Transcriptome‐wide association study of breast cancer risk by estrogen‐receptor status
Authors: Feng Helian , Gusev Alexander , Pasaniuc Bogdan , Wu Lang , Long Jirong , Abu‐full Zomoroda , Aittomäki Kristiina , Andrulis Irene L. , Anton‐Culver Hoda , Antoniou Antonis C. , Arason Adalgeir , Arndt Volker , Aronson Kristan J. , Arun Banu K. , Asseryanis Ella , Auer Paul L. , Azzollini Jacopo , Balmaña Judith , Barkardottir Rosa B. , Barnes Daniel R. , Barrowdale Daniel , Beckmann Matthias W. , Behrens Sabine , Benitez Javier , Bermisheva Marina , Białkowska Katarzyna , Blanco Ana , Blomqvist Carl , Boeckx Bram , Bogdanova Natalia V. , Bojesen Stig E. , Bolla Manjeet K. , Bonanni Bernardo , Borg Ake , Brauch Hiltrud , Brenner Hermann , Briceno Ignacio , Broeks Annegien , Brüning Thomas , Burwinkel Barbara , Cai Qiuyin , Caldés Trinidad , Caligo Maria A. , Campbell Ian , Canisius Sander , Campa Daniele , Carter Brian D. , Carter Jonathan , Castelao Jose E. , Chang‐Claude Jenny , Chanock Stephen J. , Christiansen Hans , Chung Wendy K. , Claes Kathleen B. M. , Clarke Christine L. ,   GEMO Study Collaborators,   EMBRACE Collaborators,   GC‐HBOC study Collaborators, Couch Fergus J. , Cox Angela , Cross Simon S. , Cybulski Cezary , Czene Kamila , Daly Mary B. , de la Hoya Miguel , De Leeneer Kim , Dennis Joe , Devilee Peter , Diez Orland , Domchek Susan M. , Dörk Thilo , dos‐Santos‐Silva Isabel , Dunning Alison M. , Dwek Miriam , Eccles Diana M. , Ejlertsen Bent , Ellberg Carolina , Engel Christoph , Eriksson Mikael , Fasching Peter A. , Fletcher Olivia , Flyger Henrik , Fostira Florentia , Friedman Eitan , Fritschi Lin , Frost Debra , Gabrielson Marike , 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 , Hake Christopher , He Wei , Heyworth Jane , Hogervorst Frans B.L. , Hollestelle Antoinette , Hooning Maartje J. , Hoover Robert N. , Hopper John L. , Huang Guanmengqian , Hulick Peter J. , Humphreys Keith , Imyanitov Evgeny N. ,   ABCTB Investigators,   HEBON Investigators,   BCFR Investigators,   OCGN Investigators, Isaacs Claudine , Jakimovska Milena , Jakubowska Anna , James Paul , Janavicius Ramunas , Jankowitz Rachel C. , John Esther M. , Johnson Nichola , Joseph Vijai , Jung Audrey , Karlan Beth Y. , Khusnutdinova Elza , Kiiski Johanna I. , Konstantopoulou Irene , Kristensen Vessela N. , Laitman Yael , Lambrechts Diether , Lazaro Conxi , Leroux Dominique , Leslie Goska , Lester Jenny , Lesueur Fabienne , Lindor Noralane , Lindström Sara , Lo Wing‐Yee , Loud Jennifer T. , Lubiński Jan , Makalic Enes , Mannermaa Arto , Manoochehri Mehdi , Manoukian Siranoush , Margolin Sara , Martens John W.M. , Martinez Maria E. , Matricardi Laura , Maurer Tabea , Mavroudis Dimitrios , McGuffog Lesley , Meindl Alfons , Menon Usha , Michailidou Kyriaki , Kapoor Pooja M. , Miller Austin , Montagna Marco , Moreno Fernando , Moserle Lidia , Mulligan Anna M. , Muranen Taru A. , Nathanson Katherine L. , Neuhausen Susan L. , Nevanlinna Heli , Nevelsteen Ines , Nielsen Finn C. , Nikitina‐Zake Liene , Offit Kenneth , Olah Edith , Olopade Olufunmilayo I. , Olsson Håkan , Osorio Ana , Papp Janos , Park‐Simon Tjoung‐Won , Parsons Michael T. , Pedersen Inge S. , Peixoto Ana , Peterlongo Paolo , Peto Julian , Pharoah Paul D.P. , Phillips Kelly‐Anne , Plaseska‐Karanfilska Dijana , Poppe Bruce , Pradhan Nisha , Prajzendanc Karolina , Presneau Nadege , Punie Kevin , Pylkäs Katri , Radice Paolo , Rantala Johanna , Rashid Muhammad Usman , Rennert Gad , Risch Harvey A. , Robson Mark , Romero Atocha , Saloustros Emmanouil , Sandler Dale P. , Santos Catarina , Sawyer Elinor J. , Schmidt Marjanka K. , Schmidt Daniel F. , Schmutzler Rita K. , Schoemaker Minouk J. , Scott Rodney J. , Sharma Priyanka , Shu Xiao‐Ou , Simard Jacques , Singer Christian F. , Skytte Anne‐Bine , 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. , Tollenaar Rob A. E. M. , 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 , Vieiro‐Balo Paula , Wang Qin , Wappenschmidt Barbara , Weinberg Clarice R. , Weitzel Jeffrey N. , Wendt Camilla , Winqvist Robert , Yang Xiaohong R. , Yannoukakos Drakoulis , Ziogas Argyrios , Milne Roger L. , Easton Douglas F. , Chenevix‐Trench Georgia , Zheng Wei , Kraft Peter , Jiang Xia 
Published: March 2020

Previous transcriptome‐wide association studies (TWAS) have identified breast cancer risk genes by integrating data from expression quantitative loci and genome‐wide association studies (GWAS), but analyses of breast cancer subtype‐specific associations have been limited. In this study, we conducted a TWAS using gene expression data from GTEx and summary statistics from the hitherto largest GWAS meta‐analysis conducted for breast cancer overall, and by estrogen receptor subtypes (ER+ and ER−). We further compared associations with ER+ and ER− subtypes, using a case‐only TWAS approach. We also conducted multigene conditional analyses in regions with multiple TWAS associations. Two genes, STXBP4 and HIST2H2BA, were specifically associated with ER+ but not with ER– breast cancer. We further identified 30 TWAS‐significant genes associated with overall breast cancer risk, including four that were not identified in previous studies. Conditional analyses identified single independent breast‐cancer gene in three of six regions harboring multiple TWAS‐significant genes. Our study provides new information on breast cancer genetics and biology, particularly about genomic differences between ER+ and ER− breast cancer.