13
views
0
recommends
+1 Recommend
1 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Large-scale transcriptome-wide association study identifies new prostate cancer risk regions

      research-article

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          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.

          Abstract

          Genome-wide association studies (GWAS) have identified hundreds of genomic risk regions for prostate cancer. Here, the authors perform a transcriptome wide association study (TWAS) by incorporating prostate cancer GWAS with gene expression data to identify potential novel prostate cancer risk loci and possible risk mechanisms.

          Related collections

          Most cited references57

          • Record: found
          • Abstract: found
          • Article: found
          Is Open Access

          A global reference for human genetic variation

          The 1000 Genomes Project set out to provide a comprehensive description of common human genetic variation by applying whole-genome sequencing to a diverse set of individuals from multiple populations. Here we report completion of the project, having reconstructed the genomes of 2,504 individuals from 26 populations using a combination of low-coverage whole-genome sequencing, deep exome sequencing, and dense microarray genotyping. We characterized a broad spectrum of genetic variation, in total over 88 million variants (84.7 million single nucleotide polymorphisms (SNPs), 3.6 million short insertions/deletions (indels), and 60,000 structural variants), all phased onto high-quality haplotypes. This resource includes >99% of SNP variants with a frequency of >1% for a variety of ancestries. We describe the distribution of genetic variation across the global sample, and discuss the implications for common disease studies.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found
            Is Open Access

            The Genotype-Tissue Expression (GTEx) project.

            Genome-wide association studies have identified thousands of loci for common diseases, but, for the majority of these, the mechanisms underlying disease susceptibility remain unknown. Most associated variants are not correlated with protein-coding changes, suggesting that polymorphisms in regulatory regions probably contribute to many disease phenotypes. Here we describe the Genotype-Tissue Expression (GTEx) project, which will establish a resource database and associated tissue bank for the scientific community to study the relationship between genetic variation and gene expression in human tissues.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found
              Is Open Access

              The Cancer Genome Atlas Pan-Cancer analysis project.

              The Cancer Genome Atlas (TCGA) Research Network has profiled and analyzed large numbers of human tumors to discover molecular aberrations at the DNA, RNA, protein and epigenetic levels. The resulting rich data provide a major opportunity to develop an integrated picture of commonalities, differences and emergent themes across tumor lineages. The Pan-Cancer initiative compares the first 12 tumor types profiled by TCGA. Analysis of the molecular aberrations and their functional roles across tumor types will teach us how to extend therapies effective in one cancer type to others with a similar genomic profile.
                Bookmark

