Genome-wide association and transcriptome studies identify target genes and risk loci for breast cancer
Authors: Ferreira Manuel A. , Gamazon Eric R. , Al-Ejeh Fares , Aittomäki Kristiina , Andrulis Irene L. , Anton-Culver Hoda , Arason Adalgeir , Arndt Volker , Aronson Kristan J. , Arun Banu K. , Asseryanis Ella , Azzollini Jacopo , Balmaña Judith , Barnes Daniel R. , Barrowdale Daniel , Beckmann Matthias W. , Behrens Sabine , Benitez Javier , Bermisheva Marina , Białkowska Katarzyna , Blomqvist Carl , Bogdanova Natalia V. , Bojesen Stig E. , Bolla Manjeet K. , Borg Ake , Brauch Hiltrud , Brenner Hermann , Broeks Annegien , Burwinkel Barbara , Caldés Trinidad , Caligo Maria A. , Campa Daniele , Campbell Ian , Canzian Federico , Carter Jonathan , Carter Brian D. , Castelao Jose E. , Chang-Claude Jenny , Chanock Stephen J. , Christiansen Hans , Chung Wendy K. , Claes Kathleen B. M. , Clarke Christine L. ,   EMBRACE Collaborators, Adlard Julian , Ahmed Munaza , Barwell Julian , Brady Angela , Brewer Carole , Cook Jackie , Davidson Rosemarie , Donaldson Alan , Eason Jacqueline , Eeles Ros , Evans D. Gareth , Gregory Helen , Hanson Helen , Henderson Alex , Hodgson Shirley , Izatt Louise , Kennedy M. John , Lalloo Fiona , Miller Clare , Morrison Patrick J. , Ong Kai-ren , Perkins Jo , Porteous Mary E. , Rogers Mark T. , Side Lucy E. , Snape Katie , Walker Lisa , Harrington Patricia A. ,   GC-HBOC Study Collaborators, Arnold Norbert , Auber Bernd , Bogdanova-Markov Nadja , Borde Julika , Caliebe Almuth , Ditsch Nina , Dworniczak Bernd , Engert Stefanie , Faust Ulrike , Gehrig Andrea , Hahnen Eric , Hauke Jan , Hentschel Julia , Herold Natalie , Honisch Ellen , Just Walter , Kast Karin , Larsen Mirjam , Lemke Johannes , Nguyen Huu Phuc , Niederacher Dieter , Ott Claus-Eric , Platzer Konrad , Pohl-Rescigno Esther , Ramser Juliane , Rhiem Kerstin , Steinemann Doris , Sutter Christian , Varon-Mateeva Raymonda , Wang-Gohrke Shan , Weber Bernhard H. F. ,   GEMO Study Collaborators, Prieur Fabienne , Pujol Pascal , Sagne Charlotte , Sevenet Nicolas , Sobol Hagay , Sokolowska Johanna , Stoppa-Lyonnet Dominique , Venat-Bouvet Laurence , Couch Fergus J. , Cox Angela , Cross Simon S. , Czene Kamila , Daly Mary B. , de la Hoya Miguel , Dennis Joe , Devilee Peter , Diez Orland , Dörk Thilo , Dunning Alison M. , Dwek Miriam , Eccles Diana M. , Ejlertsen Bent , Ellberg Carolina , Engel Christoph , Eriksson Mikael , Fasching Peter A. , Fletcher Olivia , Flyger Henrik , Friedman Eitan , Frost Debra , Gabrielson Marike , Gago-Dominguez Manuela , Ganz Patricia A. , Gapstur Susan M. , Garber Judy , García-Closas Montserrat , García-Sáenz José A. , Gaudet Mia M. , Giles Graham G. , Glendon Gord , Godwin Andrew K. , Goldberg Mark S. , Goldgar David E. , González-Neira Anna , Greene Mark H. , Gronwald Jacek , Guénel Pascal , Haiman Christopher A. , Hall Per , Hamann Ute , He Wei , Heyworth Jane , Hogervorst Frans B. L. , Hollestelle Antoinette , Hoover Robert N. , Hopper John L. , Hulick Peter J. , Humphreys Keith , Imyanitov Evgeny N. ,   ABCTB Investigators, Balleine Rosemary , Baxter Robert , Braye Stephen , Carpenter Jane , Dahlstrom Jane , Forbes John , Lee Soon C , Marsh Deborah , Morey Adrienne , Pathmanathan Nirmala , Simpson Peter , Spigelman Allan , Wilcken Nicholas , Yip Desmond ,   HEBON Investigators, Heemskerk-Gerritsen Bernadette A. M. , Rookus Matti A. , Seynaeve Caroline M. , van der Baan Frederieke H. , van der Hout Annemieke H. , van der Kolk Lizet E. , van