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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.
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1 Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
2 The Center for Bioinformatics and Functional Genomics, Cedars-Sinai Medical Center, Los Angeles, CA, USA
3 Dana Farber Cancer Institute, Boston, MA, USA
4 Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA
5 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
6 Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK; Royal Marsden NHS Foundation Trust, London, UK
7 Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA
8 Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
9 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