and C Vachon and J Chang-Claude and A Rudolph and P Seibold and D Flesch-Janys and J Peto and I dos-Santos-Silva and L Gibson and H Nevanlinna and TA Muranen and K Aittomaki and C Blomqvist and P Hall and JM Li and JJ Liu and K Humphreys and D Kang and JY Choi and SK Park and DY Noh and K Matsuo and H Ito and H Iwata and Y Yatabe and P Guenel and F Menegaux and M Sanchez and B Burwinkel and F Marme and A Schneeweiss and C Sohn and AH Wu and CC Tseng and {van den Berg}, D and DO Stram and J Benitez and MP Zamora and JIA Perez and P Menendez and XO Shu and W Lu and YT Gao and QY Cai and A Cox and SS Cross and MWR Reed and IL Andrulis and JA Knight and G Glendon and S Tchatchou and EJ Sawyer and I Tomlinson and MJ Kerin and N Miller and CA Haiman and BE Henderson and F Schumacher and {Le Marchand}, L and A Lindblom and S Margolin and SH Teo and CH Yip and DSC Lee and Wong, {TY (Tien Yin)} and Maartje Hooning and John Martens and Margriet Collee and {van Deurzen}, Carolien and JL Hopper and MC Southey and H Tsimiklis and MK Kapuscinski and CY Shen and PE Wu and JC Yu and ST Chen and GG Alnaes and AL Borresen-Dale and GG Giles and RL Milne and C McLean and K Muir and A Lophatananon and S Stewart-Brown and P Siriwanarangsan and M Hartman and H Miao and SAB Buhari and YY Teo and PA Fasching and L Haeberle and AB Ekici and MW Beckmann and H Brenner and AK Dieffenbach and V Arndt and C Stegmaier and A Swerdlow and A Ashworth and N Orr and MJ Schoemaker and M Garcia-Closas and J Figueroa and SJ Chanock and J Lissowska and J Simard and MS Goldberg and F Labreche and M Dumont and R Winqvist and K Pylkas and A Jukkola-Vuorinen and H Brauch and T Bruning and YD Koto and P Radice and P Peterlongo and B Bonanni and S Volorio and T Dork and NV Bogdanova and S Helbig and A Mannermaa and V Kataja and VM Kosma and JM Hartikainen and P Devilee and RAEM Tollenaar and Caroline Seynaeve and {van Asperen}, CJ and A Jakubowska and J Lubinski and K Jaworska-Bieniek and K Durda and S Slager and AE Toland and CB Ambrosone and D Yannoukakos and S Sangrajrang and V Gaborieau and P Brennan and J Mckay and U Hamann and D Torres and W Zheng and JR Long and H Anton-Culver and SL Neuhausen and C Luccarini and C Baynes and Ahmed, {S (Shahana)} and M Maranian and CS Healey and A Gonzalez-Neira and G Pita and MR Alonso and N Alvarez and D Herrero and DC Tessier and D Vincent and F Bacot and {de Santiago}, I and J Carroll and C Caldas and MA Brown and M Lupien and VN Kristensen and PDP Pharoah and G Chenevix-Trench and JD French and DF Easton and AM Dunning and Truong, {Thanh Dam}",

