Fine scale mapping of the 17q22 breast cancer locus using dense SNPs, genotyped within the Collaborative Oncological Gene-Environment Study (COGs).
Hatef Darabi,
Jonathan Beesley,
Arnaud Droit,
Siddhartha Kar,
Silje Nord,
Mahdi Moradi Marjaneh,
Penny Soucy,
Kyriaki Michailidou,
Maya Ghoussaini,
Hanna Fues Wahl,
Manjeet K Bolla,
Qin Wang,
Joe Dennis,
M Rosario Alonso,
Irene L Andrulis,
Hoda Anton-Culver,
Volker Arndt,
Matthias W Beckmann,
Javier Benitez,
Natalia V Bogdanova,
Stig E Bojesen,
Hiltrud Brauch,
Hermann Brenner,
Annegien Broeks,
Thomas Brüning,
Barbara Burwinkel,
Jenny Chang-Claude,
Ji-Yeob Choi,
Don M Conroy,
Fergus J Couch,
Angela Cox,
Simon S Cross,
Kamila Czene,
Peter Devilee,
Thilo Dörk,
Douglas F Easton,
Peter A Fasching,
Jonine Figueroa,
Olivia Fletcher,
Henrik Flyger,
Eva Galle,
Montserrat García-Closas,
Graham G Giles,
Mark S Goldberg,
Anna González-Neira,
Pascal Guénel,
Christopher A Haiman,
Emily Hallberg,
Ute Hamann,
Mikael Hartman,
Antoinette Hollestelle,
John L Hopper,
Hidemi Ito,
Anna Jakubowska,
Nichola Johnson,
Daehee Kang,
Sofia Khan,
Veli-Matti Kosma,
Mieke Kriege,
Vessela Kristensen,
Diether Lambrechts,
Loic Le Marchand,
Soo Chin Lee,
Annika Lindblom,
Artitaya Lophatananon,
Jan Lubinski,
Arto Mannermaa,
Siranoush Manoukian,
Sara Margolin,
Keitaro Matsuo,
Rebecca Mayes,
James McKay,
Alfons Meindl,
Roger L Milne,
Kenneth Muir,
Susan L Neuhausen,
Heli Nevanlinna,
Curtis Olswold,
Nick Orr,
Paolo Peterlongo,
Guillermo Pita,
Katri Pylkäs,
Anja Rudolph,
Suleeporn Sangrajrang,
Elinor J Sawyer,
Marjanka K Schmidt,
Rita K Schmutzler,
Caroline Seynaeve,
Mitul Shah,
Chen-Yang Shen,
Xiao-Ou Shu,
Melissa C Southey,
Daniel O Stram,
Harald Surowy,
Anthony Swerdlow,
Soo H Teo,
Daniel C Tessier,
Ian Tomlinson,
Diana Torres,
Thérèse Truong,
Celine M Vachon,
Daniel Vincent,
Robert Winqvist,
Anna H Wu,
Pei-Ei Wu,
Cheng Har Yip,
Wei Zheng,
Paul D P Pharoah,
Per Hall,
Stacey L Edwards,
Jacques Simard,
Juliet D French,
Georgia Chenevix-Trench,
Alison M Dunning
Abstract
Genome-wide association studies have found SNPs at 17q22 to be associated with breast cancer risk. To identify potential causal variants related to breast cancer risk, we performed a high resolution fine-mapping analysis that involved genotyping 517 SNPs using a custom Illumina iSelect array (iCOGS) followed by imputation of genotypes for 3,134 SNPs in more than 89,000 participants of European ancestry from the Breast Cancer Association Consortium (BCAC). We identified 28 highly correlated common variants, in a 53 Kb region spanning two introns of the STXBP4 gene, that are strong candidates for driving breast cancer risk (lead SNP rs2787486 (OR = 0.92; CI 0.90-0.94; P = 8.96 × 10(-15))) and are correlated with two previously reported risk-associated variants at this locus, SNPs rs6504950 (OR = 0.94, P = 2.04 × 10(-09), r(2) = 0.73 with lead SNP) and rs1156287 (OR = 0.93, P = 3.41 × 10(-11), r(2) = 0.83 with lead SNP). Analyses indicate only one causal SNP in the region and several enhancer elements targeting STXBP4 are located within the 53 kb association signal. Expression studies in breast tumor tissues found SNP rs2787486 to be associated with increased STXBP4 expression, suggesting this may be a target gene of this locus.