Association analysis identifies 65 new breast cancer risk loci
Kyriaki Michailidou(University of Cambridge), Sara Lindström(Harvard University), Joe Dennis(University of Cambridge), Jonathan Beesley(QIMR Berghofer Medical Research Institute), Shirley Hui(University of Toronto), Siddhartha Kar(University of Cambridge), Audrey Lemaçon(Centre hospitalier universitaire de Québec), Penny Soucy(Centre hospitalier universitaire de Québec), Dylan M. Glubb(QIMR Berghofer Medical Research Institute), Asha Rostamianfar(University of Toronto), Manjeet K. Bolla(University of Cambridge), Qin Wang(University of Cambridge), Jonathan P. Tyrer(University of Cambridge), Ed Dicks(University of Cambridge), Andrew Lee(University of Cambridge), Zhaoming Wang(St. Jude Children's Research Hospital), Jamie Allen(University of Cambridge), Renske Keeman(The Netherlands Cancer Institute), Ursula Eilber(German Cancer Research Center), Juliet D. French(QIMR Berghofer Medical Research Institute), Xiao Qing Chen(QIMR Berghofer Medical Research Institute), Laura Fachal(University of Cambridge), Karen McCue(QIMR Berghofer Medical Research Institute), Amy E. McCart Reed(The University of Queensland), Maya Ghoussaini(University of Cambridge), Jason S. Carroll(University of Cambridge), Xia Jiang(Harvard University), Hilary K. Finucane(Harvard University), Marcia Adams(Johns Hopkins University), Muriel A. Adank(Amsterdam UMC Location Vrije Universiteit Amsterdam), Habibul Ahsan(University of Chicago), Kristiina Aittomäki(University of Helsinki), Hoda Anton‐Culver(University of California, Irvine), Natalia Antonenkova(N.N. Alexandrov National Cancer Centre), Volker Arndt(German Cancer Research Center), Kristan J. Aronson(Queen's University), Banu Arun(The University of Texas MD Anderson Cancer Center), Paul L. Auer(Fred Hutch Cancer Center), François Bacot(McGill University and Génome Québec Innovation Centre), Myrto Barrdahl(German Cancer Research Center), Caroline Baynes(University of Cambridge), Matthias W. Beckmann(Universitätsklinikum Erlangen), Sabine Behrens(German Cancer Research Center), Javier Benı́tez(Spanish National Cancer Research Centre), Marina Bermisheva(Russian Academy of Sciences), Leslie Bernstein(City of Hope), Carl Blomqvist(University of Helsinki), Natalia Bogdanova(Medizinische Hochschule Hannover), Stig E. Bojesen(University of Copenhagen), Bernardo Bonanni(European Institute of Oncology), Anne‐Lise Børresen‐Dale(Oslo University Hospital), Judith S. Brand(Karolinska Institutet), Hiltrud Brauch(German Cancer Research Center), Paul Brennan(Centre international de recherche sur le cancer), Hermann Brenner(German Cancer Research Center), Louise A. Brinton(National Cancer Institute), Per Broberg(Lund University), Ian W. Brock(University of Sheffield), Annegien Broeks(The Netherlands Cancer Institute), Angela Brooks‐Wilson(BC Cancer Agency), Sara Y. Brucker(University of Tübingen), Thomas Brüning(Institute for Prevention and Occupational Medicine), Barbara Burwinkel(German Cancer Research Center), Katja Butterbach(German Cancer Research Center), Qiuyin Cai(Vanderbilt University), Hui Cai(Vanderbilt University), Trinidad Caldés(Instituto de Investigación Sanitaria del Hospital Clínico San Carlos), Federico Canzian(German Cancer Research Center), Ãngel Carracedo(Universidade de Santiago de Compostela), Brian D. Carter(American Cancer Society), Jose E. Castelao(Servicio Gallego de Salud), Tsun Leung Chan(Hong Kong Sanatorium and Hospital), Ting‐Yuan David Cheng(Roswell Park