year = "2014",

doi = "10.1038/ncomms5999",

language = "Undefined/Unknown",

volume = "5",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

}

Ghoussaini, M, Edwards, SL, Michailidou, K, Nord, S, Lari, RCS, Desai, K, Kar, S, Hillman, KM, Kaufmann, S, Glubb, DM, Beesley, J, Dennis, J, Bolla, MK, Wang, Q, Dicks, E, Guo, Q, Schmidt, MK, Shah, M, Luben, R, Brown, J, Czene, K, Darabi, H, Eriksson, M, Klevebring, D, Bojesen, SE, Nordestgaard, BG, Nielsen, SF, Flyger, H, Lambrechts, D, Thienpont, B, Neven, P, Wildiers, H, Broeks, A, van 't Veer, LJ, Rutgers, EJT, Couch, FJ, Olson, JE, Hallberg, E, Vachon, C, Chang-Claude, J, Rudolph, A, Seibold, P, Flesch-Janys, D, Peto, J, dos-Santos-Silva, I, Gibson, L, Nevanlinna, H, Muranen, TA, Aittomaki, K, Blomqvist, C, Hall, P, Li, JM, Liu, JJ, Humphreys, K, Kang, D, Choi, JY, Park, SK, Noh, DY, Matsuo, K, Ito, H, Iwata, H, Yatabe, Y, Guenel, P, Menegaux, F, Sanchez, M, Burwinkel, B, Marme, F, Schneeweiss, A, Sohn, C, Wu, AH, Tseng, CC, van den Berg, D, Stram, DO, Benitez, J, Zamora, MP, Perez, JIA, Menendez, P, Shu, XO, Lu, W, Gao, YT, Cai, QY, Cox, A, Cross, SS, Reed, MWR, Andrulis, IL, Knight, JA, Glendon, G, Tchatchou, S, Sawyer, EJ, Tomlinson, I, Kerin, MJ, Miller, N, Haiman, CA, Henderson, BE, Schumacher, F, Le Marchand, L, Lindblom, A, Margolin, S, Teo, SH, Yip, CH, Lee, DSC, Wong, TY, Hooning, M , Martens, J , Collee, M , van Deurzen, C, Hopper, JL, Southey, MC, Tsimiklis, H, Kapuscinski, MK, Shen, CY, Wu, PE, Yu, JC, Chen, ST, Alnaes, GG, Borresen-Dale, AL, Giles, GG, Milne, RL, McLean, C, Muir, K, Lophatananon, A, Stewart-Brown, S, Siriwanarangsan, P, Hartman, M, Miao, H, Buhari, SAB, Teo, YY, Fasching, PA, Haeberle, L, Ekici, AB, Beckmann, MW, Brenner, H, Dieffenbach, AK, Arndt, V, Stegmaier, C, Swerdlow, A, Ashworth, A, Orr, N, Schoemaker, MJ, Garcia-Closas, M, Figueroa, J, Chanock, SJ, Lissowska, J, Simard, J, Goldberg, MS, Labreche, F, Dumont, M, Winqvist, R, Pylkas, K, Jukkola-Vuorinen, A, Brauch, H, Bruning, T, Koto, YD, Radice, P, Peterlongo, P, Bonanni, B, Volorio, S, Dork, T, Bogdanova, NV, Helbig, S, Mannermaa, A, Kataja, V, Kosma, VM, Hartikainen, JM, Devilee, P, Tollenaar, RAEM, Seynaeve, C, van Asperen, CJ, Jakubowska, A, Lubinski, J, Jaworska-Bieniek, K, Durda, K, Slager, S, Toland, AE, Ambrosone, CB, Yannoukakos, D, Sangrajrang, S, Gaborieau, V, Brennan, P, Mckay, J, Hamann, U, Torres, D, Zheng, W, Long, JR, Anton-Culver, H, Neuhausen, SL, Luccarini, C, Baynes, C, Ahmed, S, Maranian, M, Healey, CS, Gonzalez-Neira, A, Pita, G, Alonso, MR, Alvarez, N, Herrero, D, Tessier, DC, Vincent, D, Bacot, F, de Santiago, I, Carroll, J, Caldas, C, Brown, MA, Lupien, M, Kristensen, VN, Pharoah, PDP, Chenevix-Trench, G, French, JD, Easton, DF, Dunning, AM & Truong, TD 2014, 'Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation', Nature Communications, vol. 5. https://doi.org/10.1038/ncomms5999

TY - JOUR

T1 - Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation

AU - Ghoussaini, M

AU - Edwards, SL

AU - Michailidou, K

AU - Nord, S

AU - Lari, RCS

AU - Desai, K

AU - Kar, S

AU - Hillman, KM

AU - Kaufmann, S

AU - Glubb, DM

AU - Beesley, J

AU - Dennis, J

AU - Bolla, MK

AU - Wang, Q (Qing)

