Genome-wide association and transcriptome studies identify target genes and risk loci for breast cancer

Manuel Ferreira (1) , Eric Gamazon (2, 3) , Fares Al-Ejeh (1) , Kristiina Aittomäki (4) , Irene Andrulis (5) , Hoda Anton-Culver (6) , Adalgeir Arason (7) , Volker Arndt (8) , Kristan Aronson (9) , Banu Arun (10) , Ella Asseryanis (11) , Jacopo Azzollini (12) , Judith Balmaña (13) , Daniel Barnes (3) , Daniel Barrowdale (14) , Matthias Beckmann (15) , Sabine Behrens (8) , Javier Benitez (16, 17) , Marina Bermisheva (18) , Katarzyna Białkowska (19) , Carl Blomqvist (20, 4) , Natalia Bogdanova (21, 22) , Stig Bojesen (23) , Manjeet Bolla (24) , Åke Borg (25) , Hiltrud Brauch (26, 27) , Hermann Brenner (28) , Annegien Broeks (29) , Barbara Burwinkel (30, 31) , Trinidad Caldés (32) , Maria Adelaide Caligo (33) , Daniele Campa (33, 8) , Ian Campbell (34) , Federico Canzian (8) , Jonathan Carter (35) , Brian Carter (36) , Jose Castelao (37) , Jenny Chang-Claude (38, 8) , Stephen Chanock (39) , Hans Christiansen (40) , Wendy Chung (41) , Kathleen Claes (42) , Christine Clarke (43) , Fergus Couch (44) , Angela Cox (45) , Simon S. Cross (45) , Kamila Czene (46) , Mary B. Daly (47) , Miguel de La Hoya (32) , Joe Dennis (24) , Peter Devilee (48) , Orland Diez (13) , Thilo Dörk (21) , Alison Dunning (3) , Miriam Dwek (49) , Bent Ejlertsen (50) , Carolina Ellberg (51) , Christoph Engel (52) , Mikael Eriksson (53) , Peter Fasching (54) , Olivia Fletcher (55) , Henrik Flyger (56) , Eitan Friedman (57, 58) , Debra Frost (24) , Marike Gabrielson (53) , Manuela Gago-Dominguez (59) , Patricia Ganz (60) , Susan Gapstur (36) , Judy Garber (61) , Montserrat García-Closas (39) , José García-Sáenz (32) , Mia Gaudet (36) , Graham G Giles (62) , Gord Glendon (5) , Andrew Godwin (63) , Mark S. Goldberg (64) , David E. Goldgar (65) , Anna González-Neira (17) , Mark Greene (39) , Jacek Gronwald (19) , Pascal Guénel (66) , Christopher Haiman (67) , Per Hall (46) , Ute Hamann (28) , Wei He (53) , Jane Heyworth (68) , Frans Hogervorst (69) , Antoinette Hollestelle (70) , Robert Hoover (71) , John Hopper (72) , Peter Hulick (73, 74) , Keith Humphreys (53) , Evgeny Imyanitov (75) , Claudine Isaacs (76) , Milena Jakimovska (77) , Anna Jakubowska (19) , Paul James (78) , Ramunas Janavicius (79) , Rachel Jankowitz (80) , Esther M. John (81) , Nichola Johnson (82) , Vijai Joseph (83) , Beth Karlan (54) , Elza K. Khusnutdinova (84) , Johanna Kiiski (4) , Yon-Dschun Ko (85) , Michael Jones (55) , Irene Konstantopoulou (86) , Vessela Kristensen (87) , Yael Laitman (58) , Diether Lambrechts (88) , Conxi Lázaro (89) , Goska Leslie (24) , Jenny Lester (54) , Fabienne Lesueur (90) , Sara Lindström (91) , Jirong Long (2) , Jennifer Loud (39) , Jan Lubiński (19) , Enes Makalic (72) , Arto Mannermaa (92) , Mehdi Manoochehri (8) , Sara Margolin (53) , Tabea Maurer (38) , Dimitrios Mavroudis (93) , Lesley Mcguffog (24) , Alfons Meindl (94) , Usha Menon (95) , Kyriaki Michailidou (96) , Austin Miller (97) , Marco Montagna (98) , Fernando Moreno (32) , Lidia Moserle (99) , Anna Marie Mulligan (5) , Katherine Nathanson (100) , Susan Neuhausen (101) , Heli Nevanlinna (4) , Ines Nevelsteen (102) , Finn Nielsen (50) , Liene Nikitina-Zake (103) , Robert Nussbaum (83) , Kenneth Offit (83) , Edith Olah (104) , Olufunmilayo Olopade (105) , Håkan Olsson (25) , Ana Osorio (17, 16) , Janos Papp (104) , Tjoung-Won Park-Simon (40) , Michael Parsons (1) , Inge Søkilde Pedersen (106) , Ana Peixoto (104) , Paolo Peterlongo (107) , Paul Pharoah (3) , Dijana Plaseska-Karanfilska (77) , Bruce Poppe (108) , Nadege Presneau (49) , Paolo Radice (109) , Johanna Rantala (53) , Gad Rennert (110) , Harvey Risch (111) , Emmanouil Saloustros (112) , Kristin Sanden (113) , Elinor Sawyer (114) , Marjanka Schmidt (69) , Rita Schmutzler (115) , Priyanka Sharma (63) , Xiao-Ou Shu (2) , Jacques Simard (116) , Christian Singer (11) , Penny Soucy (116) , Melissa Southey (117, 72) , John Spinelli (118) , Amanda Spurdle (1) , Jennifer Stone (119, 72) , Anthony Swerdlow (55) , William Tapper (120) , Jack Taylor (121) , Manuel R Teixeira (122, 123) , Mary Beth Terry (124) , Alex Teulé (89) , Mads Thomassen (125) , Kathrin Thöne (38) , Darcy Thull (80) , Marc Tischkowitz (126, 24) , Amanda Toland (127) , Diana Torres (128, 28) , Thérèse Truong (66) , Nadine Tung (129) , Celine Vachon (130) , Christi van Asperen (131) , Ans van den Ouweland (70) , Elizabeth Jansen van Rensburg (132) , Ana Vega (133) , Alessandra Viel (134) , Qin Wang (24) , Barbara Wappenschmidt (135) , Jeffrey Weitzel (136) , Camilla Wendt (53) , Robert Winqvist (137) , Xiaohong Yang (39) , Drakoulis Yannoukakos (86) , Argyrios Ziogas (138) , Peter Kraft (139) , Antonis C. Antoniou (24) , Wei Zheng (2) , Douglas F. Easton (140) , Roger L Milne (117) , Jonathan Beesley (1) , Georgia Chenevix-Trench (1) , Pascal Pujol (141)