Comprehensive Cancer Center), Kee Seng Chia(National University of Singapore), Ji‐Yeob Choi(Seoul National University), Hans Christiansen(Medizinische Hochschule Hannover), Christine L. Clarke(The University of Sydney), NBCS Collaborators(Erasmus MC), Margriet Collée(University of Cambridge), Don Conroy(Inserm), Emilie Cordina‐Duverger(Inserm), Sten Cornelissen(The Netherlands Cancer Institute), David G. Cox(Inserm), Angela Cox(University of Sheffield), Simon S. Cross(Mayo Clinic), Julie M. Cunningham(Mayo Clinic), Kamila Czene(Fox Chase Cancer Center), Mary B. Daly(Fox Chase Cancer Center), Peter Devilee(Johns Hopkins University), Kimberly F. Doheny(Johns Hopkins University), Thilo Dörk(Medizinische Hochschule Hannover), Isabel dos‐Santos‐Silva(London School of Hygiene & Tropical Medicine), Martine Dumont(Centre hospitalier universitaire de Québec), Lorraine Durcan(University of Southampton), Miriam Dwek(University of Southampton), Diana M. Eccles(Universitätsklinikum Erlangen), Arif B. Ekici(Brigham and Women's Hospital), A. Heather Eliassen(Brigham and Women's Hospital), Carolina Ellberg(Bashkir State University), Mingajeva Elvira(Bashkir State University), Christoph Engel(Karolinska Institutet), Mikael Eriksson(Karolinska Institutet), Peter A. Fasching(University of California, Los Angeles), Jonine D. Figueroa(Universität Hamburg), Dieter Flesch‐Janys(Institute of Cancer Research), Olivia Fletcher(Institute of Cancer Research), Henrik Flyger(Curtin University), Lin Fritschi(Curtin University), Valérie Gaborieau(Karolinska Institutet), Marike Gabrielson(Karolinska Institutet), Manuela Gago-Domínguez(University of California San Diego), Yu‐Tang Gao(American Cancer Society), Susan M. Gapstur(American Cancer Society), José Á. García-Sáenz(American Cancer Society), Mia M. Gaudet(American Cancer Society), V. Georgoulias(Cancer Council Victoria), Graham G. Giles(Mount Sinai Hospital), Gord Glendon(Mount Sinai Hospital), Mark S. Goldberg(University of Utah), David E. Goldgar(University of Utah), Anna González‐Neira(Oslo University Hospital), Grethe I.G. Alnæs(Oslo University Hospital), Mervi Grip(Oulu University Hospital), Jacek Gronwald(Centre Hospitalier de l’Université de Montréal), Anne Grundy(Inserm), Pascal Guénel(Inserm), Lothar Haeberle(Universitätsklinikum Erlangen), Eric Hahnen(University of Southern California), Christopher A. Haiman(University of Southern California), Niclas Håkansson(German Cancer Research Center), Ute Hamann(German Cancer Research Center), Nathalie Hamel(University of Massachusetts Amherst), Susan E. Hankinson(University of Cambridge), Patricia Harrington(University of Cambridge), Steven N. Hart(University of Eastern Finland), Jaana M. Hartikainen(National University of Singapore), Mikael Hartman(National University of Singapore), Alexander Hein(The University of Western Australia), Jane Heyworth(The University of Western Australia), Belynda Hicks(Medizinische Hochschule Hannover), Peter Hillemanns(Medizinische Hochschule Hannover), Dona N. Ho(Hong Kong Sanatorium and Hospital), Antoinette Hollestelle(Erasmus MC Cancer Institute), Maartje J. Hooning(National Cancer Institute), Robert N. Hoover(The University of Melbourne), John L. Hopper(Kaohsiung Medical University), Ming‐Feng Hou(Kaohsiung Medical University), Chia‐Ni Hsiung(German Cancer Research Center), Guanmengqian Huang(German Cancer Research Center), Keith Humphreys(Karolinska Institutet), Junko Ishiguro(Aichi Cancer Center), Hidemi Ito(National Center for Global