ALBERT

Description: A major challenge in human genetics is to devise a systematic strategy to integrate disease-associated variants with diverse genomic and biological data sets to provide insight into disease pathogenesis and guide drug discovery for complex traits such as rheumatoid arthritis (RA). Here we performed a genome-wide association study meta-analysis in a total of 〉100,000 subjects of European and Asian ancestries (29,880 RA cases and 73,758 controls), by evaluating approximately 10 million single-nucleotide polymorphisms. We discovered 42 novel RA risk loci at a genome-wide level of significance, bringing the total to 101 (refs 2 - 4). We devised an in silico pipeline using established bioinformatics methods based on functional annotation, cis-acting expression quantitative trait loci and pathway analyses--as well as novel methods based on genetic overlap with human primary immunodeficiency, haematological cancer somatic mutations and knockout mouse phenotypes--to identify 98 biological candidate genes at these 101 risk loci. We demonstrate that these genes are the targets of approved therapies for RA, and further suggest that drugs approved for other indications may be repurposed for the treatment of RA. Together, this comprehensive genetic study sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis, and provides empirical evidence that the genetics of RA can provide important information for drug discovery.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3944098/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3944098/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Okada, Yukinori -- Wu, Di -- Trynka, Gosia -- Raj, Towfique -- Terao, Chikashi -- Ikari, Katsunori -- Kochi, Yuta -- Ohmura, Koichiro -- Suzuki, Akari -- Yoshida, Shinji -- Graham, Robert R -- Manoharan, Arun -- Ortmann, Ward -- Bhangale, Tushar -- Denny, Joshua C -- Carroll, Robert J -- Eyler, Anne E -- Greenberg, Jeffrey D -- Kremer, Joel M -- Pappas, Dimitrios A -- Jiang, Lei -- Yin, Jian -- Ye, Lingying -- Su, Ding-Feng -- Yang, Jian -- Xie, Gang -- Keystone, Ed -- Westra, Harm-Jan -- Esko, Tonu -- Metspalu, Andres -- Zhou, Xuezhong -- Gupta, Namrata -- Mirel, Daniel -- Stahl, Eli A -- Diogo, Dorothee -- Cui, Jing -- Liao, Katherine -- Guo, Michael H -- Myouzen, Keiko -- Kawaguchi, Takahisa -- Coenen, Marieke J H -- van Riel, Piet L C M -- van de Laar, Mart A F J -- Guchelaar, Henk-Jan -- Huizinga, Tom W J -- Dieude, Philippe -- Mariette, Xavier -- Bridges, S Louis Jr -- Zhernakova, Alexandra -- Toes, Rene E M -- Tak, Paul P -- Miceli-Richard, Corinne -- Bang, So-Young -- Lee, Hye-Soon -- Martin, Javier -- Gonzalez-Gay, Miguel A -- Rodriguez-Rodriguez, Luis -- Rantapaa-Dahlqvist, Solbritt -- Arlestig, Lisbeth -- Choi, Hyon K -- Kamatani, Yoichiro -- Galan, Pilar -- Lathrop, Mark -- RACI consortium -- GARNET consortium -- Eyre, Steve -- Bowes, John -- Barton, Anne -- de Vries, Niek -- Moreland, Larry W -- Criswell, Lindsey A -- Karlson, Elizabeth W -- Taniguchi, Atsuo -- Yamada, Ryo -- Kubo, Michiaki -- Liu, Jun S -- Bae, Sang-Cheol -- Worthington, Jane -- Padyukov, Leonid -- Klareskog, Lars -- Gregersen, Peter K -- Raychaudhuri, Soumya -- Stranger, Barbara E -- De Jager, Philip L -- Franke, Lude -- Visscher, Peter M -- Brown, Matthew A -- Yamanaka, Hisashi -- Mimori, Tsuneyo -- Takahashi, Atsushi -- Xu, Huji -- Behrens, Timothy W -- Siminovitch, Katherine A -- Momohara, Shigeki -- Matsuda, Fumihiko -- Yamamoto, Kazuhiko -- Plenge, Robert M -- 20385/Arthritis Research UK/United Kingdom -- 79321/Canadian Institutes of Health Research/Canada -- K08-KAR055688A/PHS HHS/ -- K24 AR052403/AR/NIAMS NIH HHS/ -- P60 AR047785/AR/NIAMS NIH HHS/ -- R01 AR056768/AR/NIAMS NIH HHS/ -- R01 AR057108/AR/NIAMS NIH HHS/ -- R01 AR059648/AR/NIAMS NIH HHS/ -- R01 AR063759/AR/NIAMS NIH HHS/ -- R01-AR056291/AR/NIAMS NIH HHS/ -- R01-AR056768/AR/NIAMS NIH HHS/ -- R01-AR057108/AR/NIAMS NIH HHS/ -- R01-AR059648/AR/NIAMS NIH HHS/ -- R01-AR065944/AR/NIAMS NIH HHS/ -- R01AR063759-01A1/AR/NIAMS NIH HHS/ -- R21 AR056042/AR/NIAMS NIH HHS/ -- T15 LM007450/LM/NLM NIH HHS/ -- U01 GM092691/GM/NIGMS NIH HHS/ -- U01-GM092691/GM/NIGMS NIH HHS/ -- U19 HL065962/HL/NHLBI NIH HHS/ -- England -- Nature. 2014 Feb 20;506(7488):376-81. doi: 10.1038/nature12873. Epub 2013 Dec 25.