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A transcriptome-wide association study of 229,000 women identifies new candidate susceptibility genes for breast cancer |
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| Author: | Wu, Lang1; Shi, Wei2; Long, Jirong1; |
| Organizations: |
1Vanderbilt Univ, Sch Med, Dept Med, Div Epidemiol,Vanderbilt Epidemiol Ctr,Vanderbilt, Nashville, TN 37235 USA. 2QIMR Berghofer Med Res Inst, Canc Div, Brisbane, Qld, Australia. 3Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England.
4Cyprus Inst Neurol & Genet, Dept Electron Microscopy Mol Pathol, Nicosia, Cyprus.
5Vanderbilt Univ, Dept Mol Physiol & Biophys, Vanderbilt Genet Inst, Nashville, TN 37232 USA. 6Harvard TH Chan Sch Publ Hlth, Program Genet Epidemiol & Stat Genet, Boston, MA USA. 7Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. 8Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. 9Harvard Med Sch, Dept Med, Boston, MA USA. 10Brigham & Womens Hosp, Div Genet, 75 Francis St, Boston, MA 02115 USA. 11Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Fred A Litwin Ctr Canc Genet, Toronto, ON, Canada. 12Univ Toronto, Dept Mol Genet, Toronto, ON, Canada. 13Univ Calif Irvine, Dept Epidemiol, Irvine, CA USA. 14German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany. 15Queens Univ, Dept Publ Hlth Sci, Kingston, ON, Canada. 16Queens Univ, Canc Res Inst, Kingston, ON, Canada. 17Fred Hutchinson Canc Res Ctr, Canc Prevent Program, 1124 Columbia St, Seattle, WA 98104 USA. 18Univ Wisconsin, Zilber Sch Publ Hlth, Milwaukee, WI 53201 USA. 19German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. 20Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge, England. 21Friedrich Alexander Univ Erlangen Nuremberg, Univ Hosp Erlangen, Comprehens Canc Ctr Erlangen EMN, Dept Obstet & Gynaecol, Erlangen, Germany. 22Spanish Natl Canc Res Ctr, Human Canc Genet Program, Madrid, Spain. 23Ctr Invest Red Enfermedades Raras CIBERER, Valencia, Spain. 24Russian Acad Sci, Ufa Sci Ctr, Inst Biochem & Genet, Ufa, Russia. 25Hannover Med Sch, Gynaecol Res Unit, Hannover, Germany. 26Univ Helsinki, Helsinki Univ Hosp, Dept Oncol, Helsinki, Finland. 27Univ Orebro, Dept Oncol, Orebro, Sweden. 28Hannover Med Sch, Dept Radiat Oncol, Hannover, Germany. 29NN Alexandrov Res Inst Oncol & Med Radiol, Minsk, BELARUS. 30Copenhagen Univ Hosp, Herlev & Gentofte Hosp, Copenhagen Gen Populat Study, Herlev, Denmark. 31Copenhagen Univ Hosp, Herlev & Gentofte Hosp, Dept Clin Biochem, Herlev, Denmark. 32Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark. 33Dr Margarete Fischer Bosch Inst Clin Pharmacol, Stuttgart, Germany. 34Univ Tubingen, Tubingen, Germany. 35German Canc Res Ctr, German Canc Consortium DKTK, Heidelberg, Germany. 36German Canc Res Ctr, Div Prevent Oncol, Heidelberg, Germany. 37Natl Ctr Tumor Dis NCT, Heidelberg, Germany. 38NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. 39Lund Univ, Dept Canc Epidemiol, Clin Sci, Lund, Sweden. 40Univ Tubingen, Dept Gynecol & Obstet, Tubingen, Germany. 41Heidelberg Univ, Dept Obstet & Gynecol, Heidelberg, Germany. 42German Canc Res Ctr, Mol Epidemiol Grp, C080, Heidelberg, Germany. 43CIBERONC Hosp Clin San Carlos, Med Oncol Dept, Madrid, Spain. 44German Canc Res Ctr, Genom Epidemiol Grp, Heidelberg, Germany. 45Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. 46Xerencia Xest Integrada Vigo SERGAS, Inst Invest Biomed Galicia IISGS, Oncol & Genet Unit, Vigo, Spain. 47Univ Med Ctr Hamburg Eppendorf, Univ Canc Ctr Hamburg UCCH, Hamburg, Germany. 48Univ Florida, Dept Epidemiol, Gainesville, FL USA. 49Univ Sydney, Westmead Inst Med Res, Sydney, NSW, Australia. 50Erasmus Univ, Dept Clin Genet, Med Ctr, Rotterdam, Netherlands. 51Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Div Mol Pathol, Amsterdam, Netherlands. 52Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA. 53Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England. 54Canc Res Ctr Lyon, U1052, INSERM, Lyon, France. 55Univ Sheffield, Sheffield Inst Nucle Acids, Dept Oncol & Metab, Sheffield, S Yorkshire, England. 56Univ Sheffield, Acad Unit Pathol, Dept Neurosci, Sheffield, S Yorkshire, England. 57Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. 58Fox Chase Canc Ctr, Dept Clin Genet, 7701 Burholme Ave, Philadelphia, PA 19111 USA. 59Leiden Univ, Dept Pathol, Med Ctr, Leiden, Netherlands. 60Leiden Univ, Med Ctr, Dept Human Genet, Leiden, Netherlands. 61Johns Hopkins Univ, Sch Med, Inst Med Genet, CIDR, Baltimore, MD USA. 62London Sch Hyg & Trop Med, Dept Noncommunicable Dis Epidemiol, London, England. 63Univ Laval, Res Ctr, Ctr Hosp Univ Quebec, Genom Ctr, Quebec City, PQ, Canada. 64Univ Westminster, Fac Sci & Technol, Dept Biomed Sci, London, England. 65Univ Southampton, Canc Sci Acad Unit, Fac Med, Southampton, Hants, England. 66Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA USA. 67Univ Leipzig, Inst Med Informat Stat & Epidemiol, Leipzig, Germany. 68Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Hematol & Oncol, Los Angeles, CA 90095 USA. 69Univ Edinburgh, Sch Med, Usher Inst Populat Hlth Sci & Informat, Edinburgh, Midlothian, Scotland. 70Univ Med Ctr Hamburg Eppendorf, Inst Med Biometr & Epidemiol, Hamburg, Germany. 71Univ Med Ctr Hamburg Eppendorf, Dept Canc Epidemiol, Clin Canc Registry, Hamburg, Germany. 72Inst Canc Res, Breast Canc Now Toby Robins Res Ctr, London, England. 73Copenhagen Univ Hosp, Herlev & Gentofte Hosp, Dept Breast Surg, Herlev, Denmark. 74Curtin Univ, Sch Publ Hlth, Perth, WA, Australia. 75Complejo Hosp Univ Santiago, SERGAS, Inst Invest Sanitaria Santiago Compostela IDIS, Genom Med Grp,Galician Fdn Genom Med, Santiago De Compostela, Spain. 76Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA 92093 USA. 77Canc Council Victoria, Canc Epidemiol & Intelligence Div, Melbourne, Vic, Australia. 78Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Epidemiol & Biostat, Melbourne, Vic, Australia. 79McGill Univ, Dept Med, Montreal, PQ, Canada. 80McGill Univ, Royal Victoria Hosp, Div Clin Epidemiol, Montreal, PQ, Canada. 81Univ Utah, Sch Med, Huntsman Canc Inst, Dept Dermatol, Salt Lake City, UT USA. 82Univ Paris Saclay, Univ Paris Sud, INSERM, Canc & Environm Grp,Ctr Res Epidemiol & Populat H, Villejuif, France. 83Univ Hosp Cologne, Ctr Hereditary Breast & Ovarian Canc, Cologne, Germany. 84Univ Hosp Cologne, Ctr Integrated Oncol CIO, Cologne, Germany. 85Univ Cologne, CMMC, Cologne, Germany. 86Univ Southern Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA USA. 87Karolinska Inst, Inst Environm Med, Stockholm, Sweden. 88Soder Sjukhuset, Dept Oncol, Stockholm, Sweden. 89Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA. 90German Canc Res Ctr, Mol Genet Breast Canc, Heidelberg, Germany. 91Frederick Natl Lab Canc Res, Leidos Biomed Res, Canc Genom Res Lab, Frederick, MD USA. 92Erasmus MC Canc Inst, Family Canc Clin, Dept Med Oncol, Rotterdam, Netherlands. 93Univ Oxford, Big Data Inst, Nuffield Dept Populat Hlth, Oxford, England. 94Pomeranian Med Univ, Dept Genet & Pathol, Szczecin, Poland. 95Pomeranian Med Univ, Independent Lab Mol Biol & Genet Diagnost, Szczecin, Poland. 96Univ Hosp Ulm, Dept Gynecol & Obstet, Ulm, Germany. 97Canc Prevent Inst Calif, Dept Epidemiol, Fremont, CA USA. 98Stanford Univ, Sch Med, Dept Hlth Res & Policy Epidemiol, Stanford, CA 94305 USA. 99Stanford Univ, Sch Med, Stanford Canc Inst, Stanford, CA 94305 USA. 100Inst Canc Res, Div Genet & Epidemiol, London, England. 101Natl Univ Ireland, Sch Med, Galway, Ireland. 