                Author and article information

                Contributors
                nmancuso@mednet.ucla.edu
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                4 October 2018
                4 October 2018
                2018
                : 9
                : 4079
                Affiliations
                [1 ]ISNI 0000 0000 9632 6718, GRID grid.19006.3e, Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, , University of California, Los Angeles, ; Los Angeles, 90095 CA USA
                [2 ]ISNI 0000 0001 2152 9905, GRID grid.50956.3f, The Center for Bioinformatics and Functional Genomics, Cedars-Sinai Medical Center, ; Los Angeles, 90048 CA USA
                [3 ]ISNI 0000 0001 2106 9910, GRID grid.65499.37, Dana Farber Cancer Institute, ; Boston, 02215 MA USA
                [4 ]ISNI 0000 0001 2264 7217, GRID grid.152326.1, Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, , Vanderbilt University School of Medicine, ; Nashville, 37232 TN USA
                [5 ]ISNI 000000041936754X, GRID grid.38142.3c, Department of Epidemiology, Harvard T.H. Chan School of Public Health, ; Boston, 02115 MA USA
                [6 ]ISNI 0000 0004 0378 8294, GRID grid.62560.37, Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital/Harvard Medical School, ; Boston, 02115 MA USA
                [7 ]ISNI 0000 0001 1271 4623, GRID grid.18886.3f, Division of Genetics and Epidemiology, The Institute of Cancer Research, ; London, SW7 3RP UK
                [8 ]ISNI 0000 0001 0304 893X, GRID grid.5072.0, Royal Marsden NHS Foundation Trust, ; London, SW3 6JJ UK
                [9 ]ISNI 0000 0001 2106 9910, GRID grid.65499.37, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, ; Boston, 02215 MA USA
                [10 ]ISNI 0000 0001 2156 6853, GRID grid.42505.36, Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, , University of Southern California, ; Los Angeles, 90015 CA USA
                [11 ]ISNI 0000 0000 9632 6718, GRID grid.19006.3e, Department of Human Genetics, David Geffen School of Medicine, , University of California, Los Angeles, ; Los Angeles, 90095 CA USA
                [12 ]ISNI 0000 0000 9632 6718, GRID grid.19006.3e, Bioinformatics Interdepartmental Program, , University of California, Los Angeles, ; Los Angeles, 90095 CA USA
                [13 ]ISNI 0000000121885934, GRID grid.5335.0, Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, , University of Cambridge, Strangeways Research Laboratory, ; Cambridge, CB1 8RN UK
                [14 ]ISNI 0000 0001 2164 3847, GRID grid.67105.35, Department of Epidemiology and Biostatistics, , Case Western Reserve University, ; Cleveland, 44106-7219 OH USA
                [15 ]ISNI 0000 0004 0452 4020, GRID grid.241104.2, Seidman Cancer Center, , University Hospitals, ; Cleveland, 44106 OH USA
                [16 ]ISNI 0000000121885934, GRID grid.5335.0, University of Cambridge, Department of Clinical Neurosciences, ; Cambridge, CB2 0QQ UK
                [17 ]ISNI 0000000121662407, GRID grid.5379.8, Institute of Population Health, , University of Manchester, ; Manchester, M13 9PL UK
                [18 ]ISNI 0000 0000 8809 1613, GRID grid.7372.1, Warwick Medical School, , University of Warwick, ; Coventry, CV4 7AL UK
                [19 ]ISNI 0000 0001 2237 2479, GRID grid.420086.8, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, ; Bethesda, 21701 MD USA
                [20 ]ISNI 0000 0004 1937 0626, GRID grid.4714.6, Department of Medical Epidemiology and Biostatistics, Karolinska Institute, ; Stockholm, SE-171 77 Sweden
                [21 ]ISNI 0000 0004 0371 6485, GRID grid.422418.9, Epidemiology Research Program, American Cancer Society, ; 250 Williams Street, Atlanta, 30303 GA USA
                [22 ]ISNI 0000 0001 2180 1622, GRID grid.270240.3, SWOG Statistical Center, Fred Hutchinson Cancer Research Center, ; Seattle, 98109-1024 WA USA
                [23 ]ISNI 0000000089150953, GRID grid.1024.7, Australian Prostate Cancer Research Centre-Qld, Institute of Health and Biomedical Innovation and School of Biomedical Science, , Queensland University of Technology, ; Brisbane, 4059 Queensland Australia
