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 × 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 | English |
|---|---|
| Article number | 4999 |
| Journal | Nature Communications |
| Volume | 4 |
| DOIs | |
| Publication status | Published - 2014 |
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
- Chemistry(all)
- Physics and Astronomy(all)
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Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation. / Ghoussaini, Maya; Edwards, Stacey L.; Michailidou, Kyriaki; Nord, Silje; Cowper-Sal-lari, Richard; Desai, Kinjal; Kar, Siddhartha; Hillman, Kristine M.; Kaufmann, Susanne; Glubb, Dylan M.; Beesley, Jonathan; Dennis, Joe; Bolla, Manjeet K.; Wang, Qin; Dicks, Ed; Guo, Qi; Schmidt, Marjanka K.; Shah, Mitul; Luben, Robert; Brown, Judith; Czene, Kamila; Darabi, Hatef; Eriksson, Mikael; Klevebring, Daniel; Bojesen, Stig E.; Nordestgaard, Børge G.; Nielsen, Sune F.; Flyger, Henrik; Lambrechts, Diether; Thienpont, Bernard; Neven, Patrick; Wildiers, Hans; Broeks, Annegien; Vant Veer, Laura J.; Rutgers, Emiel J Th; Couch, Fergus J.; Olson, Janet E.; Hallberg, Emily; Vachon, Celine; Chang-Claude, Jenny; Rudolph, Anja; Seibold, Petra; Flesch-Janys, Dieter; Peto, Julian; Dos-Santos-Silva, Isabel; Gibson, Lorna; Nevanlinna, Heli; Muranen, Taru A.; Aittomäki, Kristiina; Blomqvist, Carl; Hall, Per; Li, Jingmei; Liu, Jianjun; Humphreys, Keith; Kang, Daehee; Choi, Ji Yeob; Park, Sue K.; Noh, Dong Young; Matsuo, Keitaro; Ito, Hidemi; Iwata, Hiroji; Yatabe, Yasushi; Guénel, Pascal; Truong, Thérèse; Menegaux, Florence; Sanchez, Marie; Burwinkel, Barbara; Marme, Frederik; Schneeweiss, Andreas; Sohn, Christof; Wu, Anna H.; Tseng, Chiu Chen; Van Den Berg, David; Stram, Daniel O.; Benitez, Javier; Zamora, M. Pilar; Perez, Jose Ignacio Arias; Menéndez, Primitiva; Shu, Xiao Ou; Lu, Wei; Gao, Yu Tang; Cai, Qiuyin; Cox, Angela; Cross, Simon S.; Reed, Malcolm W R; Andrulis, Irene L.; Knight, Julia A.; Glendon, Gord; Tchatchou, Sandrine; Sawyer, Elinor J.; Tomlinson, Ian; Kerin, Michael J.; Miller, Nicola; Haiman, Christopher A.; Henderson, Brian E.; Schumacher, Fredrick; Marchand, Loic Le; Lindblom, Annika; Margolin, Sara; Teo, Soo Hwang; Yip, Cheng Har; Lee, Daphne S C; Wong, Tien Y.; Hooning, Maartje J.; Martens, John W M; Collée, J. Margriet; Van Deurzen, Carolien H M; Hopper, John L.; Southey, Melissa C.; Tsimiklis, Helen; Kapuscinski, Miroslav K.; Shen, Chen Yang; Wu, Pei Ei; Yu, Jyh Cherng; Chen, Shou Tung; Alnæs, Grethe Grenaker; Borresen-Dale, Anne Lise; Giles, Graham G.; Milne, Roger L.; McLean, Catriona; Muir, Kenneth; Lophatananon, Artitaya; Stewart-Brown, Sarah; Siriwanarangsan, Pornthep; Hartman, Mikael; Miao, Hui; Buhari, Shaik Ahmad Bin Syed; Teo, Yik Ying; Fasching, Peter A.; Haeberle, Lothar; Ekici, Arif B.; Beckmann, Matthias W.; Brenner, Hermann; Dieffenbach, Aida Karina; Arndt, Volker; Stegmaier, Christa; Swerdlow, Anthony; Ashworth, Alan; Orr, Nick; Schoemaker, Minouk J.; García-Closas, Montserrat; Figueroa, Jonine; Chanock, Stephen J.; Lissowska, Jolanta; Simard, Jacques; Goldberg, Mark S.; Labrèche, France; Dumont, Martine; Winqvist, Robert; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Brauch, Hiltrud; Brüning, Thomas; Koto, Yon Dschun; Radice, Paolo; Peterlongo, Paolo; Bonanni, Bernardo; Volorio, Sara; Dörk, Thilo; Bogdanova, Natalia V.; Helbig, Sonja; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli Matti; Hartikainen, Jaana M.; Devilee, Peter; Tollenaar, Robert A E M; Seynaeve, Caroline; Van Asperen, Christi J.; Jakubowska, Anna; Lubinski, Jan; Jaworska-Bieniek, Katarzyna; Durda, Katarzyna; Slager, Susan; Toland, Amanda E.; Ambrosone, Christine B.; Yannoukakos, Drakoulis; Sangrajrang, Suleeporn; Gaborieau, Valerie; Brennan, Paul; McKay, James; Hamann, Ute; Torres, Diana; Zheng, Wei; Long, Jirong; Anton-Culver, Hoda; Neuhausen, Susan L.; Luccarini, Craig; Baynes, Caroline; Ahmed, Shahana; Maranian, Mel; Healey, Catherine S.; González-Neira, Anna; Pita, Guillermo; Alonso, M. Rosario; Álvarez, Nuria; Herrero, Daniel; Tessier, Daniel C.; Vincent, Daniel; Bacot, Francois; De Santiago, Ines; Carroll, Jason; Caldas, Carlos; Brown, Melissa A.; Lupien, Mathieu; Kristensen, Vessela N.; Pharoah, Paul D P; Chenevix-Trench, Georgia; French, Juliet D.; Easton, Douglas F.; Dunning, Alison M.; Webb, Penny; De Fazio, Anna.