1 QIMR Berghofer Medical Research Institute
2 Vanderbilt University School of Medicine [Nashville]
3 CAM - University of Cambridge [UK]
4 Helsingin yliopisto = Helsingfors universitet = University of Helsinki
5 University of Toronto
6 UC Irvine - University of California [Irvine]
7 Reykjavík University
8 DKFZ - German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg]
9 Queen's University [Kingston, Canada]
10 The University of Texas M.D. Anderson Cancer Center [Houston]
11 Medizinische Universität Wien = Medical University of Vienna
12 UNIMI - Università degli Studi di Milano = University of Milan
13 VHIO - Vall d'Hebron Institute of Oncology [Barcelone]
14 Centre for Cancer Genetic Epidemiology [Cambridge]
15 FAU - Friedrich-Alexander Universität Erlangen-Nürnberg = University of Erlangen-Nuremberg
16 CIBER de Enfermedades Raras (CIBERER)
17 CNIO - Spanish National Cancer Research Center
18 Institute of Biochemistry and Genetics of Ufa Scientific Centre
19 West Pomeranian University of Technology Szczecin
20 Örebro University Hospital [Örebro, Sweden]
21 MHH - Department of Obstetrics and Gynaecology
22 Institute of Biophysics and Cell Engineering, NASB, Minsk
23 UCPH - University of Copenhagen = Københavns Universitet
24 CRUK - Cancer Research UK Cambridge Institute [Cambridge, Royaume-Uni]
25 Skane University Hospital [Lund]
26 Dr. Margarete Fischer-Bosch Institute for Clinical Pharmacology [Stuttgart]
27 Universitätsklinikum Tübingen - University Hospital of Tübingen
28 Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ)
29 NKI - Netherlands Cancer Institute
30 Molecular Epidemiology Research Group
31 University Medical Center Heidelberg
32 IdISSC - Instituto de Investigación Sanitaria del Hospital Clínico San Carlos [Madrid, Spain]
33 University of Pisa - Università di Pisa
34 Peter MacCallum Cancer Center
35 The University of Sydney
36 American Cancer Society [Atlanta, GA, USA]
37 Instituto de Investigación Sanitaria Galicia Sur [Vigo, Spain]
38 UKE - Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg]
39 NCI-NIH - National Cancer Institute [Bethesda]
40 MHH - Medizinische Hochschule Hannover = Hannover Medical School
41 Columbia University [New York]
42 Ghent University Hospital
43 The Westmead Institute for Medical Research
44 Dpt of Oncology [Rochester]
45 University of Sheffield [Sheffield]
46 MEB - Department of Medical Epidemiology and Biostatistics
47 Fox Chase Cancer Center
48 LUMC - Leiden University Medical Center
49 UOW - University of Westminster [London]
50 Rigshospitalet [Copenhagen]
51 Department of Oncology and Pathology [Lund]
52 IMISE - Institute for Medical Informatics, Statistics and Epidemiology [Leipzig]
53 CCK - Cancer Center Karolinska [Karolinska Institutet]
54 David Geffen School of Medicine [Los Angeles]
55 The institute of cancer research [London]
56 Copenhagen University Hospital
57 CUNY - City University of New York [New York]
58 The Susanne Levy Gertner Oncogenetics Unit
59 USC - Universidade de Santiago de Compostela [Spain]
60 UCLA - University of California [Los Angeles]
61 Dana-Farber Cancer Institute [Boston]
62 University of Melbourne
63 University of Kansas Medical Center [Kansas City, KS, USA]
64 McGill University = Université McGill [Montréal, Canada]
65 Huntsman Cancer Institute [Salt Lake City]
66 CESP - Centre de recherche en épidémiologie et santé des populations
67 USC - University of Southern California
68 UWA - The University of Western Australia
69 Antoni van Leeuwenhoek Hospital
70 Erasmus MC - Erasmus University Medical Center [Rotterdam]
71 CUMC - Columbia University Medical Center
72 Melbourne Medical School [Melbourne]
73 Northwestern University [Evanston]
