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Fine-mapping identifies two additional breast cancer susceptibility loci at 9q31.2

We recently identified a novel susceptibility variant, rs865686, for estrogen-receptor positive breast cancer at 9q31.2. Here, we report a fine-mapping analysis of the 9q31.2 susceptibility locus using 43 160 cases and 42 600 controls of European ancestry ascertained from 52 studies and a further 57...

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Autores principales: Orr, Nick, Dudbridge, Frank, Dryden, Nicola, Maguire, Sarah, Novo, Daniela, Perrakis, Eleni, Johnson, Nichola, Ghoussaini, Maya, Hopper, John L., Southey, Melissa C., Apicella, Carmel, Stone, Jennifer, Schmidt, Marjanka K., Broeks, Annegien, Van't Veer, Laura J., Hogervorst, Frans B., Fasching, Peter A., Haeberle, Lothar, Ekici, Arif B., Beckmann, Matthias W., Gibson, Lorna, Aitken, Zoe, Warren, Helen, Sawyer, Elinor, Tomlinson, Ian, Kerin, Michael J., Miller, Nicola, Burwinkel, Barbara, Marme, Frederik, Schneeweiss, Andreas, Sohn, Chistof, Guénel, Pascal, Truong, Thérèse, Cordina-Duverger, Emilie, Sanchez, Marie, Bojesen, Stig E., Nordestgaard, Børge G., Nielsen, Sune F., Flyger, Henrik, Benitez, Javier, Zamora, Maria Pilar, Arias Perez, Jose Ignacio, Menéndez, Primitiva, Anton-Culver, Hoda, Neuhausen, Susan L., Brenner, Hermann, Dieffenbach, Aida Karina, Arndt, Volker, Stegmaier, Christa, Hamann, Ute, Brauch, Hiltrud, Justenhoven, Christina, Brüning, Thomas, Ko, Yon-Dschun, Nevanlinna, Heli, Aittomäki, Kristiina, Blomqvist, Carl, Khan, Sofia, Bogdanova, Natalia, Dörk, Thilo, Lindblom, Annika, Margolin, Sara, Mannermaa, Arto, Kataja, Vesa, Kosma, Veli-Matti, Hartikainen, Jaana M., Chenevix-Trench, Georgia, Beesley, Jonathan, Lambrechts, Diether, Moisse, Matthieu, Floris, Guiseppe, Beuselinck, Benoit, Chang-Claude, Jenny, Rudolph, Anja, Seibold, Petra, Flesch-Janys, Dieter, Radice, Paolo, Peterlongo, Paolo, Peissel, Bernard, Pensotti, Valeria, Couch, Fergus J., Olson, Janet E., Slettedahl, Seth, Vachon, Celine, Giles, Graham G., Milne, Roger L., McLean, Catriona, Haiman, Christopher A., Henderson, Brian E., Schumacher, Fredrick, Le Marchand, Loic, Simard, Jacques, Goldberg, Mark S., Labrèche, France, Dumont, Martine, Kristensen, Vessela, Alnæs, Grethe Grenaker, Nord, Silje, Borresen-Dale, Anne-Lise, Zheng, Wei, Deming-Halverson, Sandra, Shrubsole, Martha, Long, Jirong, Winqvist, Robert, Pylkäs, Katri, Jukkola-Vuorinen, Arja, Grip, Mervi, Andrulis, Irene L., Knight, Julia A., Glendon, Gord, Tchatchou, Sandrine, Devilee, Peter, Tollenaar, Robertus A. E. M., Seynaeve, Caroline M., Van Asperen, Christi J., Garcia-Closas, Montserrat, Figueroa, Jonine, Chanock, Stephen J., Lissowska, Jolanta, Czene, Kamila, Darabi, Hatef, Eriksson, Mikael, Klevebring, Daniel, Hooning, Maartje J., Hollestelle, Antoinette, van Deurzen, Carolien