                [24 ]ISNI 0000000406180938, GRID grid.489335.0, Translational Research Institute, ; Brisbane, 4102 Queensland Australia
                [25 ]ISNI 0000000121901201, GRID grid.83440.3b, University College London, Department of Applied Health Research, ; London, WC1E 7HB UK
                [26 ]ISNI 0000000121885934, GRID grid.5335.0, Centre for Cancer Genetic Epidemiology, Department of Oncology, , University of Cambridge, Strangeways Laboratory, ; Cambridge, WC1E 7HB UK
                [27 ]ISNI 0000 0001 2097 1371, GRID grid.1374.1, Department of Medical Biochemistry and Genetics, Institute of Biomedicine, , University of Turku, ; Turku, FI-20014 Finland
                [28 ]ISNI 0000 0004 0628 215X, GRID grid.410552.7, Tyks Microbiology and Genetics, Department of Medical Genetics, , Turku University Hospital, ; Hospital, 20521 Finland
                [29 ]ISNI 0000 0001 2314 6254, GRID grid.5509.9, BioMediTech, , University of Tampere, ; Tampere, FI-33014 Finland
                [30 ]ISNI 0000 0004 1937 0626, GRID grid.4714.6, Division of Nutritional Epidemiology, Institute of Environmental Medicine, ; Karolinska Institutet, SE-171 77 Sweden
                [31 ]Institute of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Radiotherapy Related Research, The Christie Hospital NHS Foundation Trust, Manchester, M13 9PL UK
                [32 ]ISNI 0000 0001 2150 9058, GRID grid.411439.a, CeRePP, Pitie-Salpetriere Hospital, ; Paris, F-75020 France
                [33 ]UPMC Univ Paris 06, GRC N°5 ONCOTYPE-URO, CeRePP, Tenon Hospital, Paris, F-75020 France
                [34 ]ISNI 0000 0004 0512 597X, GRID grid.154185.c, Department of Molecular Medicine, , Aarhus University Hospital, ; Aarhus N, 8200 Denmark
                [35 ]ISNI 0000 0001 1956 2722, GRID grid.7048.b, Department of Clinical Medicine, , Aarhus University, ; Aarhus N, 8200 Denmark
                [36 ]ISNI 0000 0004 0389 8485, GRID grid.55325.34, Department of Medical Genetics, , Oslo University Hospital, ; Oslo, 0424 Norway
                [37 ]ISNI 0000000121885934, GRID grid.5335.0, University of Cambridge, Department of Oncology, Addenbrooke’s Hospital, ; Cambridge, CB2 0QQ UK
                [38 ]ISNI 0000 0004 0634 2060, GRID grid.470869.4, Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, ; Cambridge, CB2 0RE UK
                [39 ]ISNI 0000 0004 1936 8948, GRID grid.4991.5, Nuffield Department of Surgical Sciences, University of Oxford, ; Oxford, OX1 2JD UK
                [40 ]Faculty of Medical Science, University of Oxford, John Radcliffe Hospital, Oxford, OX1 2JD UK
                [41 ]ISNI 0000 0004 1936 7603, GRID grid.5337.2, School of Social and Community Medicine, , University of Bristol, ; Bristol, BS8 2PS UK
                [42 ]ISNI 0000 0004 1936 8948, GRID grid.4991.5, Cancer Epidemiology, Nuffield Department of Population Health University of Oxford, ; Oxford, OX3 7LF UK
                [43 ]ISNI 0000 0001 2150 066X, GRID grid.415224.4, Department of Surgical Oncology, Princess Margaret Cancer Centre, ; Toronto, M5G 2M9 Canada
                [44 ]ISNI 0000 0001 0670 2351, GRID grid.59734.3c, Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai, ; New York, 10029 NY USA
                [45 ]ISNI 0000 0001 0670 2351, GRID grid.59734.3c, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, ; New York, 10029-5674 NY USA
                [46 ]ISNI 0000 0001 2171 1133, GRID grid.4868.2, Centre for Molecular Oncology, Barts Cancer Institute, , Queen Mary University of London, John Vane Science Centre, ; London, EC1M 6BQ UK
                [47 ]ISNI 0000 0001 1482 3639, GRID grid.3263.4, Cancer Epidemiology and Intelligence Division, The Cancer Council Victoria, Melbourne, ; Victoria, 3004 Australia
                [48 ]ISNI 0000 0001 2179 088X, GRID grid.1008.9, Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, , The University of Melbourne, ; Melbourne, VIC 3010 Australia