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. [2] Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. [3] Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts 02142, USA. ; 1] Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. [2] Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. [3] Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts 02142, USA. [4] Department of Statistics, Harvard University, Cambridge, Massachusetts 02138, USA. [5] Centre for Cancer Research, Monash Institute of Medical Research, Monash University, Clayton, Victoria 3800, Australia. ; 1] Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. [2] Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts 02142, USA. [3] Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Department of Neurology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA. ; 1] Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan. [2] Department of Rheumatology and Clinical immunology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan. ; Institute of Rheumatology, Tokyo Women's Medical University, Tokyo 162-0054, Japan. ; Laboratory for Autoimmune Diseases, Center for Integrative Medical Sciences, RIKEN, Yokohama 230-0045, Japan. ; Department of Rheumatology and Clinical immunology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan. ; Immunology Biomarkers Group, Genentech, South San Francisco, California 94080, USA. ; 1] Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA. [2] Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA. ; Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA. ; Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA. ; New York University Hospital for Joint Diseases, New York, New York 10003, USA. ; Department of Medicine, Albany Medical Center and The Center for Rheumatology, Albany, New York 12206, USA. ; Division of Rheumatology, Department of Medicine, New York, Presbyterian Hospital, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA. ; Department of Rheumatology and Immunology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai 200003, China. ; Department of Pharmacology, Second Military Medical University, Shanghai 200433, China. ; 1] University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland 4072, Australia. [2] Queensland Brain Institute, The University of Queensland, Brisbane, Queensland 4072, Australia. ; 1] Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada. [2] Toronto General Research Institute, Toronto, Ontario M5G 2M9, Canada. [3] Department of Medicine, University of Toronto, Toronto, Ontario M5S 2J7, Canada. ; Department of Medicine, Mount Sinai Hospital and University of Toronto, Toronto M5S 2J7, Canada. ; Department of Genetics, University Medical Center Groningen, University of Groningen, Hanzeplein 1, Groningen 9700 RB, the Netherlands. ; 1] Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts 02142, USA. [2] Estonian Genome Center, University of Tartu, Riia 23b, Tartu 51010, Estonia. [3] Division of Endocrinology, Children's Hospital, Boston, Massachusetts 02115, USA. ; Estonian Genome Center, University of Tartu, Riia 23b, Tartu 51010, Estonia. ; School of Computer and Information Technology, Beijing Jiaotong University, Beijing 100044, China. ; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts 02142, USA. ; The Department of Psychiatry at Mount Sinai School of Medicine, New York, New York 10029, USA. ; 1] Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. [2] Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts 02142, USA. [3] Division of Endocrinology, Children's Hospital, Boston, Massachusetts 02115, USA. ; Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan. ; Department of Human Genetics, Radboud University Medical Centre, Nijmegen 6500 HB, the Netherlands. ; Department of Rheumatology, Radboud University Medical Centre, Nijmegen 6500 HB, the Netherlands. ; Department of Rheumatology and Clinical Immunology, Arthritis Center Twente, University Twente & Medisch Spectrum Twente, Enschede 7500 AE, the Netherlands. ; Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden 2300 RC, the Netherlands. ; Department of Rheumatology, Leiden University Medical Center, Leiden 2300 RC, the Netherlands. ; 1] Service de Rhumatologie et INSERM U699 Hopital Bichat Claude Bernard, Assistance Publique des Hopitaux de Paris, Paris 75018, France. [2] Universite Paris 7-Diderot, Paris 75013, France. ; Institut National de la Sante et de la Recherche Medicale (INSERM) U1012, Universite Paris-Sud, Rhumatologie, Hopitaux Universitaires Paris-Sud, Assistance Publique-Hopitaux de Paris (AP-HP), Le Kremlin Bicetre 94275, France. ; Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA. ; 1] Department of Genetics, University Medical Center Groningen, University of Groningen, Hanzeplein 1, Groningen 9700 RB, the Netherlands. [2] Department of Rheumatology, Leiden University Medical Center, Leiden 2300 RC, the Netherlands. ; 1] AMC/University of Amsterdam, Amsterdam 1105 AZ, the Netherlands. [2] GlaxoSmithKline, Stevenage SG1 2NY, UK. [3] University of Cambridge, Cambridge CB2 1TN, UK. ; Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul 133-792, South Korea. ; Instituto de Parasitologia y Biomedicina Lopez-Neyra, CSIC, Granada 18100, Spain. ; Department