74 The University of Chicago Medicine [Chicago]
75 N.N. Petrov Institute of Oncology
76 Lombardi Comprehensive Cancer Center
77 MASA - Macedonian Academy of Sciences and Arts [Skopje, North Macedonia]
78 Peter MacCallum Cancer Centre and St Vincent's Hospital, Australian New Zealand Breast Cancer Trials Group
79 Vilnius University [Vilnius]
80 University of Pittsburgh School of Medicine
81 Stanford School of Medicine [Stanford]
82 The Breakthrough Toby Robins Breast Cancer Research Centre
83 Memorial Sloane Kettering Cancer Center [New York]
84 BASHEDU - Bashkir State University
85 Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus
86 NCSR - National Center for Scientific Research "Demokritos"
87 Oslo University Hospital [Oslo]
88 VIB-KU-CCB - Leuven Center for Cancer Biology
89 IDIBELL - Institut d'Investigació Biomèdica de Bellvitge = Bellvitge Biomedical Research Institute
90 Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe
91 University of Washington [Seattle]
92 University of Kuopio
93 UOC - University of Crete [Heraklion]
94 University-Hospital Munich-Großhadern [München]
95 UCLH - University College London Hospitals
96 UCY - University of Cyprus [Nicosia]
97 RPCI - Roswell Park Cancer Institute [Buffalo]
98 Veneto Institute of Oncology
99 Instituto Oncologico Veneto (IOV)
100 University of Pennsylvania
101 Beckman Research Institute of the City of Hope
102 Department of General Medical Oncology [Leuven]
103 Latvian Biomedical Research and Study Centre [Rīga]
104 National Institute of Oncology [Budapest, Hungary]
105 University of Chicago
106 AAU - Aalborg University [Denmark]
107 IFOM - IFOM, Istituto FIRC di Oncologia Molecolare
108 Center for Medical Genetics [Ghent]
109 IRCCS Milan - Istituto Clinico Humanitas [Milan]
110 Faculty of Medicine Haifa
111 YSPH - Yale School of Public Health
112 School of Medicine, Larissa
113 City of Hope Comprehensive Cancer Center [Duarte]
114 Guy's Hospital [London]
115 University Hospital of Cologne [Cologne]
116 ULaval - Faculté de médecine de l'Université Laval [Québec]
117 Monash University [Clayton]
118 UBC - University of British Columbia
119 Curtin University
120 University of Southampton
121 National Institute for Environmental Health Sciences Research Triangle Park
122 Universidade do Porto = University of Porto
123 Portuguese Institute of Oncology
124 Columbia Mailman School of Public Health
125 SDU - University of Southern Denmark
126 MUHC - McGill University Health Center [Montreal]
127 Department of Molecular Virology, Immunology and Medical Genetics [Colombus]
128 PUJ - Pontificia Universidad Javeriana
129 BIDMC - Beth Israel Deaconess Medical Center [Boston]
130 Mayo Clinic [Rochester]
131 Universiteit Leiden = Leiden University
132 University of Pretoria [South Africa]
133 Fundación Pública Galega de Medicina Xenómica-SERGAS & Grupo de Medicina Xenómica-USC
134 Aviano Cancer Center
135 Faculty of Medicine [Cologne]
136 City of Hope Comprehensive Cancer Center and Department of Population Sciences
137 University of Oulu
138 Department of Population Health and Disease Prevention [Irvine, CA, USA]
139 Harvard T.H. Chan School of Public Health
140 BCCHR - BC Children's Hospital Research Institute [Vancouver, BC, Canada]
141 CHRU Montpellier - Centre Hospitalier Régional Universitaire [Montpellier]

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.

Domaines: Cancer; Génétique humaine; Santé publique et épidémiologie

Manuel Ferreira, Eric Gamazon, Fares Al-Ejeh, Kristiina Aittomäki, Irene Andrulis, et al.. Genome-wide association and transcriptome studies identify target genes and risk loci for breast cancer. Nature Communications, 2019, 10 (1), ⟨10.1038/s41467-018-08053-5⟩. ⟨hal-02863912⟩