Health and Medicine), Motoki Iwasaki(National Center for Global Health and Medicine), Hiroji Iwata(Aichi Cancer Center), Anna Jakubowska(University Hospital Ulm), Wolfgang Janni(Cancer Prevention Institute of California), Esther M. John(Cancer Prevention Institute of California), Nichola Johnson(Institute of Cancer Research), Kristine Jones(Institute of Cancer Research), Michael E. Jones(Institute of Cancer Research), Arja Jukkola‐Vuorinen(German Cancer Research Center), Rudolf Kaaks(German Cancer Research Center), Maria Kabisch(German Cancer Research Center), Katarzyna Kaczmarek(Seoul National University), Daehee Kang(Seoul National University), Yoshio Kasuga(Ollscoil na Gaillimhe – University of Galway), Michael J. Kerin(University of Helsinki), Sofia Khan(University of Helsinki), Э. К. Хуснутдинова(Russian Academy of Sciences), Johanna I. Kiiski(University of Helsinki), Sung-Won Kim(Mount Sinai Hospital), Julia A. Knight(Mount Sinai Hospital), Veli‐Matti Kosma(Oslo University Hospital), Vessela N. Kristensen(Oslo University Hospital), Ute Krüger(Lund University), Ava Kwong(Hong Kong Sanatorium and Hospital), Diether Lambrechts(University of Hawaiʻi at Mānoa), Loı̈c Le Marchand(University of Southern California), Eunjung Lee(University of Southern California), Min Hyuk Lee(Ulsan College), Jong Won Lee(Ulsan College), Chuen Neng Lee(Carmel Medical Center), Flavio Lejbkowicz(Karolinska Institutet), Jingmei Li(Karolinska Institutet), Jenna Lilyquist(Karolinska Institutet), Annika Lindblom(Karolinska Institutet), Jolanta Lissowska(The Maria Sklodowska-Curie National Research Institute of Oncology), Wing‐Yee Lo(Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology), Sibylle Loibl(Vanderbilt University), Jirong Long(Vanderbilt University), Artitaya Lophatananon(University of Manchester), Jan Lubiński(University of Cambridge), Craig Luccarini(University of Cambridge), Michael P. Lux(Universitätsklinikum Erlangen), Edmond S.K.(Cancer Council Victoria), Robert J. MacInnis(The University of Melbourne), Tom Maishman(The University of Melbourne), Enes Makalic(The University of Melbourne), Kathleen E. Malone(Macedonian Academy of Sciences and Arts), Ivana Maleva Kostovska(Macedonian Academy of Sciences and Arts), Arto Mannermaa(University of Eastern Finland), Siranoush Manoukian(Harvard University), JoAnn E. Manson(Brigham and Women's Hospital), Sara Margolin(Karolinska Institutet), Shivaani Mariapun(University of California San Diego), Marı́a Elena Martı́nez(University of California San Diego), Keitaro Matsuo(Aichi Cancer Center), Dimitrios Mavroudis(University Hospital of Heraklion), James McKay(The Alfred Hospital), Catriona McLean(The Alfred Hospital), Hanne Meijers‐Heijboer(Technical University of Munich), Alfons Meindl(Hospital Monte Naranco), Primitiva Menéndez(Breast Cancer Now), Usha Menon(Mayo Clinic), Jeffery Meyer(Mayo Clinic), Hui Miao(National University of Singapore), Nicola Miller(University Malaya Medical Centre), Nur Aishah Mohd Taib(University Malaya Medical Centre), Kenneth Muir(University of Toronto), Anna Marie Mulligan(University Health Network), Claire Mulot(Inserm), Susan L. Neuhausen(University of Helsinki), Heli Nevanlinna(University of Helsinki), Patrick Neven(Gentofte Hospital), Sune F. Nielsen(Seoul National University), Dong‐Young Noh(University of Copenhagen), Børge G. Nordestgaard(University of Copenhagen), Aaron D. Norman(University of Chicago), Olufunmilayo I. Olopade(University of Chicago), Janet E. Olson(Lund