The 10q26 locus in the second intron of FGFR2 is the locus most strongly associated with estrogen-receptor-positive breast cancer in genome-wide association studies. We conducted fine-scale mapping in case-control studies genotyped with a custom chip (iCOGS), comprising 41 studies (n = 89,050) of European ancestry, 9 Asian ancestry studies (n = 13,983), and 2 African ancestry studies (n = 2,028) from the Breast Cancer Association Consortium. We identified three statistically independent risk signals within the locus. Within risk signals 1 and 3, genetic analysis identified five and two variants, respectively, highly correlated with the most strongly associated SNPs. By using a combination of genetic fine mapping, data on DNase hypersensitivity, and electrophoretic mobility shift assays to study protein-DNA binding, we identified rs35054928, rs2981578, and rs45631563 as putative functional SNPs. Chromatin immunoprecipitation showed that FOXA1 preferentially bound to the risk-associated allele (C) of rs2981578 and was able to recruit ERalpha to this site in an allele-specific manner, whereas E2F1 preferentially bound the risk variant of rs35054928. The risk alleles were preferentially found in open chromatin and bound by Ser5 phosphorylated RNA polymerase II, suggesting that the risk alleles are associated with changes in transcription. Chromatin conformation capture demonstrated that the risk region was able to interact with the promoter of FGFR2, the likely target gene of this risk region. A role for FOXA1 in mediating breast cancer susceptibility at this locus is consistent with the finding that the FGFR2 risk locus primarily predisposes to estrogen-receptor-positive disease. ; Meyer, Kerstin B O'Reilly, Martin Michailidou, Kyriaki Carlebur, Saskia Edwards, Stacey L French, Juliet D Prathalingham, Radhika Dennis, Joe Bolla, Manjeet K Wang, Qin de Santiago, Ines Hopper, John L Tsimiklis, Helen Apicella, Carmel Southey, Melissa C Schmidt, Marjanka K Broeks, Annegien Van 't Veer, Laura J Hogervorst, Frans B Muir, Kenneth Lophatananon, Artitaya Stewart-Brown, Sarah Siriwanarangsan, Pornthep Fasching, Peter A Lux, Michael P Ekici, Arif B Beckmann, Matthias W Peto, Julian Dos Santos Silva, Isabel Fletcher, Olivia Johnson, Nichola Sawyer, Elinor J Tomlinson, Ian Kerin, Michael J Miller, Nicola Marme, Federick Schneeweiss, Andreas Sohn, Christof Burwinkel, Barbara Guenel, Pascal Truong, Therese Laurent-Puig, Pierre Menegaux, Florence Bojesen, Stig E Nordestgaard, Borge G Nielsen, Sune F Flyger, Henrik Milne, Roger L Zamora, M Pilar Arias, Jose I Benitez, Javier Neuhausen, Susan Anton-Culver, Hoda Ziogas, Argyrios Dur, Christina C Brenner, Hermann Muller, Heiko Arndt, Volker Stegmaier, Christa Meindl, Alfons Schmutzler, Rita K Engel, Christoph Ditsch, Nina Brauch, Hiltrud Bruning, Thomas Ko, Yon-Dschun GENICA Network Nevanlinna, Heli Muranen, Taru A Aittomaki, Kristiina Blomqvist, Carl Matsuo, Keitaro Ito, Hidemi Iwata, Hiroji Yatabe, Yasushi Dork, Thilo Helbig, Sonja Bogdanova, Natalia V Lindblom, Annika Margolin, Sara Mannermaa, Arto Kataja, Vesa Kosma, Veli-Matti Hartikainen, Jaana M Chenevix-Trench, Georgia kConFab Investigators Australian Ovarian Cancer Study Group Wu, Anna H Tseng, Chiu-Chen Van Den Berg, David Stram, Daniel O Lambrechts, Diether Thienpont, Bernard Christiaens, Marie-Rose Smeets, Ann Chang-Claude, Jenny Rudolph, Anja Seibold, Petra Flesch-Janys, Dieter Radice, Paolo Peterlongo, Paolo Bonanni, Bernardo Bernard, Loris Couch, Fergus J Olson, Janet E Wang, Xianshu Purrington, Kristen Giles, Graham G Severi, Gianluca Baglietto, Laura McLean, Catriona Haiman, Christopher A Henderson, Brian E Schumacher, Fredrick Le Marchand, Loic Simard, Jacques Goldberg, Mark S Labreche, France Dumont, Martine Teo, Soo-Hwang Yip, Cheng-Har Phuah, Sze-Yee Kristensen, Vessela Grenaker Alnaes, Grethe Borresen-Dale, Anne-Lise Zheng, Wei Deming-Halverson, Sandra Shrubsole, Martha Long, Jirong Winqvist, Robert Pylkas, Katri Jukkola-Vuorinen, Arja Kauppila, Saila Andrulis, Irene L Knight, Julia A Glendon, Gord Tchatchou, Sandrine Devilee, Peter Tollenaar, Robert A E M Seynaeve, Caroline M Garcia-Closas, Montserrat Figueroa, Jonine Chanock, Stephen J Lissowska, Jolanta Czene, Kamila Darabi, Hartef Eriksson, Kimael Hooning, Maartje J Martens, John W M van den Ouweland, Ans M W van Deurzen, Carolien H M Hall, Per Li, Jingmei Liu, Jianjun Humphreys, Keith Shu, Xiao-Ou Lu, Wei Gao, Yu-Tang Cai, Hui Cox, Angela Reed, Malcolm W R Blot, William Signorello, Lisa B Cai, Qiuyin Pharoah, Paul D P Ghoussaini, Maya Harrington, Patricia Tyrer, Jonathan Kang, Daehee Choi, Ji-Yeob Park, Sue K Noh, Dong-Young Hartman, Mikael Hui, Miao Lim, Wei-Yen Buhari, Shaik A Hamann, Ute Forsti, Asta Rudiger, Thomas Ulmer, Hans-Ulrich Jakubowska, Anna Lubinski, Jan Jaworska, Katarzyna Durda, Katarzyna Sangrajrang, Suleeporn Gaborieau, Valerie Brennan, Paul McKay, James Vachon, Celine Slager, Susan Fostira, Florentia Pilarski, Robert Shen, Chen-Yang Hsiung, Chia-Ni Wu, Pei-Ei Hou, Ming-Feng Swerdlow, Anthony Ashworth, Alan Orr, Nick Schoemaker, Minouk J Ponder, Bruce A J Dunning, Alison M Easton, Douglas F 090532/Wellcome Trust/United Kingdom P50 CA116201/CA/NCI NIH HHS/United States United States American journal of human genetics Am J Hum Genet. 2013 Dec 5;93(6):1046-60. doi: 10.1016/j.ajhg.2013.10.026. Epub 2013 Nov 27.