                [49 ]ISNI 0000 0004 0378 8294, GRID grid.62560.37, Division of Urologic Surgery, Brigham and Womens Hospital, ; Boston, 02115 MA USA
                [50 ]Fundacion Publica Galega de Medicina Xenomica-SERGAS, Grupo de Medicina Xenomica, CIBERER, IDIS, Santiago de Compostela, 15706 Spain
                [51 ]ISNI 0000 0004 0592 275X, GRID grid.417617.2, Centre for Research in Environmental Epidemiology (CREAL), Barcelona Institute for Global Health (ISGlobal), ; Barcelona, 08003 Spain
                [52 ]ISNI 0000 0000 9314 1427, GRID grid.413448.e, CIBER Epidemiologia y Salud Publica (CIBERESP), ; Madrid, 28029 Spain
                [53 ]ISNI 0000 0004 1767 8811, GRID grid.411142.3, IMIM (Hospital del Mar Research Institute), ; Barcelona, 08003 Spain
                [54 ]ISNI 0000 0001 2172 2676, GRID grid.5612.0, Universitat Pompeu Fabra (UPF), ; Barcelona, 08002 Spain
                [55 ]ISNI 0000 0000 9891 5233, GRID grid.468198.a, Department of Cancer Epidemiology, Moffitt Cancer Center, ; Tampa, 33612 USA
                [56 ]ISNI 0000 0001 2180 1622, GRID grid.270240.3, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, ; Washington, 98109-1024 USA
                [57 ]ISNI 0000000122986657, GRID grid.34477.33, Department of Epidemiology, School of Public Health, , University of Washington, Seattle, ; Washington, 98195 USA
                [58 ]ISNI 0000 0001 1411 4349, GRID grid.107950.a, International Hereditary Cancer Center, Department of Genetics and Pathology, , Pomeranian Medical University, ; Szczecin, 70-115 Poland
                [59 ]ISNI 0000 0001 0674 042X, GRID grid.5254.6, Faculty of Health and Medical Sciences, , University of Copenhagen, ; Copenhagen, 2200 Denmark
                [60 ]ISNI 0000 0004 0646 7373, GRID grid.4973.9, Department of Clinical Biochemistry, Herlev and Gentofte Hospital, , Copenhagen University Hospital, ; Herlev, 2200 Denmark
                [61 ]ISNI 0000 0004 0492 0584, GRID grid.7497.d, Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), ; Heidelberg, D-69120 Germany
                [62 ]ISNI 0000 0004 0492 0584, GRID grid.7497.d, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), ; Heidelberg, D-69120 Germany
                [63 ]ISNI 0000 0004 0492 0584, GRID grid.7497.d, Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), ; Heidelberg, D-69120 Germany
                [64 ]GRID grid.410712.1, Institute for Human Genetics, , University Hospital Ulm, ; Ulm, 89075 Germany
                [65 ]ISNI 0000 0001 2291 4776, GRID grid.240145.6, The University of Texas M. D. Anderson Cancer Center, Department of Genitourinary Medical Oncology, ; Houston, 77030 TX USA
                [66 ]ISNI 0000 0004 0498 8300, GRID grid.280669.3, Cancer Prevention Institute of California, ; Fremont, 94538 CA USA
                [67 ]ISNI 0000000419368956, GRID grid.168010.e, Department of Health Research and Policy (Epidemiology) and Stanford Cancer Institute, , Stanford University School of Medicine, ; Stanford, 94305-5101 CA USA
                [68 ]ISNI 0000 0004 0631 0608, GRID grid.418711.a, Department of Genetics, , Portuguese Oncology Institute of Porto, ; Porto, 4200-072 Portugal
                [69 ]ISNI 0000 0001 1503 7226, GRID grid.5808.5, Biomedical Sciences Institute (ICBAS), , University of Porto, ; Porto, 4050-313 Portugal
                [70 ]ISNI 0000 0004 0421 8357, GRID grid.410425.6, Department of Population Sciences, , Beckman Research Institute of the City of Hope, ; Duarte, 91010 CA USA
                [71 ]ISNI 0000 0001 2069 7798, GRID grid.5342.0, Ghent University, Faculty of Medicine and Health Sciences, Basic Medical Sciences, ; Gent, B-9000 Belgium
                [72 ]ISNI 0000 0001 2308 5949, GRID grid.10347.31, Department of Surgery, Faculty of Medicine, , University of Malaya, ; Kuala Lumpur, 50603 Malaysia
                [73 ]ISNI 0000000122986657, GRID grid.34477.33, Department of Urology, , University of Washington, ; Seattle, 98195 WA USA
