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Institution

Broad Institute

NonprofitCambridge, Massachusetts, United States
About: Broad Institute is a nonprofit organization based out in Cambridge, Massachusetts, United States. It is known for research contribution in the topics: Population & Genome-wide association study. The organization has 6584 authors who have published 11618 publications receiving 1522743 citations. The organization is also known as: Eli and Edythe L. Broad Institute of MIT and Harvard.


Papers
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Journal ArticleDOI
TL;DR: An approach to identify disease-relevant tissues and cell types by analyzing gene expression data together with genome-wide association study (GWAS) summary statistics and found significant tissue-specific enrichments for 34 traits.
Abstract: We introduce an approach to identify disease-relevant tissues and cell types by analyzing gene expression data together with genome-wide association study (GWAS) summary statistics. Our approach uses stratified linkage disequilibrium (LD) score regression to test whether disease heritability is enriched in regions surrounding genes with the highest specific expression in a given tissue. We applied our approach to gene expression data from several sources together with GWAS summary statistics for 48 diseases and traits (average N = 169,331) and found significant tissue-specific enrichments (false discovery rate (FDR) < 5%) for 34 traits. In our analysis of multiple tissues, we detected a broad range of enrichments that recapitulated known biology. In our brain-specific analysis, significant enrichments included an enrichment of inhibitory over excitatory neurons for bipolar disorder, and excitatory over inhibitory neurons for schizophrenia and body mass index. Our results demonstrate that our polygenic approach is a powerful way to leverage gene expression data for interpreting GWAS signals.

707 citations

Journal ArticleDOI
Paul A. Northcott1, Paul A. Northcott2, Ivo Buchhalter3, Ivo Buchhalter1, A. Sorana Morrissy, Volker Hovestadt1, Joachim Weischenfeldt4, Tobias Ehrenberger5, Susanne Gröbner1, Maia Segura-Wang6, Thomas Zichner6, Vasilisa A. Rudneva, Hans-Jörg Warnatz7, Nikos Sidiropoulos4, Aaron H. Phillips2, Steven E. Schumacher8, Kortine Kleinheinz1, Sebastian M. Waszak6, Serap Erkek6, Serap Erkek1, David T.W. Jones1, Barbara C. Worst1, Marcel Kool1, Marc Zapatka1, Natalie Jäger1, Lukas Chavez1, Barbara Hutter1, Matthias Bieg1, Nagarajan Paramasivam1, Nagarajan Paramasivam3, Michael Heinold3, Michael Heinold1, Zuguang Gu1, Naveed Ishaque1, Christina Jäger-Schmidt1, Charles D. Imbusch1, Alke Jugold1, Daniel Hübschmann9, Daniel Hübschmann1, Daniel Hübschmann3, Thomas Risch7, Vyacheslav Amstislavskiy7, Francisco German Rodriguez Gonzalez4, Ursula D. Weber1, Stephan Wolf1, Giles W. Robinson2, Xin Zhou2, Gang Wu2, David Finkelstein2, Yanling Liu2, Florence M.G. Cavalli, Betty Luu, Vijay Ramaswamy, Xiaochong Wu, Jan Koster, Marina Ryzhova, Yoon Jae Cho10, Scott L. Pomeroy11, Christel Herold-Mende3, Martin U. Schuhmann12, Martin Ebinger, Linda M. Liau13, Jaume Mora14, Roger E. McLendon15, Nada Jabado16, Toshihiro Kumabe17, Eric Chuah18, Yussanne Ma18, Richard A. Moore18, Andrew J. Mungall18, Karen Mungall18, Nina Thiessen18, Kane Tse18, Tina Wong18, Steven J.M. Jones18, Olaf Witt9, Till Milde9, Andreas von Deimling9, David Capper9, Andrey Korshunov9, Marie-Laure Yaspo7, Richard W. Kriwacki2, Amar Gajjar2, Jinghui Zhang2, Rameen Beroukhim8, Ernest Fraenkel5, Jan O. Korbel6, Benedikt Brors1, Matthias Schlesner1, Roland Eils1, Roland Eils3, Marco A. Marra18, Stefan M. Pfister1, Stefan M. Pfister9, Michael D. Taylor19, Peter Lichter1 
19 Jul 2017-Nature
TL;DR: The application of integrative genomics to an extensive cohort of clinical samples derived from a single childhood cancer entity revealed a series of cancer genes and biologically relevant subtype diversity that represent attractive therapeutic targets for the treatment of patients with medulloblastoma.
Abstract: Current therapies for medulloblastoma, a highly malignant childhood brain tumour, impose debilitating effects on the developing child, and highlight the need for molecularly targeted treatments with reduced toxicity. Previous studies have been unable to identify the full spectrum of driver genes and molecular processes that operate in medulloblastoma subgroups. Here we analyse the somatic landscape across 491 sequenced medulloblastoma samples and the molecular heterogeneity among 1,256 epigenetically analysed cases, and identify subgroup-specific driver alterations that include previously undiscovered actionable targets. Driver mutations were confidently assigned to most patients belonging to Group 3 and Group 4 medulloblastoma subgroups, greatly enhancing previous knowledge. New molecular subtypes were differentially enriched for specific driver events, including hotspot in-frame insertions that target KBTBD4 and 'enhancer hijacking' events that activate PRDM6. Thus, the application of integrative genomics to an extensive cohort of clinical samples derived from a single childhood cancer entity revealed a series of cancer genes and biologically relevant subtype diversity that represent attractive therapeutic targets for the treatment of patients with medulloblastoma.