der Luijt Rob B. , van Deurzen Carolien H. M. , van Doorn Helena C. , van Engelen Klaartje , van Hest Liselotte , van Os Theo A. M. , Verhoef Senno , Vogel Maartje J. , Wijnen Juul T. ,   BCFR Investigators, Miron Alexander , Kapuscinski Miroslav , Bane Anita , Ross Eric , Buys Saundra S. , Conner Thomas A. , Isaacs Claudine , Jakimovska Milena , Jakubowska Anna , James Paul A. , Janavicius Ramunas , Jankowitz Rachel C. , John Esther M. , Johnson Nichola , Joseph Vijai , Karlan Beth Y. , Khusnutdinova Elza , Kiiski Johanna I. , Ko Yon-Dschun , Jones Michael E. , Konstantopoulou Irene , Kristensen Vessela N. , Laitman Yael , Lambrechts Diether , Lazaro Conxi , Leslie Goska , Lester Jenny , Lesueur Fabienne , Lindström Sara , Long Jirong , Loud Jennifer T. , Lubiński Jan , Makalic Enes , Mannermaa Arto , Manoochehri Mehdi , Margolin Sara , Maurer Tabea , Mavroudis Dimitrios , McGuffog Lesley , Meindl Alfons , Menon Usha , Michailidou Kyriaki , Miller Austin , Montagna Marco , Moreno Fernando , Moserle Lidia , Mulligan Anna Marie , Nathanson Katherine L. , Neuhausen Susan L. , Nevanlinna Heli , Nevelsteen Ines , Nielsen Finn C. , Nikitina-Zake Liene , Nussbaum Robert L. , Offit Kenneth , Olah Edith , Olopade Olufunmilayo I. , Olsson Håkan , Osorio Ana , Papp Janos , Park-Simon Tjoung-Won , Parsons Michael T. , Pedersen Inge Sokilde , Peixoto Ana , Peterlongo Paolo , Pharoah Paul D. P. , Plaseska-Karanfilska Dijana , Poppe Bruce , Presneau Nadege , Radice Paolo , Rantala Johanna , Rennert Gad , Risch Harvey A. , Saloustros Emmanouil , Sanden Kristin , Sawyer Elinor J. , Schmidt Marjanka K. , Schmutzler Rita K. , Sharma Priyanka , Shu Xiao-Ou , Simard Jacques , Singer Christian F. , Soucy Penny , Southey Melissa C. , Spinelli John J. , Spurdle Amanda B. , Stone Jennifer , Swerdlow Anthony J. , Tapper William J. , Taylor Jack A. , Teixeira Manuel R. , Terry Mary Beth , Teulé Alex , Thomassen Mads , Thöne Kathrin , Thull Darcy L. , Tischkowitz Marc , Toland Amanda E. , Torres Diana , Truong Thérèse , Tung Nadine , Vachon Celine M. , van Asperen Christi J. , van den Ouweland Ans M. W. , van Rensburg Elizabeth J. , Vega Ana , Viel Alessandra , Wang Qin , Wappenschmidt Barbara , Weitzel Jeffrey N. , Wendt Camilla , Winqvist Robert , Yang Xiaohong R. , Yannoukakos Drakoulis , Ziogas Argyrios , Kraft Peter , Antoniou Antonis C. , Zheng Wei , Easton Douglas F. , Milne Roger L. , Beesley Jonathan , Chenevix-Trench Georgia 
Published: April 2019

Genome-wide association studies (GWAS) have identified more than 170 breast cancer susceptibility loci. Here we hypothesize that some risk-associated variants might act in non-breast tissues, specifically adipose tissue and immune cells from blood and spleen. Using expression quantitative trait loci (eQTL) reported in these tissues, we identify 26 previously unreported, likely target genes of overall breast cancer risk variants, and 17 for estrogen receptor (ER)-negative breast cancer, several with a known immune function. We determine the directional effect of gene expression on disease risk measured based on single and multiple eQTL. In addition, using a gene-based test of association that considers eQTL from multiple tissues, we identify seven (and four) regions with variants associated with overall (and ER-negative) breast cancer risk, which were not reported in previous GWAS. Further investigation of the function of the implicated genes in breast and immune cells may provide insights into the etiology of breast cancer.