102Bashkir State Univ, Dept Genet & Fundamental Med, Ufa, Russia. 103Univ Eastern Finland, Translat Canc Res Area, Kuopio, Finland. 104Univ Eastern Finland, Inst Clin Med Pathol & Forens Med, Kuopio, Finland. 105Kuopio Univ Hosp, Dept Clin Pathol, Imaging Ctr, Kuopio, Finland. 106Radiumhosp, Oslo Univ Hosp, Inst Canc Res, Dept Canc Genet, Oslo, Norway. 107Univ Oslo, Inst Clin Med, Fac Med, Oslo, Norway. 108Univ Oslo, Oslo Univ Hosp, Dept Clin Mol Biol, Oslo, Norway. 109Katholieke Univ Leuven, VIB, Ctr Canc Biol, Leuven, Belgium. 110Katholieke Univ Leuven, Dept Human Genet, Lab Translat Genet, Leuven, Belgium. 111Univ Hawaii, Ctr Canc, Program Epidemiol, Honolulu, HI 96822 USA. 112Genome Inst Singapore, Human Genet, Singapore, Singapore. 113Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. 114Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA. 115M Sklodowska Curie Inst, Ctr Oncol, Dept Canc Epidemiol & Prevent, Warsaw, Poland. 116German Breast Grp GmbH, Neu Isenburg, Germany. 117Univ Southampton, Southampton Clin Trials Unit, Southampton, Hants, England. 118Macedonian Acad Sci & Arts, Res Ctr Genet Engn & Biotechnol Georgi D Efrernov, Skopje, Macedonia. 119Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Boston, MA USA. 120Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden. 121Univ Hosp Herakl, Dept Med Oncol, Iraklion, Greece. 122Vrije Univ Amsterdam Med Ctr, Dept Clin Genet, Amsterdam, Netherlands. 123Tech Univ Munich, Div Gynaecol & Obstet, Munich, Germany. 124UCL, Inst Womens Hlth, Womens Canc, Gynaecol Canc Res Ctr, London, England. 125Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON, Canada. 126Univ Hlth Network, Lab Program Med, Toronto, ON, Canada. 127Beckman Res Inst City Hope, Dept Populat Sci, Duarte, CA USA. 128Univ Helsinki, Helsinki Univ Hosp, Dept Obstet & Gynecol, Helsinki, Finland. 129Univ Hosp Leuven, Leuven Canc Inst, Dept Oncol, Leuven Multidisciplinary Breast Ctr, Leuven, Belgium. 130Univ Chicago, Ctr Clin Canc Genet & Global Hlth, Chicago, IL 60637 USA. 131FIRC Italian Fdn Canc Res, Inst Mol Oncol, Milan, Italy. 132Univ Oulu, Bioctr Oulu, Canc & Translat Med Res Unit, Lab Canc Genet & Tumor Biol, Oulu, Finland. 133Northern Finland Lab Ctr Oulu, Lab Canc Genet & Tumor Biol, Oulu, Finland. 134Ist Nazl Tumori INT, Fdn IRCCS, Dept Res, Unit Mol Bases Genet Risk & Genet Testing, Milan, Italy. 135Inst Canc Res, Sect Canc Genet, London, England. 136Technion Israel Inst Technol, Ruth & Bruce Rappaport Fac Med, Carmel Med Ctr, Dept Community Med & Epidemiol, Haifa, Israel. 137Clalit Natl Canc Control Ctr, Haifa, Israel. 138Hosp Univ Puerta de Hierro, Dept Med Oncol, Madrid, Spain. 139Univ Hosp Heraklion, Hereditary Canc Clin, Iraklion, Greece. 140NIEHS, Epidemiol Branch, NIH, Res Triangle Pk, NC 27709 USA. 141Kings Coll London, Guys Hosp, Res Oncol, London, England. 142Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Div Psychosocial Res & Epidemiol, Amsterdam, 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Human Genet, Bogota, Colombia. 159Helios Clin Berlin Buch, Dept Gynecol & Obstet, Berlin, Germany. 160NIEHS, Biostat & Computat Biol Branch, NIH, Res Triangle Pk, NC USA. 161Harvard TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA USA. 162Univ Calif San Francisco, Dept Med, Inst Human Genet, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA. |
| Format: | article |
| Version: | accepted version |
| Access: | open |
| Online Access: | PDF Full Text (PDF, 1.9 MB) |
| Persistent link: | http://urn.fi/urn:nbn:fi-fe201902205803 |
| Language: | English |
| Published: |
Springer Nature,
2018
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| Publish Date: | 2019-02-20 |
| Description: |
