Description: The extent to which low-frequency (minor allele frequency (MAF) between 1-5%) and rare (MAF 〈/= 1%) variants contribute to complex traits and disease in the general population is mainly unknown. Bone mineral density (BMD) is highly heritable, a major predictor of osteoporotic fractures, and has been previously associated with common genetic variants, as well as rare, population-specific, coding variants. Here we identify novel non-coding genetic variants with large effects on BMD (ntotal = 53,236) and fracture (ntotal = 508,253) in individuals of European ancestry from the general population. Associations for BMD were derived from whole-genome sequencing (n = 2,882 from UK10K (ref. 10); a population-based genome sequencing consortium), whole-exome sequencing (n = 3,549), deep imputation of genotyped samples using a combined UK10K/1000 Genomes reference panel (n = 26,534), and de novo replication genotyping (n = 20,271). We identified a low-frequency non-coding variant near a novel locus, EN1, with an effect size fourfold larger than the mean of previously reported common variants for lumbar spine BMD (rs11692564(T), MAF = 1.6%, replication effect size = +0.20 s.d., Pmeta = 2 x 10(-14)), which was also associated with a decreased risk of fracture (odds ratio = 0.85; P = 2 x 10(-11); ncases = 98,742 and ncontrols = 409,511). Using an En1(cre/flox) mouse model, we observed that conditional loss of En1 results in low bone mass, probably as a consequence of high bone turnover. We also identified a novel low-frequency non-coding variant with large effects on BMD near WNT16 (rs148771817(T), MAF = 1.2%, replication effect size = +0.41 s.d., Pmeta = 1 x 10(-11)). In general, there was an excess of association signals arising from deleterious coding and conserved non-coding variants. These findings provide evidence that low-frequency non-coding variants have large effects on BMD and fracture, thereby providing rationale for whole-genome sequencing and improved imputation reference panels to study the genetic architecture of complex traits and disease in the general population.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4755714/" 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/PMC4755714/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zheng, Hou-Feng -- Forgetta, Vincenzo -- Hsu, Yi-Hsiang -- Estrada, Karol -- Rosello-Diez, Alberto -- Leo, Paul J -- Dahia, Chitra L -- Park-Min, Kyung Hyun -- Tobias, Jonathan H -- Kooperberg, Charles -- Kleinman, Aaron -- Styrkarsdottir, Unnur -- Liu, Ching-Ti -- Uggla, Charlotta -- Evans, Daniel S -- Nielson, Carrie M -- Walter, Klaudia -- Pettersson-Kymmer, Ulrika -- McCarthy, Shane -- Eriksson, Joel -- Kwan, Tony -- Jhamai, Mila -- Trajanoska, Katerina -- Memari, Yasin -- Min, Josine -- Huang, Jie -- Danecek, Petr -- Wilmot, Beth -- Li, Rui -- Chou, Wen-Chi -- Mokry, Lauren E -- Moayyeri, Alireza -- Claussnitzer, Melina -- Cheng, Chia-Ho -- Cheung, Warren -- Medina-Gomez, Carolina -- Ge, Bing -- Chen, Shu-Huang -- Choi, Kwangbom -- Oei, Ling -- Fraser, James -- Kraaij, Robert -- Hibbs, Matthew A -- Gregson, Celia L -- Paquette, Denis -- Hofman, Albert -- Wibom, Carl -- Tranah, Gregory J -- Marshall, Mhairi -- Gardiner, Brooke B -- Cremin, Katie -- Auer, Paul -- Hsu, Li -- Ring, Sue -- Tung, Joyce Y -- Thorleifsson, Gudmar -- Enneman, Anke W -- van Schoor, Natasja M -- de Groot, Lisette C P G M -- van der Velde, Nathalie -- Melin, Beatrice -- Kemp, John P -- Christiansen, Claus -- Sayers, Adrian -- Zhou, Yanhua -- Calderari, Sophie -- van Rooij, Jeroen -- Carlson, Chris -- Peters, Ulrike -- Berlivet, Soizik -- Dostie, Josee -- Uitterlinden, Andre G -- Williams, Stephen R -- Farber, Charles -- Grinberg, Daniel -- LaCroix, Andrea Z -- Haessler, Jeff -- Chasman, Daniel I -- Giulianini, Franco -- Rose, Lynda M -- Ridker, Paul M -- Eisman, John A -- Nguyen, Tuan V -- Center, Jacqueline R -- Nogues, Xavier -- Garcia-Giralt, Natalia -- Launer, Lenore L -- Gudnason, Vilmunder -- Mellstrom, Dan -- Vandenput, Liesbeth -- Amin, Najaf -- van Duijn, Cornelia M -- Karlsson, Magnus K -- Ljunggren, Osten -- Svensson, Olle -- Hallmans, Goran -- Rousseau, Francois -- Giroux, Sylvie -- Bussiere, Johanne -- Arp, Pascal P -- Koromani, Fjorda -- Prince, Richard L -- Lewis, Joshua R -- Langdahl, Bente L -- Hermann, A Pernille -- Jensen, Jens-Erik B -- Kaptoge, Stephen -- Khaw, Kay-Tee -- Reeve, Jonathan -- Formosa, Melissa M -- Xuereb-Anastasi, Angela -- Akesson, Kristina -- McGuigan, Fiona E -- Garg, Gaurav -- Olmos, Jose M -- Zarrabeitia, Maria T -- Riancho, Jose A -- Ralston, Stuart H -- Alonso, Nerea -- Jiang, Xi -- Goltzman, David -- Pastinen, Tomi -- Grundberg, Elin -- Gauguier, Dominique -- Orwoll, Eric S -- Karasik, David -- Davey-Smith, George -- AOGC Consortium -- Smith, Albert V -- Siggeirsdottir, Kristin -- Harris, Tamara B -- Zillikens, M Carola -- van Meurs, Joyce B J -- Thorsteinsdottir, Unnur -- Maurano, Matthew T -- Timpson, Nicholas J -- Soranzo, Nicole -- Durbin, Richard -- Wilson, Scott G -- Ntzani, Evangelia E -- Brown, Matthew A -- Stefansson, Kari -- Hinds, David A -- Spector, Tim -- Cupples, L Adrienne -- Ohlsson, Claes -- Greenwood, Celia M T -- UK10K Consortium -- Jackson, Rebecca D -- Rowe, David W -- Loomis, Cynthia A -- Evans, David M -- Ackert-Bicknell, Cheryl L -- Joyner, Alexandra L -- Duncan, Emma L -- Kiel, Douglas P -- Rivadeneira, Fernando -- Richards, J Brent -- G1000143/Medical Research Council/United Kingdom -- K01 AR062655/AR/NIAMS NIH HHS/ -- MC_UU_12013/3/Medical Research Council/United Kingdom -- R01 AG005394/AG/NIA NIH HHS/ -- R01 AG005407/AG/NIA NIH HHS/ -- R01 AG027574/AG/NIA NIH HHS/ -- R01 AG027576/AG/NIA NIH HHS/ -- R01 AR035582/AR/NIAMS NIH HHS/ -- R01 AR035583/AR/NIAMS NIH HHS/ -- RC2 AR058973/AR/NIAMS NIH HHS/ -- U01 AG018197/AG/NIA NIH HHS/ -- U01 AG042140/AG/NIA NIH HHS/ -- U01 AG042143/AG/NIA NIH HHS/ -- U01 AR045580/AR/NIAMS NIH HHS/ -- U01 AR045583/AR/NIAMS NIH HHS/ -- U01 AR045614/AR/NIAMS NIH HHS/ -- U01 AR045632/AR/NIAMS NIH HHS/ -- U01 AR045647/AR/NIAMS NIH HHS/ -- U01 AR045654/AR/NIAMS NIH HHS/ -- U01 AR066160/AR/NIAMS NIH HHS/ -- England -- Nature. 2015 Oct 1;526(7571):112-7. doi: 10.1038/nature14878. Epub 2015 Sep 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Departments of Medicine, Human Genetics, Epidemiology and Biostatistics, McGill University, Montreal H3A 1A2, Canada. ; Department of Medicine, Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montreal H3T 1E2, Canada. ; Institute for Aging Research, Hebrew SeniorLife, Boston, Massachusetts 02131, USA. ; Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA. ; Broad Institute of MIT and Harvard, Boston, Massachusetts 02115, USA. ; Department of Internal Medicine, Erasmus Medical Center, Rotterdam 3015GE, The Netherlands. ; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. ; Developmental Biology Program, Sloan Kettering Institute, New York, New York 10065, USA. ; The University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Brisbane 4102, Australia. ; Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, New York 10065, USA. ; Tissue Engineering, Regeneration and Repair Program, Hospital for Special Surgery, New York 10021, USA. ; Rheumatology Divison, Hospital for Special Surgery New York, New