H. M., Kriege, Mieke, Hall, Per, Li, Jingmei, Liu, Jianjun, Humphreys, Keith, Cox, Angela, Cross, Simon S., Reed, Malcolm W. R., Pharoah, Paul D. P., Dunning, Alison M., Shah, Mitul, Perkins, Barbara J., Jakubowska, Anna, Lubinski, Jan, Jaworska-Bieniek, Katarzyna, Durda, Katarzyna, Ashworth, Alan, Swerdlow, Anthony, Jones, Michael, Schoemaker, Minouk J., Meindl, Alfons, Schmutzler, Rita K., Olswold, Curtis, Slager, Susan, Toland, Amanda E., Yannoukakos, Drakoulis, Muir, Kenneth, Lophatananon, Artitaya, Stewart-Brown, Sarah, Siriwanarangsan, Pornthep, Matsuo, Keitaro, Ito, Hidema, Iwata, Hiroji, Ishiguro, Junko, Wu, Anna H., Tseng, Chiu-chen, Van Den Berg, David, Stram, Daniel O., Teo, Soo Hwang, Yip, Cheng Har, Kang, Peter, Ikram, Mohammad Kamran, Shu, Xiao-Ou, Lu, Wei, Gao, Yu-Tang, Cai, Hui, Kang, Daehee, Choi, Ji-Yeob, Park, Sue K., Noh, Dong-Young, Hartman, Mikael, Miao, Hui, Lim, Wei Yen, Lee, Soo Chin, Sangrajrang, Suleeporn, Gaborieau, Valerie, Brennan, Paul, Mckay, James, Wu, Pei-Ei, Hou, Ming-Feng, Yu, Jyh-Cherng, Shen, Chen-Yang, Blot, William, Cai, Qiuyin, Signorello, Lisa B., Luccarini, Craig, Bayes, 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, Hunter, David J., Lindstrom, Sara, Dennis, Joe, Michailidou, Kyriaki, Bolla, Manjeet K., Easton, Douglas F., dos Santos Silva, Isabel, Fletcher, Olivia, Peto, Julian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4406292/
https://www.ncbi.nlm.nih.gov/pubmed/25652398
http://dx.doi.org/10.1093/hmg/ddv035
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author Orr, Nick
Dudbridge, Frank
Dryden, Nicola
Maguire, Sarah
Novo, Daniela
Perrakis, Eleni
Johnson, Nichola
Ghoussaini, Maya
Hopper, John L.
Southey, Melissa C.
Apicella, Carmel
Stone, Jennifer
Schmidt, Marjanka K.
Broeks, Annegien
Van't Veer, Laura J.
Hogervorst, Frans B.
Fasching, Peter A.
Haeberle, Lothar
Ekici, Arif B.
Beckmann, Matthias W.
Gibson, Lorna
Aitken, Zoe
Warren, Helen
Sawyer, Elinor
Tomlinson, Ian
Kerin, Michael J.
Miller, Nicola
Burwinkel, Barbara
Marme, Frederik
Schneeweiss, Andreas
Sohn, Chistof
Guénel, Pascal
Truong, Thérèse
Cordina-Duverger, Emilie
Sanchez, Marie
Bojesen, Stig E.
Nordestgaard, Børge G.
Nielsen, Sune F.
Flyger, Henrik
Benitez, Javier
Zamora, Maria Pilar
Arias Perez, Jose Ignacio
Menéndez, Primitiva
Anton-Culver, Hoda
Neuhausen, Susan L.
Brenner, Hermann
Dieffenbach, Aida Karina
Arndt, Volker
Stegmaier, Christa
Hamann, Ute
Brauch, Hiltrud
Justenhoven, Christina
Brüning, Thomas
Ko, Yon-Dschun
Nevanlinna, Heli
Aittomäki, Kristiina
Blomqvist, Carl
Khan, Sofia
Bogdanova, Natalia
Dörk, Thilo
Lindblom, Annika
Margolin, Sara
Mannermaa, Arto
Kataja, Vesa
Kosma, Veli-Matti
Hartikainen, Jaana M.
Chenevix-Trench, Georgia
Beesley, Jonathan
Lambrechts, Diether
Moisse, Matthieu
Floris, Guiseppe
Beuselinck, Benoit
Chang-Claude, Jenny
Rudolph, Anja
Seibold, Petra
Flesch-Janys, Dieter
Radice, Paolo
Peterlongo, Paolo
Peissel, Bernard
Pensotti, Valeria
Couch, Fergus J.