University), Håkan Olsson(Lund University), Curtis Olswold(Institute of Cancer Research), Nick Orr(Institute of Cancer Research), V. Shane Pankratz(University of New Mexico), Sue K. Park(Seoul National University), Tjoung‐Won Park‐Simon(The University of Western Australia), Rachel Lloyd(The University of Western Australia), José Ignacio Arias Pérez(IFOM), Paolo Peterlongo(London School of Hygiene & Tropical Medicine), Julian Peto(The University of Melbourne), Kelly‐Anne Phillips(The University of Melbourne), Mila Pinchev(Macedonian Academy of Sciences and Arts), Dijana Plaseska‐Karanfilska(Macedonian Academy of Sciences and Arts), Ross L. Prentice(Fred Hutch Cancer Center), Nadège Presneau(Bashkir State University), Darya Prokofyeva(Bashkir State University), Elizabeth Pugh(Johns Hopkins University), Katri Pylkäs(NordLab), Brigitte Rack(Fondazione IRCCS Istituto Nazionale dei Tumori), Paolo Radice(Institute of Cancer Research), Nazneen Rahman(Institute of Cancer Research), Gad Rennert(Carmel Medical Center), Hedy S. Rennert(University of Cambridge), Valerie Rhenius(University of Cambridge), Atocha Romero(Johns Hopkins University), Jane Romm(Mayo Clinic), Kathryn J. Ruddy(Mayo Clinic), Thomas Rüdiger(German Cancer Research Center), Anja Rudolph(German Cancer Research Center), Matthias Ruebner(The Netherlands Cancer Institute), Emiel J. Rutgers(The Netherlands Cancer Institute), Emmanouil Saloustros(National Institute of Environmental Health Sciences), Dale P. Sandler(National Institute of Environmental Health Sciences), Suleeporn Sangrajrang(Guy's Hospital), Elinor J. Sawyer(Guy's Hospital), Daniel F. Schmidt(The University of Melbourne), Rita K. Schmutzler(University of Cologne), Andreas Schneeweiß(Institute of Cancer Research), Minouk J. Schoemaker(Institute of Cancer Research), Fredrick R. Schumacher(Medizinische Hochschule Hannover), Peter Schürmann(John Hunter Hospital), Rodney J. Scott(John Hunter Hospital), Christopher G. Scott(Institute of Cancer Research), Sheila Seal(Institute of Cancer Research), Caroline Seynaeve(University of Cambridge), Mitul Shah(University of Cambridge), Priyanka Sharma(China Medical University), Chen‐Yang Shen(University of Southern California), Grace Sheng(University of Southern California), Mark E. Sherman(Vanderbilt University), Martha J. Shrubsole(Vanderbilt University), Xiao‐Ou Shu(Vanderbilt University), Ann Smeets(Heidelberg University), Christof Sohn(The University of Melbourne), Melissa C. Southey(BC Cancer Agency), John J. Spinelli(BC Cancer Agency), Christa Stegmaier(University of Warwick), Sarah Stewart‐Brown(The University of Western Australia), Jennifer Stone(University of Southern California), Daniel O. Stram(University of Southern California), Harald Surowy(Institute of Cancer Research), Anthony J. Swerdlow(Harvard University), Rulla M. Tamimi(Brigham and Women's Hospital), Jack A. Taylor(University of Eastern Finland), Maria Tengström(University of Eastern Finland), Soo‐Hwang Teo(University Malaya Medical Centre), Mary Beth Terry(McGill University and Génome Québec Innovation Centre), Daniel C. Tessier(Ministry of Public Health), Somchai Thanasitthichai(Ministry of Public Health), Kathrin Thöne(Universität Hamburg), Rob A.�E.