York 10021, USA. ; School of Clinical Science, University of Bristol, Bristol BS10 5NB, UK. ; MRC Integrative Epidemiology Unit, University of Bristol, Bristol BS8 2BN, UK. ; Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA. ; Department of Research, 23andMe, Mountain View, California 94041, USA. ; Department of Population Genomics, deCODE Genetics, Reykjavik IS-101, Iceland. ; Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts 02118, USA. ; Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg S-413 45, Sweden. ; California Pacific Medical Center Research Institute, San Francisco, California 94158, USA. ; Department of Public Health and Preventive Medicine, Oregon Health &Science University, Portland, Oregon 97239, USA. ; Bone &Mineral Unit, Oregon Health &Science University, Portland, Oregon 97239, USA. ; Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge CB10 1SA, UK. ; Departments of Pharmacology and Clinical Neurosciences, Umea University, Umea S-901 87, Sweden. ; Department of Public Health and Clinical Medicine, Umea University, Umea SE-901 87, Sweden. ; Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg S-413 45, Sweden. ; McGill University and Genome Quebec Innovation Centre, Montreal H3A 0G1, Canada. ; Department of Epidemiology, Erasmus Medical Center, Rotterdam 3015GE, The Netherlands. ; Oregon Clinical and Translational Research Institute, Oregon Health &Science University, Portland, Oregon 97239, USA. ; Department of Medical and Clinical Informatics, Oregon Health &Science University, Portland, Oregon 97239, USA. ; Farr Institute of Health Informatics Research, University College London, London NW1 2DA, UK. ; Department of Twin Research and Genetic Epidemiology, King's College London, London SE1 7EH, UK. ; Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, USA. ; Department of Human Genetics, McGill University, Montreal H3A 1B1, Canada. ; Netherlands Genomics Initiative (NGI)-sponsored Netherlands Consortium for Healthy Aging (NCHA), Leiden 2300RC, The Netherlands. ; Center for Musculoskeletal Research, University of Rochester, Rochester, New York 14642, USA. ; Department of Biochemistry and Goodman Cancer Research Center, McGill University, Montreal H3G 1Y6, Canada. ; Department of Computer Science, Trinity University, San Antonio, Texas 78212, USA. ; Musculoskeletal Research Unit, University of Bristol, Bristol BS10 5NB, UK. ; Department of Radiation Sciences, Umea University, Umea S-901 87, Sweden. ; School of Public Health, University of Wisconsin, Milwaukee, Wisconsin 53726, USA. ; School of Social and Community Medicine, University of Bristol, Bristol BS8 2BN, UK. ; Department of Statistics, deCODE Genetics, Reykjavik IS-101, Iceland. ; Department of Epidemiology and Biostatistics and the EMGO Institute for Health and Care Research, VU University Medical Center, Amsterdam 1007 MB, The Netherlands. ; Department of Human Nutrition, Wageningen University, Wageningen 6700 EV, The Netherlands. ; Department of Internal Medicine, Section Geriatrics, Academic Medical Center, Amsterdam 1105, The Netherlands. ; Nordic Bioscience, Herlev 2730, Denmark. ; Cordeliers Research Centre, INSERM UMRS 1138, Paris 75006, France. ; Institute of Cardiometabolism and Nutrition, University Pierre &Marie Curie, Paris 75013, France. ; Departments of Medicine (Cardiovascular Medicine), Centre for Public Health Genomics, University of Virginia, Charlottesville, Virginia 22908, USA. ; Department of Genetics, University of Barcelona, Barcelona 08028, Spain. ; U-720, Centre for Biomedical Network Research on Rare Diseases (CIBERER), Barcelona 28029, Spain. ; Department