Olson, Janet E.
Slettedahl, Seth
Vachon, Celine
Giles, Graham G.
Milne, Roger L.
McLean, Catriona
Haiman, Christopher A.
Henderson, Brian E.
Schumacher, Fredrick
Le Marchand, Loic
Simard, Jacques
Goldberg, Mark S.
Labrèche, France
Dumont, Martine
Kristensen, Vessela
Alnæs, Grethe Grenaker
Nord, Silje
Borresen-Dale, Anne-Lise
Zheng, Wei
Deming-Halverson, Sandra
Shrubsole, Martha
Long, Jirong
Winqvist, Robert
Pylkäs, Katri
Jukkola-Vuorinen, Arja
Grip, Mervi
Andrulis, Irene L.
Knight, Julia A.
Glendon, Gord
Tchatchou, Sandrine
Devilee, Peter
Tollenaar, Robertus A. E. M.
Seynaeve, Caroline M.
Van Asperen, Christi J.
Garcia-Closas, Montserrat
Figueroa, Jonine
Chanock, Stephen J.
Lissowska, Jolanta
Czene, Kamila
Darabi, Hatef
Eriksson, Mikael
Klevebring, Daniel
Hooning, Maartje J.
Hollestelle, Antoinette
van Deurzen, Carolien H. M.
Kriege, Mieke
Hall, Per
Li, Jingmei
Liu, Jianjun
Humphreys, Keith
Cox, Angela
Cross, Simon S.
Reed, Malcolm W. R.
Pharoah, Paul D. P.
Dunning, Alison M.
Shah, Mitul
Perkins, Barbara J.
Jakubowska, Anna
Lubinski, Jan
Jaworska-Bieniek, Katarzyna
Durda, Katarzyna
Ashworth, Alan
Swerdlow, Anthony
Jones, Michael
Schoemaker, Minouk J.
Meindl, Alfons
Schmutzler, Rita K.
Olswold, Curtis
Slager, Susan
Toland, Amanda E.
Yannoukakos, Drakoulis
Muir, Kenneth
Lophatananon, Artitaya
Stewart-Brown, Sarah
Siriwanarangsan, Pornthep
Matsuo, Keitaro
Ito, Hidema
Iwata, Hiroji
Ishiguro, Junko
Wu, Anna H.
Tseng, Chiu-chen
Van Den Berg, David
Stram, Daniel O.
Teo, Soo Hwang
Yip, Cheng Har
Kang, Peter
Ikram, Mohammad Kamran
Shu, Xiao-Ou
Lu, Wei
Gao, Yu-Tang
Cai, Hui
Kang, Daehee
Choi, Ji-Yeob
Park, Sue K.
Noh, Dong-Young
Hartman, Mikael
Miao, Hui
Lim, Wei Yen
Lee, Soo Chin
Sangrajrang, Suleeporn
Gaborieau, Valerie
Brennan, Paul
Mckay, James
Wu, Pei-Ei
Hou, Ming-Feng
Yu, Jyh-Cherng
Shen, Chen-Yang
Blot, William
Cai, Qiuyin
Signorello, Lisa B.
Luccarini, Craig
Bayes, 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
Hunter, David J.
Lindstrom, Sara
Dennis, Joe
Michailidou, Kyriaki
Bolla, Manjeet K.
Easton, Douglas F.
dos Santos Silva, Isabel
Fletcher, Olivia
Peto, Julian
author_facet Orr, Nick
Dudbridge, Frank
Dryden, Nicola
Maguire, Sarah
Novo, Daniela
Perrakis, Eleni
Johnson, Nichola
Ghoussaini, Maya
Hopper, John L.
Southey, Melissa C.
Apicella, Carmel
Stone, Jennifer
Schmidt, Marjanka K.
Broeks, Annegien
Van't Veer, Laura J.
Hogervorst, Frans B.
Fasching, Peter A.
Haeberle, Lothar
Ekici, Arif B.
Beckmann, Matthias W.
