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Transcriptome‐wide association study of breast cancer risk by estrogen‐receptor status
Helian Feng, Alexander Gusev, Bogdan Paşaniuc, Lang Wu, Jirong Long, Zomoroda Abu-Full, Kristiina Aittomäki, Irene L. Andrulis, Hoda Anton‐Culver, Antonis C. Antoniou, Aðalgeir Arason, Volker Arndt, Kristan J. Aronson, Banu Arun, Ella Asseryanis, Paul L. Auer, Jacopo Azzollini, Judith Balmañà, Rósa B. Barkardóttir, Daniel R. Barnes, Daniel Barrowdale, Matthias W. Beckmann, Sabine Behrens, Javier Benı́tez, Marina Bermisheva, Katarzyna Białkowska, Ana Blanco, Carl Blomqvist, Bram Boeckx, Natalia Bogdanova, Stig E. Bojesen, Manjeet K. Bolla, Bernardo Bonanni, Åke Borg, Hiltrud Brauch, Hermann Brenner, Ignacio Briceño, 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 Claes, Christine L. Clarke, 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 Dı́ez, Susan M. Domchek, Thilo Dörk, Isabel dos‐Santos‐Silva, Alison M. Dunning, Miriam Dwek, 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 E. Garber, Montserrat García‐Closas, José Á. García-Sáenz, Mia M. Gaudet, Graham G. Giles, Gord Glendon, Andrew K. Godwin, Mark S. Goldberg, Anna González‐Neira, Mark H. Greene, Jacek Gronwald, Pascal Guénel, Christopher A. Haiman, Per Hall, Ute Hamann, Christopher R. 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, Claudine Isaacs, Milena Jakimovska, Anna Jakubowska, Paul A. James, Ramunas Janavicius, Rachel C. Jankowitz, Esther M. John, Nichola Johnson, Joseph Vijai, Audrey Jung, Beth Y. Karlan, Э. К. Хуснутдинова, Johanna I. Kiiski, Irene Konstantopoulou, Vessela N. Kristensen, Yael Laitman, Diether Lambrechts, Conxi Lázaro, Dominique Leroux, Goska Leslie, Jenny Lester, Fabienne Lesueur, Noralane M. Lindor, Sara Lindström, Wing‐Yee Lo, Jennifer T. Loud, Jan Lubiński, Enes Makalic, Mehdi Manoochehri, Siranoush Manoukian, Sara Margolin, John W.M. Martens, Marı́a Elena Martı́nez, Laura Matricardi, Tabea Maurer, Dimitrios Mavroudis, Lesley McGuffog, Alfons Meindl, Usha Menon, Kyriaki Michailidou, Pooja Middha, Austin Miller, Marco Montagna, Fernando Moreno, Lidia Moserle, Anna Marie Mulligan, Taru Muranen, Katherine L. Nathanson, Susan L. Neuhausen, Heli Nevanlinna, Ines Nevelsteen, Finn Cilius Nielsen, Liene Ņikitina-Zaķe, Kenneth Offit, Edith Oláh, Olufunmilayo I. Olopade, Håkan Olsson, Ana Osório, J. Papp, Tjoung‐Won Park‐Simon, Michael T. Parsons, Inge Søkilde Pedersen, Ana Peixoto, Paolo Peterlongo, Julian Peto, Paul D.P. Pharoah, Kelly‐Anne Phillips, Dijana Plaseska‐Karanfilska, Bruce Poppe, Nisha Pradhan, Karolina Prajzendanc, Nadège Presneau, Kevin Punie, Katri Pylkäs, Paolo Radice, Johanna Rantala, Muhammad Usman Rashid, Gad Rennert, Harvey A. Risch, Mark E. 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 Tapper, Jack A. Taylor, Manuel R. Teixeira, Mary Beth Terry, Àlex 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
Bibliographic record
VenueGenetic Epidemiology · 2020
Typearticle
Languageen
FieldBiochemistry, Genetics and Molecular Biology
TopicGenetic Associations and Epidemiology
Canadian institutionsUniversity of British ColumbiaUniversité LavalBC Cancer AgencyCentre hospitalier universitaire de QuébecMcGill UniversityUniversity Health NetworkUniversity of TorontoRoyal Victoria HospitalQueen's UniversityLunenfeld-Tanenbaum Research InstituteMount Sinai Hospital
FundersMedical Research and Materiel CommandFogarty International CenterNational Institute of General Medical SciencesNIH Office of the DirectorNational Human Genome Research InstituteNational Institute of Mental HealthNational Institute on AgingServicio Gallego de SaludInstituto de Salud Carlos IIICancer Council Western AustraliaCancer Council NSWCancer Council VictoriaWorld Cancer Research FundMedical Research CouncilHellenic Health FoundationFreistaat SachsenInstitut Català de la SalutCentro de Investigación Biomédica en Red de CáncerBiomedical Research CouncilFederal Agency for Scientific OrganizationsMutuelle Générale de l'Education NationaleInstitut Gustave-RoussyMinistero dello Sviluppo EconomicoRadboud Universitair Medisch CentrumNational Health and Medical Research CouncilMinistry of Education, Science and TechnologyAcademia SinicaDeutsche KrebshilfeCancer Institute NSWMedizinischen Hochschule HannoverCancer Council South AustraliaCentre International de Recherche sur le CancerKreftforeningenInstitut National Du CancerOak FoundationLeids Universitair Medisch CentrumKarolinska InstitutetAssociazione Italiana per la Ricerca sul CancroKWF KankerbestrijdingVetenskapsrådetFondation de FranceStavros