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