Gibson, Lorna
Aitken, Zoe
Warren, Helen
Sawyer, Elinor
Tomlinson, Ian
Kerin, Michael J.
Miller, Nicola
Burwinkel, Barbara
Marme, Frederik
Schneeweiss, Andreas
Sohn, Chistof
Guénel, Pascal
Truong, Thérèse
Cordina-Duverger, Emilie
Sanchez, Marie
Bojesen, Stig E.
Nordestgaard, Børge G.
Nielsen, Sune F.
Flyger, Henrik
Benitez, Javier
Zamora, Maria Pilar
Arias Perez, Jose Ignacio
Menéndez, Primitiva
Anton-Culver, Hoda
Neuhausen, Susan L.
Brenner, Hermann
Dieffenbach, Aida Karina
Arndt, Volker
Stegmaier, Christa
Hamann, Ute
Brauch, Hiltrud
Justenhoven, Christina
Brüning, Thomas
Ko, Yon-Dschun
Nevanlinna, Heli
Aittomäki, Kristiina
Blomqvist, Carl
Khan, Sofia
Bogdanova, Natalia
Dörk, Thilo
Lindblom, Annika
Margolin, Sara
Mannermaa, Arto
Kataja, Vesa
Kosma, Veli-Matti
Hartikainen, Jaana M.
Chenevix-Trench, Georgia
Beesley, Jonathan
Lambrechts, Diether
Moisse, Matthieu
Floris, Guiseppe
Beuselinck, Benoit
Chang-Claude, Jenny
Rudolph, Anja
Seibold, Petra
Flesch-Janys, Dieter
Radice, Paolo
Peterlongo, Paolo
Peissel, Bernard
Pensotti, Valeria
Couch, Fergus J.
Olson, Janet E.
Slettedahl, Seth
Vachon, Celine
Giles, Graham G.
Milne, Roger L.
McLean, Catriona
Haiman, Christopher A.
Henderson, Brian E.
Schumacher, Fredrick
Le Marchand, Loic
Simard, Jacques
Goldberg, Mark S.
Labrèche, France
Dumont, Martine
Kristensen, Vessela
Alnæs, Grethe Grenaker
Nord, Silje
Borresen-Dale, Anne-Lise
Zheng, Wei
Deming-Halverson, Sandra
Shrubsole, Martha
Long, Jirong
Winqvist, Robert
Pylkäs, Katri
Jukkola-Vuorinen, Arja
Grip, Mervi
Andrulis, Irene L.
Knight, Julia A.
Glendon, Gord
Tchatchou, Sandrine
Devilee, Peter
Tollenaar, Robertus A. E. M.
Seynaeve, Caroline M.
Van Asperen, Christi J.
Garcia-Closas, Montserrat
Figueroa, Jonine
Chanock, Stephen J.
Lissowska, Jolanta
Czene, Kamila
Darabi, Hatef
Eriksson, Mikael
Klevebring, Daniel
Hooning, Maartje J.
Hollestelle, Antoinette
van Deurzen, Carolien H. M.
Kriege, Mieke
Hall, Per
Li, Jingmei
Liu, Jianjun
Humphreys, Keith
Cox, Angela
Cross, Simon S.
Reed, Malcolm W. R.
Pharoah, Paul D. P.
Dunning, Alison M.
Shah, Mitul
Perkins, Barbara J.
Jakubowska, Anna
Lubinski, Jan
Jaworska-Bieniek, Katarzyna
Durda, Katarzyna
Ashworth, Alan
Swerdlow, Anthony
Jones, Michael
Schoemaker, Minouk J.
Meindl, Alfons
Schmutzler, Rita K.
Olswold, Curtis
Slager, Susan
Toland, Amanda E.
Yannoukakos, Drakoulis
Muir, Kenneth
Lophatananon, Artitaya
Stewart-Brown, Sarah
Siriwanarangsan, Pornthep
Matsuo, Keitaro
Ito, Hidema
Iwata, Hiroji
Ishiguro, Junko
Wu, Anna H.
Tseng, Chiu-chen
Van Den Berg, David
Stram, Daniel O.