706 citations

Journal ArticleDOI
05 Jun 2008-Nature
TL;DR: It is shown that Drosophila generates a third small RNA class, endogenous small interfering RNAs, in both gonadal and somatic tissues, adding a class that blurs distinctions based on known biogenesis mechanisms and functional roles.
Abstract: Drosophila endogenous small RNAs are categorized according to their mechanisms of biogenesis and the Argonaute protein to which they bind. MicroRNAs are a class of ubiquitously expressed RNAs of approximately 22 nucleotides in length, which arise from structured precursors through the action of Drosha-Pasha and Dicer-1-Loquacious complexes. These join Argonaute-1 to regulate gene expression. A second endogenous small RNA class, the Piwi-interacting RNAs, bind Piwi proteins and suppress transposons. Piwi-interacting RNAs are restricted to the gonad, and at least a subset of these arises by Piwi-catalysed cleavage of single-stranded RNAs. Here we show that Drosophila generates a third small RNA class, endogenous small interfering RNAs, in both gonadal and somatic tissues. Production of these RNAs requires Dicer-2, but a subset depends preferentially on Loquacious rather than the canonical Dicer-2 partner, R2D2 (ref. 14). Endogenous small interfering RNAs arise both from convergent transcription units and from structured genomic loci in a tissue-specific fashion. They predominantly join Argonaute-2 and have the capacity, as a class, to target both protein-coding genes and mobile elements. These observations expand the repertoire of small RNAs in Drosophila, adding a class that blurs distinctions based on known biogenesis mechanisms and functional roles.

706 citations

Journal ArticleDOI
24 May 2012-Nature
TL;DR: A wide range of point mutation rates was observed: lowest in melanomas whose primaries arose on non-ultraviolet-exposed hairless skin of the extremities (3 and 14 per megabase (Mb) of genome, intermediate in those originating from hair-bearing skin on the trunk (5-55 per Mb), and highest in a patient with a documented history of chronic sun exposure (111 per Mb).
Abstract: Melanoma is notable for its metastatic propensity, lethality in the advanced setting and association with ultraviolet exposure early in life. To obtain a comprehensive genomic view of melanoma in humans, we sequenced the genomes of 25 metastatic melanomas and matched germline DNA. A wide range of point mutation rates was observed: lowest in melanomas whose primaries arose on non-ultraviolet-exposed hairless skin of the extremities (3 and 14 per megabase (Mb) of genome), intermediate in those originating from hair-bearing skin of the trunk (5-55 per Mb), and highest in a patient with a documented history of chronic sun exposure (111 per Mb). Analysis of whole-genome sequence data identified PREX2 (phosphatidylinositol-3,4,5-trisphosphate-dependent Rac exchange factor 2)--a PTEN-interacting protein and negative regulator of PTEN in breast cancer--as a significantly mutated gene with a mutation frequency of approximately 14% in an independent extension cohort of 107 human melanomas. PREX2 mutations are biologically relevant, as ectopic expression of mutant PREX2 accelerated tumour formation of immortalized human melanocytes in vivo. Thus, whole-genome sequencing of human melanoma tumours revealed genomic evidence of ultraviolet pathogenesis and discovered a new recurrently mutated gene in melanoma.

705 citations

Journal ArticleDOI
15 Jan 2010-Science
TL;DR: The development and application of a high-throughput, quantitative screen for drugs that alter the behavior of larval zebrafish are reported and it is found that the multidimensional nature of observed phenotypes enabled the hierarchical clustering of molecules according to shared behaviors.
Abstract: A major obstacle for the discovery of psychoactive drugs is the inability to predict how small molecules will alter complex behaviors. We report the development and application of a high-throughput, quantitative screen for drugs that alter the behavior of larval zebrafish. We found that the multidimensional nature of observed phenotypes enabled the hierarchical clustering of molecules according to shared behaviors. Behavioral profiling revealed conserved functions of psychotropic molecules and predicted the mechanisms of action of poorly characterized compounds. In addition, behavioral profiling implicated new factors such as ether-a-go-go–related gene (ERG) potassium channels and immunomodulators in the control of rest and locomotor activity. These results demonstrate the power of high-throughput behavioral profiling in zebrafish to discover and characterize psychotropic drugs and to dissect the pharmacology of complex behaviors.

704 citations


Authors

Showing all 7146 results

NameH-indexPapersCitations
Eric S. Lander301826525976
Albert Hofman2672530321405
Frank B. Hu2501675253464
David J. Hunter2131836207050
Kari Stefansson206794174819
Mark J. Daly204763304452
Lewis C. Cantley196748169037
Matthew Meyerson194553243726
Gad Getz189520247560
Stacey Gabriel187383294284
Stuart H. Orkin186715112182
Ralph Weissleder1841160142508
Chris Sander178713233287
Michael I. Jordan1761016216204
Richard A. Young173520126642
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Performance
Metrics
No. of papers from the Institution in previous years
YearPapers
202337
2022627
20211,727
20201,534
20191,364
20181,107