of Human Molecular Genetics, The Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona 08028, Spain. ; Women's Health Center of Excellence Family Medicine and Public Health, University of California - San Diego, San Diego, California 92093, USA. ; Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02215, USA. ; Osteoporosis &Bone Biology Program, Garvan Institute of Medical Research, Sydney 2010, Australia. ; School of Medicine Sydney, University of Notre Dame Australia, Sydney 6959, Australia. ; St. Vincent's Hospital &Clinical School, NSW University, Sydney 2010, Australia. ; Musculoskeletal Research Group, Institut Hospital del Mar d'Investigacions Mediques, Barcelona 08003, Spain. ; Cooperative Research Network on Aging and Fragility (RETICEF), Institute of Health Carlos III, 28029, Spain. ; Department of Internal Medicine, Hospital del Mar, Universitat Autonoma de Barcelona, Barcelona 08193, Spain. ; Neuroepidemiology Section, National Institute on Aging, National Institutes of Health, Bethesda, Maryland 20892, USA. ; Icelandic Heart Association, Kopavogur IS-201, Iceland. ; Faculty of Medicine, University of Iceland, Reykjavik IS-101, Iceland. ; Genetic epidemiology unit, Department of Epidemiology, Erasmus MC, Rotterdam 3000CA, The Netherlands. ; Department of Orthopaedics, Skane University Hospital Malmo 205 02, Sweden. ; Department of Medical Sciences, University of Uppsala, Uppsala 751 85, Sweden. ; Department of Surgical and Perioperative Sciences, Umea Unviersity, Umea 901 85, Sweden. ; Department of Molecular Biology, Medical Biochemistry and Pathology, Universite Laval, Quebec City G1V 0A6, Canada. ; Axe Sante des Populations et Pratiques Optimales en Sante, Centre de recherche du CHU de Quebec, Quebec City G1V 4G2, Canada. ; Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands 6009, Australia. ; Department of Medicine, University of Western Australia, Perth 6009, Australia. ; Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus C 8000, Denmark. ; Department of Endocrinology, Odense University Hospital, Odense C 5000, Denmark. ; Department of Endocrinology, Hvidovre University Hospital, Hvidovre 2650, Denmark. ; Clinical Gerontology Unit, University of Cambridge, Cambridge CB2 2QQ, UK. ; Medicine and Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK. ; Institute of Musculoskeletal Sciences, The Botnar Research Centre, University of Oxford, Oxford OX3 7LD, UK. ; Department of Applied Biomedical Science, Faculty of Health Sciences, University of Malta, Msida MSD 2080, Malta. ; Clinical and Molecular Osteoporosis Research Unit, Department of Clinical Sciences Malmo, Lund University, 205 02, Sweden. ; Department of Medicine and Psychiatry, University of Cantabria, Santander 39011, Spain. ; Department of Internal Medicine, Hospital U.M. Valdecilla- IDIVAL, Santander 39008, Spain. ; Department of Legal Medicine, University of Cantabria, Santander 39011, Spain. ; Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, Western General Hospital, University of Edinburgh, Edinburgh EH4 2XU, UK. ; Department of Reconstructive Sciences, College of Dental Medicine, University of Connecticut Health Center, Farmington, Connecticut 06030, USA. ; Department of Medicine and Physiology, McGill University, Montreal H4A 3J1, Canada. ; Department of Medicine, Oregon Health &Science University, Portland, Oregon 97239, USA. ; Faculty of Medicine in the Galilee, Bar-Ilan University, Safed 13010, Israel. ; Laboratory of Epidemiology, National Institute on Aging, National Institutes of Health, Bethesda, Maryland 20892, USA. ; Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA. ; School