Teo, Soo Hwang
Yip, Cheng Har
Kang, Peter
Ikram, Mohammad Kamran
Shu, Xiao-Ou
Lu, Wei
Gao, Yu-Tang
Cai, Hui
Kang, Daehee
Choi, Ji-Yeob
Park, Sue K.
Noh, Dong-Young
Hartman, Mikael
Miao, Hui
Lim, Wei Yen
Lee, Soo Chin
Sangrajrang, Suleeporn
Gaborieau, Valerie
Brennan, Paul
Mckay, James
Wu, Pei-Ei
Hou, Ming-Feng
Yu, Jyh-Cherng
Shen, Chen-Yang
Blot, William
Cai, Qiuyin
Signorello, Lisa B.
Luccarini, Craig
Bayes, 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
Hunter, David J.
Lindstrom, Sara
Dennis, Joe
Michailidou, Kyriaki
Bolla, Manjeet K.
Easton, Douglas F.
dos Santos Silva, Isabel
Fletcher, Olivia
Peto, Julian
author_sort Orr, Nick
collection PubMed
description We recently identified a novel susceptibility variant, rs865686, for estrogen-receptor positive breast cancer at 9q31.2. Here, we report a fine-mapping analysis of the 9q31.2 susceptibility locus using 43 160 cases and 42 600 controls of European ancestry ascertained from 52 studies and a further 5795 cases and 6624 controls of Asian ancestry from nine studies. Single nucleotide polymorphism (SNP) rs676256 was most strongly associated with risk in Europeans (odds ratios [OR] = 0.90 [0.88–0.92]; P-value = 1.58 × 10(−25)). This SNP is one of a cluster of highly correlated variants, including rs865686, that spans ∼14.5 kb. We identified two additional independent association signals demarcated by SNPs rs10816625 (OR = 1.12 [1.08–1.17]; P-value = 7.89 × 10(−09)) and rs13294895 (OR = 1.09 [1.06–1.12]; P-value = 2.97 × 10(−11)). SNP rs10816625, but not rs13294895, was also associated with risk of breast cancer in Asian individuals (OR = 1.12 [1.06–1.18]; P-value = 2.77 × 10(−05)). Functional genomic annotation using data derived from breast cancer cell-line models indicates that these SNPs localise to putative enhancer elements that bind known drivers of hormone-dependent breast cancer, including ER-α, FOXA1 and GATA-3. In vitro analyses indicate that rs10816625 and rs13294895 have allele-specific effects on enhancer activity and suggest chromatin interactions with the KLF4 gene locus. These results demonstrate the power of dense genotyping in large studies to identify independent susceptibility variants. Analysis of associations using subjects with different ancestry, combined with bioinformatic and genomic characterisation, can provide strong evidence for the likely causative alleles and their functional basis.
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spelling pubmed-44062922015-04-27 Fine-mapping identifies two additional breast cancer susceptibility loci at 9q31.2 Orr, Nick Dudbridge, Frank Dryden, Nicola Maguire, Sarah Novo, Daniela Perrakis, Eleni Johnson, Nichola Ghoussaini, Maya Hopper, John L. Southey, Melissa C. Apicella, Carmel Stone, Jennifer Schmidt, Marjanka K. Broeks, Annegien Van't Veer, Laura J. Hogervorst, Frans B. Fasching, Peter A. Haeberle, Lothar Ekici, Arif B. Beckmann, Matthias W. Gibson, Lorna Aitken, Zoe Warren, Helen Sawyer, Elinor Tomlinson, Ian Kerin, Michael J. Miller, Nicola Burwinkel, Barbara Marme, Frederik Schneeweiss, Andreas Sohn, Chistof Guénel, Pascal Truong, Thérèse Cordina-Duverger, Emilie Sanchez, Marie Bojesen, Stig E. Nordestgaard, Børge