of Rheumatology, Hospital Marques de Valdecilla, IFIMAV, Santander 39008, Spain. ; Hospital Clinico San Carlos, Madrid 28040, Spain. ; 1] Department of Public Health and Clinical Medicine, Umea University, Umea SE-901 87, Sweden. [2] Department of Rheumatology, Umea University, Umea SE-901 87, Sweden. ; 1] Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston 02115, Massachusetts, USA. [2] Section of Rheumatology, Boston University School of Medicine, Boston, Massachusetts 02118, USA. [3] Clinical Epidemiology Research and Training Unit, Boston University School of Medicine, Boston, Massachusetts 02118, USA. ; Centre d'Etude du Polymorphisme Humain (CEPH), Paris 75010, France. ; Universite Paris 13 Sorbonne Paris Cite, UREN (Nutritional Epidemiology Research Unit), Inserm (U557), Inra (U1125), Cnam, Bobigny 93017, France. ; McGill University and Genome Quebec Innovation Centre, Montreal, Quebec H3A 0G1 Canada. ; 1] Arthritis Research UK Epidemiology Unit, Centre for Musculoskeletal Research, University of Manchester, Manchester Academic Health Science Centre, Manchester M13 9NT, UK. [2] National Institute for Health Research, Manchester Musculoskeletal Biomedical Research Unit, Central Manchester University Hospitals National Health Service Foundation Trust, Manchester Academic Health Sciences Centre, Manchester M13 9NT, UK. ; Arthritis Research UK Epidemiology Unit, Centre for Musculoskeletal Research, University of Manchester, Manchester Academic Health Science Centre, Manchester M13 9NT, UK. ; Department of Clinical Immunology and Rheumatology & Department of Genome Analysis, Academic Medical Center/University of Amsterdam, Amsterdam 1105 AZ, the Netherlands. ; Division of Rheumatology and Clinical Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA. ; Rosalind Russell Medical Research Center for Arthritis, Division of Rheumatology, Department of Medicine, University of California San Francisco, San Francisco, California 94117, USA. ; Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. ; Unit of Statistical Genetics, Center for Genomic Medicine Graduate School of Medicine Kyoto University, Kyoto 606-8507, Japan. ; Laboratory for Genotyping Development, Center for Integrative Medical Sciences, RIKEN, Yokohama 230-0045, Japan. ; Department of Statistics, Harvard University, Cambridge, Massachusetts 02138, USA. ; Rheumatology Unit, Department of Medicine (Solna), Karolinska Institutet, Stockholm SE-171 76, Sweden. ; The Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, New York 11030, USA. ; 1] Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. [2] Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. [3] Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts 02142, USA. [4] NIHR Manchester Musculoskeletal Biomedical, Research Unit, Central Manchester NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester M13 9NT, UK. ; 1] Section of Genetic Medicine, University of Chicago, Chicago, Illinois 60637, USA. [2] Institute for Genomics and Systems Biology, University of Chicago, Chicago, Illinois 60637, USA. ; University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland 4072, Australia. ; Laboratory for Statistical Analysis, Center for Integrative Medical Sciences, RIKEN, Yokohama 230-0045, Japan. ; 1] Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan. [2] Core Research for Evolutional Science and Technology (CREST) program, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan. [3] Institut National de la Sante et de la Recherche Medicale (INSERM) Unite U852, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan. ; 1] Laboratory for Autoimmune Diseases, Center for Integrative Medical Sciences, RIKEN, Yokohama 230-0045, Japan. [2] Department of Allergy and Rheumatology, Graduate School of Medicine, the University of Tokyo, Tokyo 113-0033, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24390342" target="_blank"〉PubMed〈/a〉

Description: Schizophrenia is a common disease with a complex aetiology, probably involving multiple and heterogeneous genetic factors. Here, by analysing the exome sequences of 2,536 schizophrenia cases and 2,543 controls, we demonstrate a polygenic burden primarily arising from rare (less than 1 in 10,000), disruptive mutations distributed across many genes. Particularly enriched gene sets include the voltage-gated calcium ion channel and the signalling complex formed by the activity-regulated cytoskeleton-associated scaffold protein (ARC) of the postsynaptic density, sets previously implicated by genome-wide association and copy-number variation studies. Similar to reports in autism, targets of the fragile X mental retardation protein (FMRP, product of FMR1) are enriched for case mutations. No individual gene-based test achieves significance after correction for multiple testing and we do not detect any alleles of moderately low frequency (approximately 0.5 to 1 per cent) and moderately large effect. Taken together, these data suggest that population-based exome sequencing can discover risk alleles and complements established gene-mapping paradigms in neuropsychiatric disease.