In: Nature Communications, Vol. 4, 4999, 2014.Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation
AU - Ghoussaini, Maya
AU - Edwards, Stacey L.
AU - Michailidou, Kyriaki
AU - Nord, Silje
AU - Cowper-Sal-lari, Richard
AU - Desai, Kinjal
AU - Kar, Siddhartha
AU - Hillman, Kristine M.
AU - Kaufmann, Susanne
AU - Glubb, Dylan M.
AU - Beesley, Jonathan
AU - Dennis, Joe
AU - Bolla, Manjeet K.
AU - Wang, Qin
AU - Dicks, Ed
AU - Guo, Qi
AU - Schmidt, Marjanka K.
AU - Shah, Mitul
AU - Luben, Robert
AU - Brown, Judith
AU - Czene, Kamila
AU - Darabi, Hatef
AU - Eriksson, Mikael
AU - Klevebring, Daniel
AU - Bojesen, Stig E.
AU - Nordestgaard, Børge G.
AU - Nielsen, Sune F.
AU - Flyger, Henrik
AU - Lambrechts, Diether
AU - Thienpont, Bernard
AU - Neven, Patrick
AU - Wildiers, Hans
AU - Broeks, Annegien
AU - Vant Veer, Laura J.
AU - Rutgers, Emiel J Th
AU - Couch, Fergus J.
AU - Olson, Janet E.
AU - Hallberg, Emily
AU - Vachon, Celine
AU - Chang-Claude, Jenny
AU - Rudolph, Anja
AU - Seibold, Petra
AU - Flesch-Janys, Dieter
AU - Peto, Julian
AU - Dos-Santos-Silva, Isabel
AU - Gibson, Lorna
AU - Nevanlinna, Heli
AU - Muranen, Taru A.
AU - Aittomäki, Kristiina
AU - Blomqvist, Carl
AU - Hall, Per
AU - Li, Jingmei
AU - Liu, Jianjun
AU - Humphreys, Keith
AU - Kang, Daehee
AU - Choi, Ji Yeob
AU - Park, Sue K.
AU - Noh, Dong Young
AU - Matsuo, Keitaro
AU - Ito, Hidemi
AU - Iwata, Hiroji
AU - Yatabe, Yasushi
AU - Guénel, Pascal
AU - Truong, Thérèse
AU - Menegaux, Florence
AU - Sanchez, Marie
AU - Burwinkel, Barbara
AU - Marme, Frederik
AU - Schneeweiss, Andreas
AU - Sohn, Christof
AU - Wu, Anna H.
AU - Tseng, Chiu Chen
AU - Van Den Berg, David
AU - Stram, Daniel O.
AU - Benitez, Javier
AU - Zamora, M. Pilar
AU - Perez, Jose Ignacio Arias
AU - Menéndez, Primitiva
AU - Shu, Xiao Ou
AU - Lu, Wei
AU - Gao, Yu Tang
AU - Cai, Qiuyin
AU - Cox, Angela
AU - Cross, Simon S.
AU - Reed, Malcolm W R
AU - Andrulis, Irene L.
AU - Knight, Julia A.
AU - Glendon, Gord
AU - Tchatchou, Sandrine
AU - Sawyer, Elinor J.
AU - Tomlinson, Ian
AU - Kerin, Michael J.