G. Nielsen, Sune F. Flyger, Henrik Benitez, Javier Zamora, Maria Pilar Arias Perez, Jose Ignacio Menéndez, Primitiva Anton-Culver, Hoda Neuhausen, Susan L. Brenner, Hermann Dieffenbach, Aida Karina Arndt, Volker Stegmaier, Christa Hamann, Ute Brauch, Hiltrud Justenhoven, Christina Brüning, Thomas Ko, Yon-Dschun Nevanlinna, Heli Aittomäki, Kristiina Blomqvist, Carl Khan, Sofia Bogdanova, Natalia Dörk, Thilo Lindblom, Annika Margolin, Sara Mannermaa, Arto Kataja, Vesa Kosma, Veli-Matti Hartikainen, Jaana M. Chenevix-Trench, Georgia Beesley, Jonathan Lambrechts, Diether Moisse, Matthieu Floris, Guiseppe Beuselinck, Benoit Chang-Claude, Jenny Rudolph, Anja Seibold, Petra Flesch-Janys, Dieter Radice, Paolo Peterlongo, Paolo Peissel, Bernard Pensotti, Valeria Couch, Fergus J. Olson, Janet E. Slettedahl, Seth Vachon, Celine Giles, Graham G. Milne, Roger L. McLean, Catriona Haiman, Christopher A. Henderson, Brian E. Schumacher, Fredrick Le Marchand, Loic Simard, Jacques Goldberg, Mark S. Labrèche, France Dumont, Martine Kristensen, Vessela Alnæs, Grethe Grenaker Nord, Silje Borresen-Dale, Anne-Lise Zheng, Wei Deming-Halverson, Sandra Shrubsole, Martha Long, Jirong Winqvist, Robert Pylkäs, Katri Jukkola-Vuorinen, Arja Grip, Mervi Andrulis, Irene L. Knight, Julia A. Glendon, Gord Tchatchou, Sandrine Devilee, Peter Tollenaar, Robertus A. E. M. Seynaeve, Caroline M. Van Asperen, Christi J. Garcia-Closas, Montserrat Figueroa, Jonine Chanock, Stephen J. Lissowska, Jolanta Czene, Kamila Darabi, Hatef Eriksson, Mikael Klevebring, Daniel Hooning, Maartje J. Hollestelle, Antoinette van Deurzen, Carolien H. M. Kriege, Mieke Hall, Per Li, Jingmei Liu, Jianjun Humphreys, Keith Cox, Angela Cross, Simon S. Reed, Malcolm W. R. Pharoah, Paul D. P. Dunning, Alison M. Shah, Mitul Perkins, Barbara J. Jakubowska, Anna Lubinski, Jan Jaworska-Bieniek, Katarzyna Durda, Katarzyna Ashworth, Alan Swerdlow, Anthony Jones, Michael Schoemaker, Minouk J. Meindl, Alfons Schmutzler, Rita K. Olswold, Curtis Slager, Susan Toland, Amanda E. Yannoukakos, Drakoulis Muir, Kenneth Lophatananon, Artitaya Stewart-Brown, Sarah Siriwanarangsan, Pornthep Matsuo, Keitaro Ito, Hidema Iwata, Hiroji Ishiguro, Junko Wu, Anna H. Tseng, Chiu-chen Van Den Berg, David Stram, Daniel O. Teo, Soo Hwang Yip, Cheng Har Kang, Peter Ikram, Mohammad Kamran Shu, Xiao-Ou Lu, Wei Gao, Yu-Tang Cai, Hui Kang, Daehee Choi, Ji-Yeob Park, Sue K. Noh, Dong-Young Hartman, Mikael Miao, Hui Lim, Wei Yen Lee, Soo Chin Sangrajrang, Suleeporn Gaborieau, Valerie Brennan, Paul Mckay, James Wu, Pei-Ei Hou, Ming-Feng Yu, Jyh-Cherng Shen, Chen-Yang Blot, William Cai, Qiuyin Signorello, Lisa B. Luccarini, Craig Bayes, 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 Hunter, David J. Lindstrom, Sara Dennis, Joe Michailidou, Kyriaki Bolla, Manjeet K. Easton, Douglas F. dos Santos Silva, Isabel Fletcher, Olivia Peto, Julian Hum Mol Genet Association Studies Articles We recently identified a novel susceptibility variant, rs865686, for estrogen-receptor positive breast cancer at 9q31.2. Here, we report a fine-mapping analysis of the 9q31.2 susceptibility locus using 43 160 cases and 42 600 controls of European ancestry ascertained from 52 