Abstract

Although genome-wide association studies (GWAS) for prostate cancer (PrCa) have identified more than 100 risk regions, most of the risk genes at these regions remain largely unknown. Here we integrate the largest PrCa GWAS (N = 142,392) with gene expression measured in 45 tissues (N = 4458), including normal and tumor prostate, to perform a multi-tissue transcriptome-wide association study (TWAS) for PrCa. We identify 217 genes at 84 independent 1 Mb regions associated with PrCa risk, 9 of which are regions with no genome-wide significant SNP within 2 Mb. 23 genes are significant in TWAS only for alternative splicing models in prostate tumor thus supporting the hypothesis of splicing driving risk for continued oncogenesis. Finally, we use a Bayesian probabilistic approach to estimate credible sets of genes containing the causal gene at a pre-defined level; this reduced the list of 217 associations to 109 genes in the 90% credible set. Overall, our findings highlight the power of integrating expression with PrCa GWAS to identify novel risk loci and prioritize putative causal genes at known risk loci.

Details

Title
Large-scale transcriptome-wide association study identifies new prostate cancer risk regions
Author
Mancuso, Nicholas 1   VIAFID ORCID Logo  ; Gayther, Simon 2 ; Gusev, Alexander 3   VIAFID ORCID Logo  ; Zheng, Wei 4   VIAFID ORCID Logo  ; Penney, Kathryn L 5 ; Kote-Jarai, Zsofia 6 ; Eeles, Rosalind 6   VIAFID ORCID Logo  ; Freedman, Matthew 7 ; Haiman, Christopher 8 ; Pasaniuc, Bogdan 9 ; Henderson, Brian E 8 ; Benlloch, Sara 10 ; Schumacher, Fredrick R 11 ; Ali Amin Al Olama 12 ; Muir, Kenneth 13 ; Berndt, Sonja I 14 ; Conti, David V 8 ; Wiklund, Fredrik 15 ; Chanock, Stephen 14 ; Stevens, Victoria L 16 ; Tangen, Catherine M 17 ; Batra, Jyotsna 18 ; Clements, Judith 18 ; Gronberg, Henrik 15 ; Pashayan, Nora 19 ; Schleutker, Johanna 20 ; Albanes, Demetrius 14 ; Weinstein, Stephanie 14 ; Wolk, Alicja 21 ; West, Catharine 22 ; Mucci, Lorelei 23 ; Cancel-Tassin, Géraldine 24 ; Koutros, Stella 14 ; Karina Dalsgaard Sorensen 25 ; Maehle, Lovise 26 ; Neal, David E 27 ; Hamdy, Freddie C 28 ; Donovan, Jenny L 29 ; Travis, Ruth C 30 ; Hamilton, Robert J 31 ; Ingles, Sue Ann 8 ; Rosenstein, Barry 32 ; Yong-Jie, Lu 33 ; Giles, Graham G 34 ; Kibel, Adam S 35 ; Vega, Ana 36 ; Kogevinas, Manolis 37 ; Park, Jong Y 38 ; Stanford, Janet L 39 ; Cybulski, Cezary 40 ; Nordestgaard, Børge G 41 ; Brenner, Hermann 42 ; Maier, Christiane 43 ; Kim, Jeri 44 ; John, Esther M 45 ; Teixeira, Manuel R 46 ; Neuhausen, Susan L 47 ; Kim De Ruyck 48 ; Razack, Azad 49 ; Newcomb, Lisa F 50 ; Lessel, Davor 51 ; Kaneva, Radka 52 ; Usmani, Nawaid 53 ; Claessens, Frank 54 ; Townsend, Paul A 55 ; Gago-Dominguez, Manuela 56 ; Roobol, Monique J 57 ; Menegaux, Florence 58 ; Kay-Tee Khaw 59 ; Cannon-Albright, Lisa 60 ; Pandha, Hardev 61 ; Thibodeau, Stephen N 62 ; Hunter, David J 63 ; Kraft, Peter 63 

 Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA 
 The Center for Bioinformatics and Functional Genomics, Cedars-Sinai Medical Center, Los Angeles, CA, USA 
 Dana Farber Cancer Institute, Boston, MA, USA 
 Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA 
 Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital/Harvard Medical School, Boston, MA, USA 
 Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK; Royal Marsden NHS Foundation Trust, London, UK 
 Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA 
 Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA 
 Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Bioinformatics Interdepartmental Program, University of California, Los Angeles, Los Angeles, CA, USA 
10  Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK; Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK 
11  Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH, USA; Seidman Cancer Center, University Hospitals, Cleveland, OH, USA 
12  Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK; University of Cambridge, Department of Clinical Neurosciences, Cambridge, UK 
13  Institute of Population Health, University of Manchester, Manchester, UK; Warwick Medical School, University of Warwick, Coventry, UK 
14  Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD, USA 
15  Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden 
16  Epidemiology Research Program, American Cancer Society, Atlanta, GA, USA 
17  SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA, USA 
18  Australian Prostate Cancer Research Centre-Qld, Institute of Health and Biomedical Innovation and School of Biomedical Science, Queensland University of Technology, Brisbane, Queensland, Australia; Translational Research Institute, Brisbane, Queensland, Australia 
19  University College London, Department of Applied Health Research, London, UK; Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Strangeways Laboratory, Cambridge, UK 
20  Department of Medical Biochemistry and Genetics, Institute of Biomedicine, University of Turku, Turku, Finland; Tyks Microbiology and Genetics, Department of Medical Genetics, Turku University Hospital, Hospital, Finland; BioMediTech, University of Tampere, Tampere, Finland 
21  Division of Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Sweden 
22  Institute of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Radiotherapy Related Research, The Christie Hospital NHS Foundation Trust, Manchester, UK 
23  Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA 
24  CeRePP, Pitie-Salpetriere Hospital, Paris, France; UPMC Univ Paris 06, GRC N°5 ONCOTYPE-URO, CeRePP, Tenon Hospital, Paris, France 
25  Department of Molecular Medicine, Aarhus University Hospital, Aarhus N, Denmark; Department of Clinical Medicine, Aarhus University, Aarhus N, Denmark 
26  Department of Medical Genetics, Oslo University Hospital, Oslo, Norway 
27  University of Cambridge, Department of Oncology, Addenbrooke’s Hospital, Cambridge, UK; Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Cambridge, UK 
28  Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK; Faculty of Medical Science, University of Oxford, John Radcliffe Hospital, Oxford, UK 
29  School of Social and Community Medicine, University of Bristol, Bristol, UK 
30  Cancer Epidemiology, Nuffield Department of Population Health University of Oxford, Oxford, UK 
31  Department of Surgical Oncology, Princess Margaret Cancer Centre, Toronto, Canada 
32  Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA 
33  Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, London, UK 
34  Cancer Epidemiology and Intelligence Division, The Cancer Council Victoria, Melbourne, Victoria, Australia; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia 
35  Division of Urologic Surgery, Brigham and Womens Hospital, Boston, MA, USA 
36  Fundacion Publica Galega de Medicina Xenomica-SERGAS, Grupo de Medicina Xenomica, CIBERER, IDIS, Santiago de Compostela, Spain 
37  Centre for Research in Environmental Epidemiology (CREAL), Barcelona Institute for Global Health (ISGlobal), Barcelona, Spain; CIBER Epidemiologia y Salud Publica (CIBERESP), Madrid, Spain; IMIM (Hospital del Mar Research Institute), Barcelona, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain 
38  Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, USA 
39  Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA; Department of Epidemiology, School of Public Health, University of Washington, Seattle, Washington, USA 
40  International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland 
41  Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark 
42  Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany; Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany 
43  Institute for Human Genetics, University Hospital Ulm, Ulm, Germany 
44  The University of Texas M. D. Anderson Cancer Center, Department of Genitourinary Medical Oncology, Houston, TX, USA 
45  Cancer Prevention Institute of California, Fremont, CA, USA; Department of Health Research and Policy (Epidemiology) and Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA 
46  Department of Genetics, Portuguese Oncology Institute of Porto, Porto, Portugal; Biomedical Sciences Institute (ICBAS), University of Porto, Porto, Portugal 
47  Department of Population Sciences, Beckman Research Institute of the City of Hope, Duarte, CA, USA 
48  Ghent University, Faculty of Medicine and Health Sciences, Basic Medical Sciences, Gent, Belgium 
49  Department of Surgery, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia 
50  Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA; Department of Urology, University of Washington, Seattle, WA, USA 
51  Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany 
52  Molecular Medicine Center, Department of Medical Chemistry and Biochemistry, Medical University, Sofia, Bulgaria 
53  Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, Alberta, Canada; Division of Radiation Oncology, Cross Cancer Institute, Edmonton, Alberta, Canada 
54  Molecular Endocrinology Laboratory, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium 
55  Institute of Cancer Sciences, Manchester Cancer Research Centre, University of Manchester, Manchester Academic Health Science Centre, St Mary’s Hospital, Manchester, UK 
56  Genomic Medicine Group, Galician Foundation of Genomic Medicine, Instituto de Investigacion Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago, Servicio Galego de Saude, SERGAS, Santiago De Compostela, Spain; University of California San Diego, Moores Cancer Center, La Jolla, CA, USA 
57  Department of Urology, Erasmus University Medical Center, Rotterdam, The Netherlands 
58  Cancer and Environment Group, Center for Research in Epidemiology and Population Health (CESP), INSERM, University Paris-Sud, University Paris-Saclay, Villejuif, France 
59  Clinical Gerontology Unit, University of Cambridge, Cambridge, UK 
60  Division of Genetic Epidemiology, Department of Medicine, University of Utah School of Medicine, Salt Lake City, Utah, USA; George E. Wahlen Department of Veterans Affairs Medical Center, Salt Lake City, UT, USA 
61  The University of Surrey, Guildford, Surrey, UK 
62  Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA 
63  Program in Genetic Epidemiology and Statistical Genetics, Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA 
Pages
1-11
Publication year
2018
Publication date
Oct 2018
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2116412519
Copyright
© 2018. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.