AU - Dicks, E

AU - Guo, Q

AU - Schmidt, MK (Marjanka)

AU - Shah, M

AU - Luben, R

AU - Brown, J

AU - Czene, K

AU - Darabi, H

AU - Eriksson, M

AU - Klevebring, D

AU - Bojesen, SE

AU - Nordestgaard, BG

AU - Nielsen, SF

AU - Flyger, H

AU - Lambrechts, D

AU - Thienpont, B

AU - Neven, P

AU - Wildiers, H

AU - Broeks, A

AU - van 't Veer, LJ (Laura)

AU - Rutgers, EJT

AU - Couch, FJ

AU - Olson, JE

AU - Hallberg, E

AU - Vachon, C

AU - Chang-Claude, J

AU - Rudolph, A

AU - Seibold, P

AU - Flesch-Janys, D

AU - Peto, J

AU - dos-Santos-Silva, I

AU - Gibson, L

AU - Nevanlinna, H

AU - Muranen, TA

AU - Aittomaki, K

AU - Blomqvist, C

AU - Hall, P

AU - Li, JM

AU - Liu, JJ

AU - Humphreys, K

AU - Kang, D

AU - Choi, JY

AU - Park, SK

AU - Noh, DY

AU - Matsuo, K

AU - Ito, H

AU - Iwata, H

AU - Yatabe, Y

AU - Guenel, P

AU - Menegaux, F

AU - Sanchez, M

AU - Burwinkel, B

AU - Marme, F

AU - Schneeweiss, A

AU - Sohn, C

AU - Wu, AH

AU - Tseng, CC

AU - van den Berg, D

AU - Stram, DO

AU - Benitez, J

AU - Zamora, MP

AU - Perez, JIA

AU - Menendez, P

AU - Shu, XO

AU - Lu, W

AU - Gao, YT

AU - Cai, QY

AU - Cox, A

AU - Cross, SS

AU - Reed, MWR

AU - Andrulis, IL

AU - Knight, JA

AU - Glendon, G

AU - Tchatchou, S

AU - Sawyer, EJ

AU - Tomlinson, I

AU - Kerin, MJ

AU - Miller, N

AU - Haiman, CA

AU - Henderson, BE

AU - Schumacher, F

AU - Le Marchand, L

AU - Lindblom, A

AU - Margolin, S

AU - Teo, SH

AU - Yip, CH

AU - Lee, DSC

AU - Wong, TY (Tien Yin)