Niarchos FoundationUniversity of WestminsterLigue Contre le CancerKorea Health Industry Development InstituteHungarian Scientific Research FundMinisterio de Economía y CompetitividadErasmus Medisch CentrumJapan Agency for Medical Research and DevelopmentDeutsche Gesetzliche UnfallversicherungNederlandse Organisatie voor Wetenschappelijk OnderzoekKing's College LondonFondation ARC pour la Recherche sur le CancerGentofte HospitalCalifornia Breast Cancer Research ProgramGeneralitat de CatalunyaAlexander von Humboldt-StiftungCancerfondenAmerican Cancer SocietyCancer AustraliaRadboud UniversiteitRussian Foundation for Basic ResearchKuopion Yliopistollinen SairaalaNational Medical Research CouncilNorges ForskningsrådStockholms Läns LandstingUniversiteit MaastrichtVrije Universiteit AmsterdamAcademy of FinlandMaastricht Universitair Medisch CentrumNational Heart, Lung, and Blood InstituteOhio State UniversityUniversiteit LeidenUniversity of CreteInstitut National de la Santé et de la Recherche MédicaleAgency for Science, Technology and ResearchCanadian Institutes of Health ResearchEuropean CommissionAvon Foundation for WomenBreast Cancer Research TrustFondation du cancer du sein du QuébecNational Cancer InstituteEuropean Regional Development FundMinisterio de Sanidad, Servicios Sociales e IgualdadUniversity of CambridgeNemzeti Kutatási Fejlesztési és Innovációs HivatalVirginia Department of HealthGovernment of CanadaGeorgetown UniversityBreast Cancer CampaignNational Research FoundationNIHR Biomedical Research Centre, Royal Marsden NHS Foundation Trust/Institute of Cancer ResearchNational Breast Cancer FoundationAgence Nationale de Sécurité Sanitaire de l’Alimentation, de l’Environnement et du TravailNational Institute of Environmental Health SciencesSwedish Cancer FoundationLon V. Smith FoundationFundación Mutua MadrileñaMinistère du Développement Économique, de l’Innovation et de l’ExportationInstitute of Biomedical Sciences, Academia SinicaDavid F. and Margaret T. Grohne Family FoundationConsejo Nacional de Ciencia y TecnologíaSundhed og Sygdom, Det Frie ForskningsrådDeutsches KrebsforschungszentrumUniversity College LondonNational Research Foundation of KoreaCalifornia Department of Public HealthGenome CanadaCancer Council TasmaniaItä-Suomen YliopistoProgramme Grants for Applied ResearchRobert Bosch StiftungCenter for Agroforestry, University of MissouriOulun YliopistoFundación CellexFisher Center for Alzheimer's Research FoundationCenters for Disease Control and PreventionNational Institute for Health and Care ResearchSusan G. Komen for the CureTaiwan BiobankU.S. Department of Health and Human ServicesAgence Nationale de la RechercheU.S. ArmyLandspítali HáskólasjúkrahúsNational Center for Advancing Translational SciencesBundesministerium für Bildung und ForschungMinistry of Education, Culture, Sports, Science and TechnologyOvarian Cancer Research FundNational Institutes of HealthDivision of Cancer Prevention, National Cancer InstituteCancer Research UKBreast Cancer Research FoundationRijksuniversiteit GroningenDeutscher Akademischer AustauschdienstYayasan Sime DarbyXunta de GaliciaDr. Ralph and Marian Falk Medical Research TrustFonds Wetenschappelijk Onderzoek
KeywordsBreast cancerGenome-wide association studyEstrogen receptorTranscriptomeBiologyGenetic associationOncologyGeneCancerEstrogen receptor alphaGeneticsComputational biologyMedicineSingle-nucleotide polymorphismGene expressionGenotype
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.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
metaresearch head score (Codex)0.001
metaresearch head score (Gemma)0.002
Version: metacan-v3-hybrid-931329e0061cValidation status: machine_predicted_unvalidated
Candidate categoriesnone
Consensus categoriesnone
DomainCandidate signal: none · Consensus signal: none
Study designCandidate signal: Observational · Consensus signal: Observational
GenreCandidate signal: Empirical · Consensus signal: Empirical
Teacher disagreement score0.003
Threshold uncertainty score0.006
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.002 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
Opus teacher head0.017
GPT teacher head0.282
Teacher spread0.265 · how far apart the two teachers sit on this one work
Validation status
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
The models applied no category: nothing in the taxonomy fit this work.
Study designObservational
Domainnot available
GenreEmpirical
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".
Quick stats
Citations45
Published2020
Admission routes2
Has abstractyes