studies and a further 5795 cases and 6624 controls of Asian ancestry from nine studies. Single nucleotide polymorphism (SNP) rs676256 was most strongly associated with risk in Europeans (odds ratios [OR] = 0.90 [0.88–0.92]; P-value = 1.58 × 10(−25)). This SNP is one of a cluster of highly correlated variants, including rs865686, that spans ∼14.5 kb. We identified two additional independent association signals demarcated by SNPs rs10816625 (OR = 1.12 [1.08–1.17]; P-value = 7.89 × 10(−09)) and rs13294895 (OR = 1.09 [1.06–1.12]; P-value = 2.97 × 10(−11)). SNP rs10816625, but not rs13294895, was also associated with risk of breast cancer in Asian individuals (OR = 1.12 [1.06–1.18]; P-value = 2.77 × 10(−05)). Functional genomic annotation using data derived from breast cancer cell-line models indicates that these SNPs localise to putative enhancer elements that bind known drivers of hormone-dependent breast cancer, including ER-α, FOXA1 and GATA-3. In vitro analyses indicate that rs10816625 and rs13294895 have allele-specific effects on enhancer activity and suggest chromatin interactions with the KLF4 gene locus. These results demonstrate the power of dense genotyping in large studies to identify independent susceptibility variants. Analysis of associations using subjects with different ancestry, combined with bioinformatic and genomic characterisation, can provide strong evidence for the likely causative alleles and their functional basis. Oxford University Press 2015-05-15 2015-02-04 /pmc/articles/PMC4406292/ /pubmed/25652398 http://dx.doi.org/10.1093/hmg/ddv035 Text en © The Author 2015. Published by Oxford University Press. http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Association Studies Articles
Orr, Nick
Dudbridge, Frank
Dryden, Nicola
Maguire, Sarah
Novo, Daniela
Perrakis, Eleni
Johnson, Nichola
Ghoussaini, Maya
Hopper, John L.
Southey, Melissa C.
Apicella, Carmel
Stone, Jennifer
Schmidt, Marjanka K.
Broeks, Annegien
Van't Veer, Laura J.
Hogervorst, Frans B.
Fasching, Peter A.
Haeberle, Lothar
Ekici, Arif B.
Beckmann, Matthias W.
Gibson, Lorna
Aitken, Zoe
Warren, Helen
Sawyer, Elinor
Tomlinson, Ian
Kerin, Michael J.
Miller, Nicola
Burwinkel, Barbara
Marme, Frederik
Schneeweiss, Andreas
Sohn, Chistof
Guénel, Pascal
Truong, Thérèse
Cordina-Duverger, Emilie
Sanchez, Marie
Bojesen, Stig E.
Nordestgaard, Børge G.
Nielsen, Sune F.
Flyger, Henrik
Benitez, Javier
Zamora, Maria Pilar
Arias Perez, Jose Ignacio
Menéndez, Primitiva
Anton-Culver, Hoda
Neuhausen, Susan L.
Brenner, Hermann
Dieffenbach, Aida Karina
Arndt, Volker
Stegmaier, Christa
Hamann, Ute
Brauch, Hiltrud
Justenhoven, Christina
Brüning, Thomas
Ko, Yon-Dschun
Nevanlinna, Heli
Aittomäki, Kristiina
Blomqvist, Carl
Khan, Sofia
Bogdanova, Natalia
Dörk, Thilo
Lindblom, Annika
Margolin, Sara
Mannermaa, Arto
Kataja, Vesa
Kosma, Veli-Matti
Hartikainen, Jaana M.
Chenevix-Trench, Georgia
Beesley, Jonathan
Lambrechts, Diether
Moisse, Matthieu
Floris, Guiseppe
Beuselinck, Benoit
Chang-Claude, Jenny
Rudolph, Anja
Seibold, Petra
Flesch-Janys, Dieter
Radice, Paolo
Peterlongo, Paolo
Peissel, Bernard
Pensotti, Valeria
Couch, Fergus J.
Olson, Janet E.
Slettedahl, Seth
Vachon, Celine
Giles, Graham G.