AbstractThe breast cancer risk variants identified in genome-wide association studies explain only a small fraction of the familial relative risk, and the genes responsible for these associations remain largely unknown. To identify novel risk loci and likely causal genes, we performed a transcriptome-wide association study evaluating associations of genetically predicted gene expression with breast cancer risk in 122,977 cases and 105,974 controls of European ancestry. We used data from the Genotype-Tissue Expression Project to establish genetic models to predict gene expression in breast tissue and evaluated model performance using data from The Cancer Genome Atlas. Of the 8,597 genes evaluated, significant associations were identified for 48 at a Bonferroni-corrected threshold of P < 5.82 × 10−6, including 14 genes at loci not yet reported for breast cancer. We silenced 13 genes and showed an effect for 11 on cell proliferation and/or colony-forming efficiency. Our study provides new insights into breast cancer genetics and biology. see all
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| Series: |
Nature genetics |
| ISSN: | 1061-4036 |
| ISSN-E: | 1546-1718 |
| ISSN-L: | 1061-4036 |
| Volume: | 50 |
| Issue: | 7 |
| Pages: | 968 - 978 |
| DOI: | 10.1038/s41588-018-0132-x |
| OADOI: | https://oadoi.org/10.1038/s41588-018-0132-x |
| Type of Publication: |
A1 Journal article – refereed |
| Field of Science: |
3111 Biomedicine 1184 Genetics, developmental biology, physiology |
| Subjects: | |
| Funding: |
This project at Vanderbilt University Medical Center was supported in part by grants R01CA158473 and R01CA148677 from the US National Institutes of Health as well as funds from Anne Potter Wilson endowment. L.W. is supported by NCI K99 CA218892 and the Vanderbilt Molecular and Genetic Epidemiology of Cancer (MAGEC) training program (US NCI grant R25 CA160056 awarded to X.-O.S.). Genotyping of the OncoArray was principally funded from three sources: the PERSPECTIVE project, funded by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the Ministère de l’Économie, de la Science et de l’Innovation du Québec through Genome Québec and the Quebec Breast Cancer Foundation; the NCI Genetic Associations and Mechanisms in Oncology (GAME-ON) initiative and the Discovery, Biology and Risk of Inherited Variants in Breast Cancer (DRIVE) project (National Institutes of Health (NIH) grants U19 CA148065 and X01HG007492); and Cancer Research UK (C1287/A10118 and C1287/A16563). BCAC is funded by Cancer Research UK (C1287/A16563), by the European Community’s Seventh Framework Programme under grant agreement 223175 (HEALTH-F2-2009-223175) (COGS) and by the European Union’s Horizon 2020 Research and Innovation Programme under grant agreements 633784 (B-CAST) and 634935 (BRIDGES). Genotyping of the iCOGS array was funded by the European Union (HEALTH-F2-2009-223175), Cancer Research UK (C1287/A10710), the Canadian Institutes of Health Research for the ‘CIHR Team in Familial Risks of Breast Cancer’ program, and the Ministry of Economic Development, Innovation and Export Trade of Quebec—grant no. PSR-SIIRI-701. Combining of the GWAS data was supported in part by the NIH Cancer Post-Cancer GWAS initiative grant U19 CA 148065 (DRIVE, part of the GAME-ON initiative). A full description of funding and acknowledgments for BCAC studies, along with consortium membership, are included in the Supplementary Note. |
| Copyright information: |
© 2018 Nature America Inc., part of Springer Nature. All rights reserved. This is a post-peer-review, pre-copyedit version of an article published in Nature Genetics. The final authenticated version is available online at: https://doi.org/10.1038/s41588-018-0132-x.
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