�M. Tollenaar(Centre for Human Genetics), Ian Tomlinson(Centre for Human Genetics), Ling Tong(German Cancer Research Center), Diana Torres(Inserm), Thérèse Truong(University of Southern California), Chiu-Chen Tseng(University of Southern California), Shoichiro Tsugane(Klinikum Mittelbaden), Hans-Ulrich Ulmer(Klinikum Mittelbaden), Giske Ursin(University of Oslo), Michael Untch(Mayo Clinic in Florida), Celine M. Vachon(Leiden University Medical Center), Christi J. van Asperen(University of Southern California), David Van Den Berg(University of Southern California), Ans M.W. van den Ouweland(Erasmus MC), Lizet van der Kolk(The Netherlands Cancer Institute), Rob B. van der Luijt(University Medical Center Utrecht), Daniel Vincent(Mayo Clinic), Jason Vollenweider(Mayo Clinic), Quinten Waisfisz(Universität Ulm), Shan Wang‐Gohrke(Universität Ulm), Clarice R. Weinberg(Karolinska Institutet), Camilla Wendt(Karolinska Institutet), Alice S. Whittemore(Stanford Health Care), Hans Wildiers(Harvard University), Walter C. Willett(Harvard University), Robert Winqvist(Karolinska Institutet), Alicja Wolk(University of Southern California), Anna H. Wu(University of Southern California), Lucy Xia(University of Southern California), Taiki Yamaji(National Center for Global Health and Medicine), Xiaohong R. Yang(National Cancer Institute), Cheng Har Yip(Seoul National University), Keun-Young Yoo(Tri-Service General Hospital), Jyh‐Cherng Yu(Tri-Service General Hospital), Wei Zheng(Vanderbilt University), Ying Zheng(National Cancer Institute), Bin Zhu(University of California, Irvine), Argyrios Ziogas(University of California, San Francisco), Elad Ziv(University of California, San Francisco), ABCTB Investigators(University of Cambridge), ConFab/AOCS Investigators(Centre hospitalier universitaire de Québec), Sunil R. Lakhani(Mount Sinai Hospital), Antonis C. Antoniou(Dartmouth College), Arnaud Droit(Mayo Clinic), Irene L. Andrulis(Mount Sinai Hospital), Christopher I. Amos(Dartmouth College), Fergus J. Couch(Mayo Clinic), Paul D.P. Pharoah(Harvard University), Jenny Chang‐Claude(Universität Hamburg), Per Hall(Karolinska Institutet), David J. Hunter(Harvard University), Roger L. Milne(The University of Melbourne), Montserrat García‐Closas(University of Cambridge), Marjanka K. Schmidt(QIMR Berghofer Medical Research Institute), Stephen J. Chanock(University of Toronto), Alison M. Dunning(QIMR Berghofer Medical Research Institute), Stacey L. Edwards(QIMR Berghofer Medical Research Institute), Gary D. Bader(Harvard University), Georgia Chenevix‐Trench(QIMR Berghofer Medical Research Institute), Jacques Simard(Centre hospitalier universitaire de Québec), Peter Kraft(Harvard University), Douglas F. Easton(University of Cambridge)
Cited by 1,575Open Access
Abstract
Lists of authors and their affiliations appear in the online version of the paper Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry 1 . We identified 65 new loci that are associated with overall breast cancer risk at P < 5 10 -8 . The majority of credible risk single-nucleotide polymorphisms in these loci fall in distal regulatory elements, and by integrating in silico data to predict target genes in breast cells at each locus, we demonstrate a strong overlap between candidate target genes and somatic driver genes in breast tumours. We also find that heritability of breast cancer due to all single-nucleotide polymorphisms in regulatory features was 2-5-fold enriched relative to the genomewide average, with strong enrichment for particular transcription factor binding sites. These results provide further insight into genetic susceptibility to breast cancer and will improve the use of genetic risk scores for individualized screening and prevention.
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