AU - Hooning, Maartje

AU - Martens, John

AU - Collee, Margriet

AU - van Deurzen, Carolien

AU - Hopper, JL

AU - Southey, MC

AU - Tsimiklis, H

AU - Kapuscinski, MK

AU - Shen, CY

AU - Wu, PE

AU - Yu, JC

AU - Chen, ST

AU - Alnaes, GG

AU - Borresen-Dale, AL

AU - Giles, GG

AU - Milne, RL

AU - McLean, C

AU - Muir, K

AU - Lophatananon, A

AU - Stewart-Brown, S

AU - Siriwanarangsan, P

AU - Hartman, M

AU - Miao, H

AU - Buhari, SAB

AU - Teo, YY

AU - Fasching, PA

AU - Haeberle, L

AU - Ekici, AB

AU - Beckmann, MW

AU - Brenner, H

AU - Dieffenbach, AK

AU - Arndt, V

AU - Stegmaier, C

AU - Swerdlow, A

AU - Ashworth, A

AU - Orr, N

AU - Schoemaker, MJ

AU - Garcia-Closas, M

AU - Figueroa, J

AU - Chanock, SJ

AU - Lissowska, J

AU - Simard, J

AU - Goldberg, MS

AU - Labreche, F

AU - Dumont, M

AU - Winqvist, R

AU - Pylkas, K

AU - Jukkola-Vuorinen, A

AU - Brauch, H

AU - Bruning, T

AU - Koto, YD

AU - Radice, P

AU - Peterlongo, P

AU - Bonanni, B

AU - Volorio, S

AU - Dork, T

AU - Bogdanova, NV

AU - Helbig, S

AU - Mannermaa, A

AU - Kataja, V

AU - Kosma, VM

AU - Hartikainen, JM

AU - Devilee, P

AU - Tollenaar, RAEM

AU - Seynaeve, Caroline

AU - van Asperen, CJ

AU - Jakubowska, A

AU - Lubinski, J

AU - Jaworska-Bieniek, K

AU - Durda, K

AU - Slager, S

AU - Toland, AE

AU - Ambrosone, CB

AU - Yannoukakos, D

AU - Sangrajrang, S

AU - Gaborieau, V

AU - Brennan, P

AU - Mckay, J

AU - Hamann, U

AU - Torres, D

AU - Zheng, W

AU - Long, JR

AU - Anton-Culver, H

AU - Neuhausen, SL

AU - Luccarini, C

AU - Baynes, C

AU - Ahmed, S (Shahana)

AU - Maranian, M

AU - Healey, CS

AU - Gonzalez-Neira, A

AU - Pita, G

AU - Alonso, MR

AU - Alvarez, N

AU - Herrero, D

AU - Tessier, DC

AU - Vincent, D

AU - Bacot, F

AU - de Santiago, I

AU - Carroll, J

AU - Caldas, C

AU - Brown, MA

AU - Lupien, M

AU - Kristensen, VN

AU - Pharoah, PDP

AU - Chenevix-Trench, G

AU - French, JD

AU - Easton, DF

AU - Dunning, AM

AU - Truong, Thanh Dam

PY - 2014

Y1 - 2014

N2 - GWAS have identified a breast cancer susceptibility locus on 2q35. Here we report the fine mapping of this locus using data from 101,943 subjects from 50 case-control studies. We genotype 276 SNPs using the 'iCOGS' genotyping array and impute genotypes for a further 1,284 using 1000 Genomes Project data. All but two, strongly correlated SNPs (rs4442975 G/T and rs6721996 G/A) are excluded as candidate causal variants at odds against >100:1. The best functional candidate, rs4442975, is associated with oestrogen receptor positive (ER+) disease with an odds ratio (OR) in Europeans of 0.85 (95% confidence interval = 0.84 - 0.87; P = 1.7 x 10(-43)) per t-allele. This SNP flanks a transcriptional enhancer that physically interacts with the promoter of IGFBP5 (encoding insulin-like growth factor-binding protein 5) and displays allele-specific gene expression, FOXA1 binding and chromatin looping. Evidence suggests that the g-allele confers increased breast cancer susceptibility through relative downregulation of IGFBP5, a gene with known roles in breast cell biology.

AB - GWAS have identified a breast cancer susceptibility locus on 2q35. Here we report the fine mapping of this locus using data from 101,943 subjects from 50 case-control studies. We genotype 276 SNPs using the 'iCOGS' genotyping array and impute genotypes for a further 1,284 using 1000 Genomes Project data. All but two, strongly correlated SNPs (rs4442975 G/T and rs6721996 G/A) are excluded as candidate causal variants at odds against >100:1. The best functional candidate, rs4442975, is associated with oestrogen receptor positive (ER+) disease with an odds ratio (OR) in Europeans of 0.85 (95% confidence interval = 0.84 - 0.87; P = 1.7 x 10(-43)) per t-allele. This SNP flanks a transcriptional enhancer that physically interacts with the promoter of IGFBP5 (encoding insulin-like growth factor-binding protein 5) and displays allele-specific gene expression, FOXA1 binding and chromatin looping. Evidence suggests that the g-allele confers increased breast cancer susceptibility through relative downregulation of IGFBP5, a gene with known roles in breast cell biology.

U2 - 10.1038/ncomms5999

DO - 10.1038/ncomms5999

M3 - Article

C2 - 25248036

SN - 2041-1723

VL - 5

JO - Nature Communications

JF - Nature Communications

ER -