                [74 ]ISNI 0000 0001 2180 3484, GRID grid.13648.38, Institute of Human Genetics, , University Medical Center Hamburg-Eppendorf, ; Hamburg, D-20246 Germany
                [75 ]ISNI 0000 0004 0621 0092, GRID grid.410563.5, Molecular Medicine Center, Department of Medical Chemistry and Biochemistry, , Medical University, ; Sofia, 1431 Bulgaria
                [76 ]GRID grid.17089.37, Department of Oncology, Cross Cancer Institute, , University of Alberta, ; Edmonton, AB T6G 1Z2 Alberta Canada
                [77 ]GRID grid.17089.37, Division of Radiation Oncology, Cross Cancer Institute, ; Edmonton, AB T6G 1Z2 Alberta Canada
                [78 ]Molecular Endocrinology Laboratory, Department of Cellular and Molecular Medicine, KU Leuven, BE-3000 Leuven Belgium
                [79 ]ISNI 0000000121662407, GRID grid.5379.8, Institute of Cancer Sciences, Manchester Cancer Research Centre, , University of Manchester, Manchester Academic Health Science Centre, St Mary’s Hospital, ; Manchester, M13 9WL UK
                [80 ]ISNI 0000 0000 8816 6945, GRID grid.411048.8, 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, 15706 Spain
                [81 ]ISNI 0000 0001 2107 4242, GRID grid.266100.3, University of California San Diego, Moores Cancer Center, ; La Jolla, 92037 CA USA
                [82 ]ISNI 000000040459992X, GRID grid.5645.2, Department of Urology, , Erasmus University Medical Center, ; Rotterdam, 3015 CE The Netherlands
                [83 ]ISNI 0000 0001 2171 2558, GRID grid.5842.b, Cancer and Environment Group, Center for Research in Epidemiology and Population Health (CESP), INSERM, , University Paris-Sud, University Paris-Saclay, ; Villejuif, 94807 France
                [84 ]ISNI 0000000121885934, GRID grid.5335.0, Clinical Gerontology Unit, , University of Cambridge, ; Cambridge, CB2 2QQ UK
                [85 ]ISNI 0000 0001 2193 0096, GRID grid.223827.e, Division of Genetic Epidemiology, Department of Medicine, , University of Utah School of Medicine, ; Salt Lake City, 84112 Utah USA
                [86 ]GRID grid.413886.0, George E. Wahlen Department of Veterans Affairs Medical Center, ; Salt Lake City, 84148 UT USA
                [87 ]ISNI 0000 0004 0407 4824, GRID grid.5475.3, The University of Surrey, ; Guildford, GU2 7XH Surrey UK
                [88 ]ISNI 0000 0004 0459 167X, GRID grid.66875.3a, Department of Laboratory Medicine and Pathology, Mayo Clinic, ; Rochester, 55905 MN USA
                [89 ]ISNI 000000041936754X, GRID grid.38142.3c, Program in Genetic Epidemiology and Statistical Genetics, Department of Epidemiology, Harvard T.H. Chan School of Public Health, ; Boston, 02115 MA USA
                Author information
                http://orcid.org/0000-0002-9352-5927
                http://orcid.org/0000-0002-7980-4620
                http://orcid.org/0000-0003-1226-070X
                http://orcid.org/0000-0002-3698-6241
                Article
                6302
                10.1038/s41467-018-06302-1
                6172280
                30287866
                24a4c802-3808-494b-9eed-addd691c1acd
                © The Author(s) 2018

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 11 June 2018
                : 28 August 2018
                Funding
                Funded by: FundRef https://doi.org/10.13039/100000051, U.S. Department of Health & Human Services | NIH | National Human Genome Research Institute (NHGRI);
                Award ID: R01-HG009120
                Award ID: R01-HG006399
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/100000054, U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI);
                Award ID: U01-CA194393
                Award Recipient :
                Categories
                Article
                Custom metadata
                © The Author(s) 2018

                Uncategorized
                Uncategorized

                Comments

                Comment on this article

                scite_

                Similar content213

                Cited by59

                Most referenced authors3,529