TY - JOUR
T1 - Transcriptome-wide association study of breast cancer risk by estrogen-receptor status
AU - ABCTB Investigators
AU - HEBON Investigators
AU - BCFR Investigators
AU - OCGN Investigators
AU - GEMO Study Collaborators
AU - EMBRACE Collaborators
AU - GC-HBOC Study Collaborators
AU - Feng, Helian
AU - Gusev, Alexander
AU - Pasaniuc, Bogdan
AU - Wu, Lang
AU - Long, Jirong
AU - Abu-full, Zomoroda
AU - Aittomäki, Kristiina
AU - Andrulis, Irene L.
AU - Anton-Culver, Hoda
AU - Antoniou, Antonis C.
AU - Arason, Adalgeir
AU - Arndt, Volker
AU - Aronson, Kristan J.
AU - Arun, Banu K.
AU - Asseryanis, Ella
AU - Auer, Paul L.
AU - Azzollini, Jacopo
AU - Balmaña, Judith
AU - Barkardottir, Rosa B.
AU - Barnes, Daniel R.
AU - Barrowdale, Daniel
AU - Beckmann, Matthias W.
AU - Behrens, Sabine
AU - Benitez, Javier
AU - Bermisheva, Marina
AU - Białkowska, Katarzyna
AU - Blanco, Ana
AU - Blomqvist, Carl
AU - Boeckx, Bram
AU - Bogdanova, Natalia V.
AU - Bojesen, Stig E.
AU - Bolla, Manjeet K.
AU - Bonanni, Bernardo
AU - Borg, Ake
AU - Brauch, Hiltrud
AU - Brenner, Hermann
AU - Briceno, Ignacio
AU - Broeks, Annegien
AU - Brüning, Thomas
AU - Burwinkel, Barbara
AU - Cai, Qiuyin
AU - Caldés, Trinidad
AU - Caligo, Maria A.
AU - Campbell, Ian
AU - Canisius, Sander
AU - Campa, Daniele
AU - Carter, Brian D.
AU - Couch, Fergus J.
AU - Lindor, Noralane
AU - Vachon, Celine M.
N1 - Funding Information:
The breast cancer genome‐wide association (BCAC) is funded by Cancer Research UK (C1287/A16563, C1287/A10118), the European Union's Horizon 2020 Research and Innovation Programme (grant nos. 634935 and 633784 for BRIDGES and B‐CAST, respectively), and by the European Community's Seventh Framework Programme under grant agreement number 223175 (grant no. HEALTH‐F2‐2009‐223175) (COGS). The EU Horizon 2020 Research and Innovation Programme funding source had no role in study design, data collection, data analysis, data interpretation or writing of the report.
Funding Information:
Genotyping of the OncoArray was funded by the NIH grant U19 CA148065, and Cancer UK grant C1287/A16563 and the PERSPECTIVE project supported by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research (grant GPH‐129344), and the Ministère de l’Économie, Science et Innovation du Québec through Genome Québec and the PSRSIIRI‐701 grant, and the Quebec Breast Cancer Foundation. Funding for the iCOGS infrastructure came from: the European Community's Seventh Framework Programme under grant agreement no. 223175 (HEALTH‐F2‐2009‐223175; COGS), Cancer Research UK (C1287/A10118, C1287/A10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, and C8197/A16565), the National Institutes of Health (CA128978) and Post‐Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065, and 1U19 CA148112—the GAME‐ON initiative), the Department of Defence (W81XWH‐10‐1‐0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, and Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. The DRIVE Consortium was funded by U19 CA148065.
Funding Information:
OSUCCC was funded by the Ohio State University Comprehensive Cancer Center. Leigha Senter, Kevin Sweet, Caroline Craven, Julia Cooper, Amber Aielts, and Michelle O'Conor aided in the recruitment of BRCA1/2 study participants and data collection. Robert Pilarski aided in recruitment and data collection of TNBC cases from the Stefanie Spielman Breast Bank.
Funding Information:
Clinical Genetics Branch, NCI: the Intramural Research Program of the US National Cancer Institute, NIH, Division of Cancer Epidemiology and Genetics, and by support services contracts NO2‐CP‐11019‐50, N02‐CP‐21013‐63 and N02‐CP‐65504 with Westat, Inc, Rockville, MD.
Funding Information:
ILUH was funded by the Icelandic Association “Walking for Breast Cancer Research” and by the Landspitali University Hospital Research Fund.
Funding Information:
The HEBON study is supported by the Dutch Cancer Society grants NKI1998‐1854, NKI2004‐3088, NKI2007‐3756, the Netherlands Organisation of Scientific Research grant NWO 91109024, the Pink Ribbon grants 110005 and 2014‐187.WO76, the BBMRI grant NWO 184.021.007/CP46, and the Transcan grant JTC 2012 Cancer 12‐054.
Funding Information:
N.N. Petrov Institute of Oncology is supported by the Russian Foundation for Basic Research (grants 17‐00‐00171, 18‐515‐45012 and 19‐515‐25001).
Funding Information:
M. W. B. conducts research funded by Amgen, Novartis, and Pfizer. P. A. F. conducts research funded by Amgen, Novartis, and Pfizer. He received Honoraria from Roche, Novartis and Pfizer.
Publisher Copyright:
© 2020 The Authors. Genetic Epidemiology published by Wiley Periodicals, Inc.
PY - 2020/7/1
Y1 - 2020/7/1
N2 - 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.
AB - 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.
KW - GWAS
KW - TWAS
KW - breast cancer subtype
KW - causal gene
UR - http://www.scopus.com/inward/record.url?scp=85081379482&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85081379482&partnerID=8YFLogxK
U2 - 10.1002/gepi.22288
DO - 10.1002/gepi.22288
M3 - Article
AN - SCOPUS:85081379482
SN - 0741-0395
VL - 44
SP - 442
EP - 468
JO - Genetic Epidemiology
JF - Genetic Epidemiology
IS - 5
ER -