Fine scale mapping of the 17q22 breast cancer locus using dense SNPs, genotyped within the Collaborative Oncological Gene-Environment Study (COGs)
Authors: Darabi Hatef , Beesley Jonathan , Droit Arnaud , Kar Siddhartha , Nord Silje , Moradi Marjaneh Mahdi , Soucy Penny , Michailidou Kyriaki , Ghoussaini Maya , Fues Wahl Hanna , Bolla Manjeet K. , Wang Qin , Dennis Joe , Alonso M. Rosario , Andrulis Irene L. , Anton-Culver Hoda , Arndt Volker , Beckmann Matthias W. , Benitez Javier , Bogdanova Natalia V. , Bojesen Stig E. , Brauch Hiltrud , Brenner Hermann , Broeks Annegien , Brüning Thomas , Burwinkel Barbara , Chang-Claude Jenny , Choi Ji-Yeob , Conroy Don M. , Couch Fergus J. , Cox Angela , Cross Simon S. , Czene Kamila , Devilee Peter , Dörk Thilo , Easton Douglas F. , Fasching Peter A. , Figueroa Jonine , Fletcher Olivia , Flyger Henrik , Galle Eva , García-Closas Montserrat , Giles Graham G. , Goldberg Mark S. , González-Neira Anna , Guénel Pascal , Haiman Christopher A. , Hallberg Emily , Hamann Ute , Hartman Mikael , Hollestelle Antoinette , Hopper John L. , Ito Hidemi , Jakubowska Anna , Johnson Nichola , Kang Daehee , Khan Sofia , Kosma Veli-Matti , Kriege Mieke , Kristensen Vessela , Lambrechts Diether , Le Marchand Loic , Lee Soo Chin , Lindblom Annika , Lophatananon Artitaya , Lubinski Jan , Mannermaa Arto , Manoukian Siranoush , Margolin Sara , Matsuo Keitaro , Mayes Rebecca , McKay James , Meindl Alfons , Milne Roger L. , Muir Kenneth , Neuhausen Susan L. , Nevanlinna Heli , Olswold Curtis , Orr Nick , Peterlongo Paolo , Pita Guillermo , Pylkäs Katri , Rudolph Anja , Sangrajrang Suleeporn , Sawyer Elinor J. , Schmidt Marjanka K. , Schmutzler Rita K. , Seynaeve Caroline , Shah Mitul , Shen Chen-Yang , Shu Xiao-Ou , Southey Melissa C. , Stram Daniel O. , Surowy Harald , Swerdlow Anthony , Teo Soo H. , Tessier Daniel C. , Tomlinson Ian , Torres Diana , Truong Thérèse , Vachon Celine M. , Vincent Daniel , Winqvist Robert , Wu Anna H. , Wu Pei-Ei , Yip Cheng Har , Zheng Wei , Pharoah Paul D. P. , Hall Per , Edwards Stacey L. , Simard Jacques , French Juliet D. , Chenevix-Trench Georgia , Dunning Alison M. 
Published: September 2016

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, r2 = 0.73 with lead SNP) and rs1156287 (OR = 0.93, P = 3.41 × 10−11, r2 = 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.