AU - Miller, Nicola
AU - Haiman, Christopher A.
AU - Henderson, Brian E.
AU - Schumacher, Fredrick
AU - Marchand, Loic Le
AU - Lindblom, Annika
AU - Margolin, Sara
AU - Teo, Soo Hwang
AU - Yip, Cheng Har
AU - Lee, Daphne S C
AU - Wong, Tien Y.
AU - Hooning, Maartje J.
AU - Martens, John W M
AU - Collée, J. Margriet
AU - Van Deurzen, Carolien H M
AU - Hopper, John L.
AU - Southey, Melissa C.
AU - Tsimiklis, Helen
AU - Kapuscinski, Miroslav K.
AU - Shen, Chen Yang
AU - Wu, Pei Ei
AU - Yu, Jyh Cherng
AU - Chen, Shou Tung
AU - Alnæs, Grethe Grenaker
AU - Borresen-Dale, Anne Lise
AU - Giles, Graham G.
AU - Milne, Roger L.
AU - McLean, Catriona
AU - Muir, Kenneth
AU - Lophatananon, Artitaya
AU - Stewart-Brown, Sarah
AU - Siriwanarangsan, Pornthep
AU - Hartman, Mikael
AU - Miao, Hui
AU - Buhari, Shaik Ahmad Bin Syed
AU - Teo, Yik Ying
AU - Fasching, Peter A.
AU - Haeberle, Lothar
AU - Ekici, Arif B.
AU - Beckmann, Matthias W.
AU - Brenner, Hermann
AU - Dieffenbach, Aida Karina
AU - Arndt, Volker
AU - Stegmaier, Christa
AU - Swerdlow, Anthony
AU - Ashworth, Alan
AU - Orr, Nick
AU - Schoemaker, Minouk J.
AU - García-Closas, Montserrat
AU - Figueroa, Jonine
AU - Chanock, Stephen J.
AU - Lissowska, Jolanta
AU - Simard, Jacques
AU - Goldberg, Mark S.
AU - Labrèche, France
AU - Dumont, Martine
AU - Winqvist, Robert
AU - Pylkäs, Katri
AU - Jukkola-Vuorinen, Arja
AU - Brauch, Hiltrud
AU - Brüning, Thomas
AU - Koto, Yon Dschun
AU - Radice, Paolo
AU - Peterlongo, Paolo
AU - Bonanni, Bernardo
AU - Volorio, Sara
AU - Dörk, Thilo
AU - Bogdanova, Natalia V.
AU - Helbig, Sonja
AU - Mannermaa, Arto
AU - Kataja, Vesa
AU - Kosma, Veli Matti
AU - Hartikainen, Jaana M.
AU - Devilee, Peter
AU - Tollenaar, Robert A E M
AU - Seynaeve, Caroline
AU - Van Asperen, Christi J.
AU - Jakubowska, Anna
AU - Lubinski, Jan
AU - Jaworska-Bieniek, Katarzyna
AU - Durda, Katarzyna
AU - Slager, Susan
AU - Toland, Amanda E.
AU - Ambrosone, Christine B.
AU - Yannoukakos, Drakoulis
AU - Sangrajrang, Suleeporn
AU - Gaborieau, Valerie
AU - Brennan, Paul
AU - McKay, James
AU - Hamann, Ute
AU - Torres, Diana
AU - Zheng, Wei
AU - Long, Jirong
AU - Anton-Culver, Hoda
AU - Neuhausen, Susan L.
AU - Luccarini, Craig
AU - Baynes, Caroline
AU - Ahmed, Shahana
AU - Maranian, Mel
AU - Healey, Catherine S.
AU - González-Neira, Anna
AU - Pita, Guillermo
AU - Alonso, M. Rosario
AU - Álvarez, Nuria
AU - Herrero, Daniel
AU - Tessier, Daniel C.
AU - Vincent, Daniel
AU - Bacot, Francois
AU - De Santiago, Ines
AU - Carroll, Jason
AU - Caldas, Carlos
AU - Brown, Melissa A.
AU - Lupien, Mathieu
AU - Kristensen, Vessela N.
AU - Pharoah, Paul D P
AU - Chenevix-Trench, Georgia
AU - French, Juliet D.
AU - Easton, Douglas F.
AU - Dunning, Alison M.
AU - Webb, Penny
AU - De Fazio, Anna
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 × 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 × 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.
UR - http://www.scopus.com/inward/record.url?scp=84920763076&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84920763076&partnerID=8YFLogxK
U2 - 10.1038/ncomms5999
DO - 10.1038/ncomms5999
M3 - Article
C2 - 25248036
AN - SCOPUS:84920763076
VL - 4
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
M1 - 4999
ER -