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4136494/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4136494/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Purcell, Shaun M -- Moran, Jennifer L -- Fromer, Menachem -- Ruderfer, Douglas -- Solovieff, Nadia -- Roussos, Panos -- O'Dushlaine, Colm -- Chambert, Kimberly -- Bergen, Sarah E -- Kahler, Anna -- Duncan, Laramie -- Stahl, Eli -- Genovese, Giulio -- Fernandez, Esperanza -- Collins, Mark O -- Komiyama, Noboru H -- Choudhary, Jyoti S -- Magnusson, Patrik K E -- Banks, Eric -- Shakir, Khalid -- Garimella, Kiran -- Fennell, Tim -- DePristo, Mark -- Grant, Seth G N -- Haggarty, Stephen J -- Gabriel, Stacey -- Scolnick, Edward M -- Lander, Eric S -- Hultman, Christina M -- Sullivan, Patrick F -- McCarroll, Steven A -- Sklar, Pamela -- G0802238/Medical Research Council/United Kingdom -- I01 BX002395/BX/BLRD VA/ -- R01 HG005827/HG/NHGRI NIH HHS/ -- R01 MH077139/MH/NIMH NIH HHS/ -- R01 MH091115/MH/NIMH NIH HHS/ -- R01 MH095034/MH/NIMH NIH HHS/ -- R01 MH095088/MH/NIMH NIH HHS/ -- R01 MH099126/MH/NIMH NIH HHS/ -- RC2MH089905/MH/NIMH NIH HHS/ -- T32 MH017119/MH/NIMH NIH HHS/ -- TT32MH017119/MH/NIMH NIH HHS/ -- U54 HG003067/HG/NHGRI NIH HHS/ -- U54HG003067/HG/NHGRI NIH HHS/ -- Medical Research Council/United Kingdom -- Wellcome Trust/United Kingdom -- England -- Nature. 2014 Feb 13;506(7487):185-90. doi: 10.1038/nature12975. Epub 2014 Jan 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA [2] Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA [3] Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA [4] Analytic and Translational Genetics Unit, Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA [5] Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA. ; 1] Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA [2]. ; 1] Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA [2] Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA [3] Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA [4] Analytic and Translational Genetics Unit, Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA [5]. ; 1] Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA [2] Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA [3]. ; Analytic and Translational Genetics Unit, Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. ; 1] Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA [2] Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA. ; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA. ; 1] Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA [2] Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm SE-171 77, Sweden. ; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm SE-171 77, Sweden. ; 1] Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA [2] Analytic and Translational Genetics Unit, Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA [3] Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA. ; 1] Center for Human Genetics, KU Leuven, 3000 Leuven, Belgium [2] VIB Center for Biology of Disease, 3000 Leuven, Belgium. ; Proteomic Mass Spectrometry, The Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK. ; Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA. ; Genes to Cognition Programme, Centre for Clinical Brain Sciences and Centre for Neuroregeneration, The University of Edinburgh, Edinburgh EH16 4SB, UK. ; 1] Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA [2] Analytic and Translational Genetics Unit, Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA [3] Department of Neurology, Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. ; Departments of Genetics and Psychiatry, University of North Carolina, Chapel Hill, North Carolina 27599-7264, USA. ; 1] Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA [2] Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA [3] Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA. ; 1] Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA [2] Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA [3] Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24463508" target="_blank"〉PubMed〈/a〉