Milne, Roger L.
McLean, Catriona
Haiman, Christopher A.
Henderson, Brian E.
Schumacher, Fredrick
Le Marchand, Loic
Simard, Jacques
Goldberg, Mark S.
Labrèche, France
Dumont, Martine
Kristensen, Vessela
Alnæs, Grethe Grenaker
Nord, Silje
Borresen-Dale, Anne-Lise
Zheng, Wei
Deming-Halverson, Sandra
Shrubsole, Martha
Long, Jirong
Winqvist, Robert
Pylkäs, Katri
Jukkola-Vuorinen, Arja
Grip, Mervi
Andrulis, Irene L.
Knight, Julia A.
Glendon, Gord
Tchatchou, Sandrine
Devilee, Peter
Tollenaar, Robertus A. E. M.
Seynaeve, Caroline M.
Van Asperen, Christi J.
Garcia-Closas, Montserrat
Figueroa, Jonine
Chanock, Stephen J.
Lissowska, Jolanta
Czene, Kamila
Darabi, Hatef
Eriksson, Mikael
Klevebring, Daniel
Hooning, Maartje J.
Hollestelle, Antoinette
van Deurzen, Carolien H. M.
Kriege, Mieke
Hall, Per
Li, Jingmei
Liu, Jianjun
Humphreys, Keith
Cox, Angela
Cross, Simon S.
Reed, Malcolm W. R.
Pharoah, Paul D. P.
Dunning, Alison M.
Shah, Mitul
Perkins, Barbara J.
Jakubowska, Anna
Lubinski, Jan
Jaworska-Bieniek, Katarzyna
Durda, Katarzyna
Ashworth, Alan
Swerdlow, Anthony
Jones, Michael
Schoemaker, Minouk J.
Meindl, Alfons
Schmutzler, Rita K.
Olswold, Curtis
Slager, Susan
Toland, Amanda E.
Yannoukakos, Drakoulis
Muir, Kenneth
Lophatananon, Artitaya
Stewart-Brown, Sarah
Siriwanarangsan, Pornthep
Matsuo, Keitaro
Ito, Hidema
Iwata, Hiroji
Ishiguro, Junko
Wu, Anna H.
Tseng, Chiu-chen
Van Den Berg, David
Stram, Daniel O.
Teo, Soo Hwang
Yip, Cheng Har
Kang, Peter
Ikram, Mohammad Kamran
Shu, Xiao-Ou
Lu, Wei
Gao, Yu-Tang
Cai, Hui
Kang, Daehee
Choi, Ji-Yeob
Park, Sue K.
Noh, Dong-Young
Hartman, Mikael
Miao, Hui
Lim, Wei Yen
Lee, Soo Chin
Sangrajrang, Suleeporn
Gaborieau, Valerie
Brennan, Paul
Mckay, James
Wu, Pei-Ei
Hou, Ming-Feng
Yu, Jyh-Cherng
Shen, Chen-Yang
Blot, William
Cai, Qiuyin
Signorello, Lisa B.
Luccarini, Craig
Bayes, 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
Hunter, David J.
Lindstrom, Sara
Dennis, Joe
Michailidou, Kyriaki
Bolla, Manjeet K.
Easton, Douglas F.
dos Santos Silva, Isabel
Fletcher, Olivia
Peto, Julian
Fine-mapping identifies two additional breast cancer susceptibility loci at 9q31.2
title Fine-mapping identifies two additional breast cancer susceptibility loci at 9q31.2
title_full Fine-mapping identifies two additional breast cancer susceptibility loci at 9q31.2
title_fullStr Fine-mapping identifies two additional breast cancer susceptibility loci at 9q31.2
title_full_unstemmed Fine-mapping identifies two additional breast cancer susceptibility loci at 9q31.2
title_short Fine-mapping identifies two additional breast cancer susceptibility loci at 9q31.2
title_sort fine-mapping identifies two additional breast cancer susceptibility loci at 9q31.2
topic Association Studies Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4406292/
https://www.ncbi.nlm.nih.gov/pubmed/25652398
http://dx.doi.org/10.1093/hmg/ddv035
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