Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation.
Maya Ghoussaini,
Stacey L Edwards,
Kyriaki Michailidou,
Silje Nord,
Richard Cowper-Sal Lari,
Kinjal Desai,
Siddhartha Kar,
Kristine M Hillman,
Susanne Kaufmann,
Dylan M Glubb,
Jonathan Beesley,
Joe Dennis,
Manjeet K Bolla,
Qin Wang,
Ed Dicks,
Qi Guo,
Marjanka K Schmidt,
Mitul Shah,
Robert Luben,
Judith Brown,
Kamila Czene,
Hatef Darabi,
Mikael Eriksson,
Daniel Klevebring,
Stig E Bojesen,
Børge G Nordestgaard,
Sune F Nielsen,
Henrik Flyger,
Diether Lambrechts,
Bernard Thienpont,
Patrick Neven,
Hans Wildiers,
Annegien Broeks,
Laura J Van't Veer,
Emiel J Th Rutgers,
Fergus J Couch,
Janet E Olson,
Emily Hallberg,
Celine Vachon,
Jenny Chang-Claude,
Anja Rudolph,
Petra Seibold,
Dieter Flesch-Janys,
Julian Peto,
Isabel Dos-Santos-Silva,
Lorna Gibson,
Heli Nevanlinna,
Taru A Muranen,
Kristiina Aittomäki,
Carl Blomqvist,
Per Hall,
Jingmei Li,
Jianjun Liu,
Keith Humphreys,
Daehee Kang,
Ji-Yeob Choi,
Sue K Park,
Dong-Young Noh,
Keitaro Matsuo,
Hidemi Ito,
Hiroji Iwata,
Yasushi Yatabe,
Pascal Guénel,
Thérèse Truong,
Florence Menegaux,
Marie Sanchez,
Barbara Burwinkel,
Frederik Marme,
Andreas Schneeweiss,
Christof Sohn,
Anna H Wu,
Chiu-Chen Tseng,
David Van Den Berg,
Daniel O Stram,
Javier Benitez,
M Pilar Zamora,
Jose Ignacio Arias Perez,
Primitiva Menéndez,
Xiao-Ou Shu,
Wei Lu,
Yu-Tang Gao,
Qiuyin Cai,
Angela Cox,
Simon S Cross,
Malcolm W R Reed,
Irene L Andrulis,
Julia A Knight,
Gord Glendon,
Sandrine Tchatchou,
Elinor J Sawyer,
Ian Tomlinson,
Michael J Kerin,
Nicola Miller,
Christopher A Haiman,
Brian E Henderson,
Fredrick Schumacher,
Loic Le Marchand,
Annika Lindblom,
Sara Margolin,
Soo Hwang Teo,
Cheng Har Yip,
Daphne S C Lee,
Tien Y Wong,
Maartje J Hooning,
John W M Martens,
J Margriet Collée,
Carolien H M van Deurzen,
John L Hopper,
Melissa C Southey,
Helen Tsimiklis,
Miroslav K Kapuscinski,
Chen-Yang Shen,
Pei-Ei Wu,
Jyh-Cherng Yu,
Shou-Tung Chen,
Grethe Grenaker Alnæs,
Anne-Lise Borresen-Dale,
Graham G Giles,
Roger L Milne,
Catriona McLean,
Kenneth Muir,
Artitaya Lophatananon,
Sarah Stewart-Brown,
Pornthep Siriwanarangsan,
Mikael Hartman,
Hui Miao,
Shaik Ahmad Bin Syed Buhari,
Yik Ying Teo,
Peter A Fasching,
Lothar Haeberle,
Arif B Ekici,
Matthias W Beckmann,
Hermann Brenner,
Aida Karina Dieffenbach,
Volker Arndt,
Christa Stegmaier,
Anthony Swerdlow,
Alan Ashworth,
Nick Orr,
Minouk J Schoemaker,
Montserrat García-Closas,
Jonine Figueroa,
Stephen J Chanock,
Jolanta Lissowska,
Jacques Simard,
Mark S Goldberg,
France Labrèche,
Martine Dumont,
Robert Winqvist,
Katri Pylkäs,
Arja Jukkola-Vuorinen,
Hiltrud Brauch,
Thomas Brüning,
Yon-Dschun Koto,
Paolo Radice,
Paolo Peterlongo,
Bernardo Bonanni,
Sara Volorio,
Thilo Dörk,
Natalia V Bogdanova,
Sonja Helbig,
Arto Mannermaa,
Vesa Kataja,
Veli-Matti Kosma,
Jaana M Hartikainen,
Peter Devilee,
Robert A E M Tollenaar,
Caroline Seynaeve,
Christi J Van Asperen,
Anna Jakubowska,
Jan Lubinski,
Katarzyna Jaworska-Bieniek,
Katarzyna Durda,
Susan Slager,
Amanda E Toland,
Christine B Ambrosone,
Drakoulis Yannoukakos,
Suleeporn Sangrajrang,
Valerie Gaborieau,
Paul Brennan,
James McKay,
Ute Hamann,
Diana Torres,
Wei Zheng,
Jirong Long,
Hoda Anton-Culver,
Susan L Neuhausen,
Craig Luccarini,
Caroline Baynes,
Shahana Ahmed,
Mel Maranian,
Catherine S Healey,
Anna González-Neira,
Guillermo Pita,
M Rosario Alonso,
Nuria Alvarez,
Daniel Herrero,
Daniel C Tessier,
Daniel Vincent,
Francois Bacot,
Ines de Santiago,
Jason Carroll,
Carlos Caldas,
Melissa A Brown,
Mathieu Lupien,
Vessela N Kristensen,
Paul D P Pharoah,
Georgia Chenevix-Trench,
Juliet D French,
Douglas F Easton,
Alison M Dunning,
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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.