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      Quantifying the heritability of glioma using genome-wide complex trait analysis

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          Abstract

          Genome-wide association studies (GWAS) have successfully identified a number of common single-nucleotide polymorphisms (SNPs) influencing glioma risk. While these SNPs only explain a small proportion of the genetic risk it is unclear how much is left to be detected by other, yet to be identified, common SNPs. Therefore, we applied Genome-Wide Complex Trait Analysis (GCTA) to three GWAS datasets totalling 3,373 cases and 4,571 controls and performed a meta-analysis to estimate the heritability of glioma. Our results identify heritability estimates of 25% (95% CI: 20–31%, P = 1.15 × 10 −17) for all forms of glioma - 26% (95% CI: 17–35%, P = 1.05 × 10 −8) for glioblastoma multiforme (GBM) and 25% (95% CI: 17–32%, P = 1.26 × 10 −10) for non-GBM tumors. This is a substantial increase from the genetic variance identified by the currently identified GWAS risk loci (~6% of common heritability), indicating that most of the heritable risk attributable to common genetic variants remains to be identified.

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          Most cited references 41

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          PLINK: a tool set for whole-genome association and population-based linkage analyses.

          Whole-genome association studies (WGAS) bring new computational, as well as analytic, challenges to researchers. Many existing genetic-analysis tools are not designed to handle such large data sets in a convenient manner and do not necessarily exploit the new opportunities that whole-genome data bring. To address these issues, we developed PLINK, an open-source C/C++ WGAS tool set. With PLINK, large data sets comprising hundreds of thousands of markers genotyped for thousands of individuals can be rapidly manipulated and analyzed in their entirety. As well as providing tools to make the basic analytic steps computationally efficient, PLINK also supports some novel approaches to whole-genome data that take advantage of whole-genome coverage. We introduce PLINK and describe the five main domains of function: data management, summary statistics, population stratification, association analysis, and identity-by-descent estimation. In particular, we focus on the estimation and use of identity-by-state and identity-by-descent information in the context of population-based whole-genome studies. This information can be used to detect and correct for population stratification and to identify extended chromosomal segments that are shared identical by descent between very distantly related individuals. Analysis of the patterns of segmental sharing has the potential to map disease loci that contain multiple rare variants in a population-based linkage analysis.
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            The 2007 WHO Classification of Tumours of the Central Nervous System

            The fourth edition of the World Health Organization (WHO) classification of tumours of the central nervous system, published in 2007, lists several new entities, including angiocentric glioma, papillary glioneuronal tumour, rosette-forming glioneuronal tumour of the fourth ventricle, papillary tumour of the pineal region, pituicytoma and spindle cell oncocytoma of the adenohypophysis. Histological variants were added if there was evidence of a different age distribution, location, genetic profile or clinical behaviour; these included pilomyxoid astrocytoma, anaplastic medulloblastoma and medulloblastoma with extensive nodularity. The WHO grading scheme and the sections on genetic profiles were updated and the rhabdoid tumour predisposition syndrome was added to the list of familial tumour syndromes typically involving the nervous system. As in the previous, 2000 edition of the WHO ‘Blue Book’, the classification is accompanied by a concise commentary on clinico-pathological characteristics of each tumour type. The 2007 WHO classification is based on the consensus of an international Working Group of 25 pathologists and geneticists, as well as contributions from more than 70 international experts overall, and is presented as the standard for the definition of brain tumours to the clinical oncology and cancer research communities world-wide.
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              The human genome browser at UCSC.

              As vertebrate genome sequences near completion and research refocuses to their analysis, the issue of effective genome annotation display becomes critical. A mature web tool for rapid and reliable display of any requested portion of the genome at any scale, together with several dozen aligned annotation tracks, is provided at http://genome.ucsc.edu. This browser displays assembly contigs and gaps, mRNA and expressed sequence tag alignments, multiple gene predictions, cross-species homologies, single nucleotide polymorphisms, sequence-tagged sites, radiation hybrid data, transposon repeats, and more as a stack of coregistered tracks. Text and sequence-based searches provide quick and precise access to any region of specific interest. Secondary links from individual features lead to sequence details and supplementary off-site databases. One-half of the annotation tracks are computed at the University of California, Santa Cruz from publicly available sequence data; collaborators worldwide provide the rest. Users can stably add their own custom tracks to the browser for educational or research purposes. The conceptual and technical framework of the browser, its underlying MYSQL database, and overall use are described. The web site currently serves over 50,000 pages per day to over 3000 different users.
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                Author and article information

                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group
                2045-2322
                02 December 2015
                2015
                : 5
                Affiliations
                [1 ]Division of Genetics and Epidemiology, The Institute of Cancer Research , 15 Cotswold Road, Sutton, Surrey SM2 5NG, UK
                [2 ]Department of Neurosurgery, University of Bonn Medical Center , Sigmund-Freud-Str. 25, 53105 Bonn, Germany
                [3 ]Sorbonne Universités UPMC Univ Paris 06, INSERM CNRS, U1127, UMR 7225, ICM , F-75013 Paris, France
                [4 ]AP-HP, GH Pitié-Salpêtrière, Service de Neurologie Mazarin , 47 bld de l’Hôpital, 75651 Paris, France
                [5 ]Onconeurotek , F-75013 Paris, France
                [6 ]Institute of Epidemiology I, Helmholtz Zentrum München, German Research Center for Environmental Health , Ingolstädter Landstr. 1, 85764 Neuherberg, Germany
                [7 ]Institute of Medical Informatics, Biometry and Epidemiology, Chair of Epidemiology, Ludwig-Maximilians-Universität , Geschwister-Scholl-Platz 1, 80539 Munich, Germany
                [8 ]Institute of Medical Statistics and Epidemiology, Technical University Munich, Germany
                [9 ]1st Medical Department, University Clinic Schleswig-Holstein, Campus Kiel , House 6, Arnold-Heller-Str. 3, 24105 Kiel, Germany
                [10 ]Institute of Clinical Molecular Biology, Christian-Albrechts-University Kiel , Arnold-Heller-Straβe 3, 24105 Kiel, Germany
                [11 ]Institute of Human Genetics, University of Bonn , Bonn, Germany
                [12 ]AP-HP, GH Pitié-Salpêtrière, Laboratoire de neuropathologie R Escourolle , F-75013 Paris, France
                [13 ]Fondation Jean Dausset-CEPH , 27 Rue Juliette Dodu, 75010 Paris, France
                [14 ]Génome Québec, Department of Human Genetics, McGill University , Montreal, Quebec, H3A 0G1, Canada
                [15 ]Department of Pediatrics, Division of Hematology-Oncology, Dan L. Duncan Cancer Center, Baylor College of Medicine , Houston, Texas, USA
                Author notes
                Article
                srep17267
                10.1038/srep17267
                4667278
                26625949
                Copyright © 2015, Macmillan Publishers Limited

                This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

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