Description: We present the key technologies and capabilities that will enable a future, large-aperture ultravioletopticalinfrared (UVOIR) space observatory. These include starlight suppression systems, vibration isolation and control systems, lightweight mirror segments, detector systems, and mirror coatings. These capabilities will provide major advances over current and near-future observatories for sensitivity, angular resolution, and starlight suppression. The goals adopted in our study for the starlight suppression system are 10-10 contrast with an inner working angle of 40 milliarcsec and broad bandpass. We estimate that a vibration and isolation control system that achieves a total system vibration isolation of 140 dB for a vibration-isolated mass of 5000 kg is required to achieve the high wavefront error stability needed for exoplanet coronagraphy. Technology challenges for lightweight mirror segments include diffraction-limited optical quality and high wavefront error stability as well as low cost, low mass, and rapid fabrication. Key challenges for the detector systems include visible-blind, high quantum efficiency UV arrays, photon counting visible and NIR arrays for coronagraphic spectroscopy and starlight wavefront sensing and control, and detectors with deep full wells with low persistence and radiation tolerance to enable transit imaging and spectroscopy at all wavelengths. Finally, mirror coatings with high reflectivity ( 90), high uniformity ( 1) and low polarization ( 1) that are scalable to large diameter mirror substrates will be essential for ensuring that both high throughput UV observations and high contrast observations can be performed by the same observatory.

Description: ASTRO2010 Decadal Survey stated that an advanced large-aperture ultraviolet, optical, near-infrared (UVOIR) telescope is required to enable the next generation of compelling astrophysics and exoplanet science; and, that present technology is not mature enough to affordably build and launch any potential UVOIR mission concept. AMTD is a multiyear effort to develop, demonstrate and mature critical technologies to TRL-6 by 2018 so that a viable flight mission can be proposed to the 2020 Decadal Review. AMTD builds on the state of art (SOA) defined by over 30 years of monolithic & segmented ground & space-telescope mirror technology to mature six key technologies: center dotLarge-Aperture, Low Areal Density, High Stiffness Mirror Substrates: Both (4 to 8 m) monolithic and (8 to 16 m) segmented telescopes require larger and stiffer mirrors. center dotSupport System: Large-aperture mirrors require large support systems to ensure that they survive launch, deploy on orbit, and maintain a stable, undistorted shape. center dotMid/High Spatial Frequency Figure Error: Very smooth mirror is critical for producing high-quality point spread function (PSF) for high contrast imaging. center dotSegment Edges: The quality of segment edges impacts PSF for high-contrast imaging applications, contributes to stray light noise, and affects total collecting aperture. center dotSegment to Segment Gap Phasing: Segment phasing is critical for producing high-quality temporally-stable PSF. center dotIntegrated Model Validation: On-orbit performance is driven by mechanical & thermal stability. Compliance cannot be 100% tested, but relies on modeling. Because we cannot predict the future, AMTD is pursuing multiple design paths to provide the science community with options to enable either large aperture monolithic or segmented mirrors with clear engineering metrics traceable to science requirements

Description: AMTD is using a Science Driven Systems Engineering approach to develop Engineering Specifications based on Science Measurement Requirements and Implementation Constraints. Science requirements meet the needs of both Exoplanet and General Astrophysics science. Engineering Specifications are guiding our effort to mature to TRL-6 the critical technologies needed to produce 4-m or larger flight-qualified UVOIR mirrors by 2018 so that a viable mission can be considered by the 2020 Decadal Review.

Description: The Advance Mirror Technology Development (AMTD) project is in Phase 2 of a multiyear effort, initiated in FY12, to mature by at least a half TRL step six critical technologies required to enable 4 meter or larger UVOIR space telescope primary mirror assemblies for both general astrophysics and ultra-high contrast observations of exoplanets. AMTD uses a science-driven systems engineering approach. We mature technologies required to enable the highest priority science AND provide a high-performance low-cost low-risk system. To give the science community options, we are pursuing multiple technology paths. A key task is deriving engineering specifications for advanced normal-incidence monolithic and segmented mirror systems needed to enable both general astrophysics and ultra-high contrast observations of exoplanets missions as a function of potential launch vehicles and their mass and volume constraints. A key finding of this effort is that the science requires an 8 meter or larger aperture telescope