of Medicine and Pharmacology, University of Western Australia, Crawley 6009, Australia. ; Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina 45110, Greece. ; Department of Health Services, Policy and Practice, Brown University School of Public Health, Providence, Rhode Island 02903, USA. ; deCODE Genetics, Reykjavik IS-101, Iceland. ; Framingham Heart Study, Framingham, Massachusetts 01702, USA. ; Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal H3A 1A2, Canada. ; Department of Oncology, Gerald Bronfman Centre, McGill University, Montreal H2W 1S6, Canada. ; Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, The Ohio State University, Columbus, Ohio 43210, USA. ; The Ronald O. Perelman Department of Dermatology and Department of Cell Biology, New York University School of Medicine, New York, New York 10016, USA. ; Department of Diabetes and Endocrinology, Royal Brisbane and Women's Hospital, Brisbane 4029, Australia.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26367794" target="_blank"〉PubMed〈/a〉

Description: Gibbons are small arboreal apes that display an accelerated rate of evolutionary chromosomal rearrangement and occupy a key node in the primate phylogeny between Old World monkeys and great apes. Here we present the assembly and analysis of a northern white-cheeked gibbon (Nomascus leucogenys) genome. We describe the propensity for a gibbon-specific retrotransposon (LAVA) to insert into chromosome segregation genes and alter transcription by providing a premature termination site, suggesting a possible molecular mechanism for the genome plasticity of the gibbon lineage. We further show that the gibbon genera (Nomascus, Hylobates, Hoolock and Symphalangus) experienced a near-instantaneous radiation approximately 5 million years ago, coincident with major geographical changes in southeast Asia that caused cycles of habitat compression and expansion. Finally, we identify signatures of positive selection in genes important for forelimb development (TBX5) and connective tissues (COL1A1) that may have been involved in the adaptation of gibbons to their arboreal habitat.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4249732/" 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/PMC4249732/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Carbone, Lucia -- Harris, R Alan -- Gnerre, Sante -- Veeramah, Krishna R -- Lorente-Galdos, Belen -- Huddleston, John -- Meyer, Thomas J -- Herrero, Javier -- Roos, Christian -- Aken, Bronwen -- Anaclerio, Fabio -- Archidiacono, Nicoletta -- Baker, Carl -- Barrell, Daniel -- Batzer, Mark A -- Beal, Kathryn -- Blancher, Antoine -- Bohrson, Craig L -- Brameier, Markus -- Campbell, Michael S -- Capozzi, Oronzo -- Casola, Claudio -- Chiatante, Giorgia -- Cree, Andrew -- Damert, Annette -- de Jong, Pieter J -- Dumas, Laura -- Fernandez-Callejo, Marcos -- Flicek, Paul -- Fuchs, Nina V -- Gut, Ivo -- Gut, Marta -- Hahn, Matthew W -- Hernandez-Rodriguez, Jessica -- Hillier, LaDeana W -- Hubley, Robert -- Ianc, Bianca -- Izsvak, Zsuzsanna -- Jablonski, Nina G -- Johnstone, Laurel M -- Karimpour-Fard, Anis -- Konkel, Miriam K -- Kostka, Dennis -- Lazar, Nathan H -- Lee, Sandra L -- Lewis, Lora R -- Liu, Yue -- Locke, Devin P -- Mallick, Swapan -- Mendez, Fernando L -- Muffato, Matthieu -- Nazareth, Lynne V -- Nevonen, Kimberly A -- O'Bleness, Majesta -- Ochis, Cornelia -- Odom, Duncan T -- Pollard, Katherine S -- Quilez, Javier -- Reich, David -- Rocchi, Mariano -- Schumann, Gerald G -- Searle, Stephen -- Sikela, James M -- Skollar, Gabriella -- Smit, Arian -- Sonmez, Kemal -- ten Hallers, Boudewijn -- Terhune, Elizabeth -- Thomas, Gregg W C -- Ullmer, Brygg -- Ventura, Mario -- Walker, Jerilyn A -- Wall, Jeffrey D -- Walter, Lutz -- Ward, Michelle C -- Wheelan, Sarah J -- Whelan, Christopher W -- White, Simon -- Wilhelm, Larry J -- Woerner, August E -- Yandell, Mark -- Zhu, Baoli -- Hammer, Michael F -- Marques-Bonet, Tomas -- Eichler, Evan E -- Fulton, Lucinda -- Fronick, Catrina -- Muzny, Donna M -- Warren, Wesley C -- Worley, Kim C -- Rogers, Jeffrey -- Wilson, Richard K -- Gibbs, Richard A -- 095908/Wellcome Trust/United Kingdom -- 15603/Cancer Research UK/United Kingdom -- 260372/European Research Council/International -- HG002385/HG/NHGRI NIH HHS/ -- P30 AA019355/AA/NIAAA NIH HHS/ -- P30CA006973/CA/NCI NIH HHS/ -- P51 RR000163/RR/NCRR NIH HHS/ -- R01 GM059290/GM/NIGMS NIH HHS/ -- R01 GM59290/GM/NIGMS NIH HHS/ -- R01 HG002385/HG/NHGRI NIH HHS/ -- R01 HG002939/HG/NHGRI NIH HHS/ -- R01 HG005226/HG/NHGRI NIH HHS/ -- R01 MH081203/MH/NIMH NIH HHS/ -- R01_HG005226/HG/NHGRI NIH HHS/ -- T15 LM007088/LM/NLM NIH HHS/ -- U41 HG007497/HG/NHGRI NIH HHS/ -- U41 HG007497-01/HG/NHGRI NIH HHS/ -- U41HG007234/HG/NHGRI NIH HHS/ -- U54 HG003079/HG/NHGRI NIH HHS/ -- U54 HG003273/HG/NHGRI NIH HHS/ -- U54HG003273/HG/NHGRI NIH HHS/ -- WT095908/Wellcome Trust/United Kingdom -- WT098051/Wellcome Trust/United Kingdom -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Sep 11;513(7517):195-201. doi: 10.1038/nature13679.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Oregon Health &Science University, Department of Behavioral Neuroscience, 3181 SW Sam Jackson Park Road Portland, Oregon 97239, USA. [2] Oregon National Primate Research Center, Division of Neuroscience, 505 NW 185th Avenue, Beaverton, Oregon 97006, USA. [3] Oregon Health &Science University, Department of Molecular &Medical Genetics, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, USA. [4] Oregon Health &Science University, Bioinformatics and Computational Biology Division, Department of Medical Informatics &Clinical Epidemiology, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, USA. ; Baylor College of Medicine, Department of Molecular and Human Genetics, One Baylor Plaza, Houston, Texas 77030, USA. ; Nabsys, 60 Clifford Street, Providence, Rhode Island 02903, USA. ; 1] University of Arizona, ARL Division of Biotechnology, Tucson, Arizona 85721, USA. [2] Stony Brook University, Department of Ecology and Evolution, Stony Brook, New York 11790, USA. ; IBE, Institut de Biologia Evolutiva (UPF-CSIC), Universitat Pompeu Fabra, PRBB, Doctor Aiguader, 88, 08003 Barcelona, Spain. ; 1] Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA. [2] Howard Hughes Medical Institute, 1705 NE Pacific Street, Seattle, Washington 98195, USA. ; Oregon Health &Science University, Department of Behavioral Neuroscience, 3181 SW Sam Jackson Park Road Portland, Oregon 97239, USA. ; 1] European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK. [2] The Genome Analysis Centre, Norwich Research Park, Norwich NR4 7UH, UK. [3] Bill Lyons Informatics Center, UCL Cancer Institute, University College London, London WC1E 6DD, UK (J.He); Seven Bridges Genomics, Cambridge, Massachusetts 02138, USA (D.P.L.); Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA (F.L.M.); BioNano Genomics, San Diego, California 92121, USA (B.t.H.); University of Chicago, Department of Human Genetics, Chicago, Illinois 60637, USA (M.C.W.); Stanley Center for Psychiatric Research, Broad Institute, Cambridge, Massachusetts 02138, USA (C.W.W.); The CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China (B.Z.). ; Leibniz Institute for Primate Research, Gene Bank of Primates, German Primate Center, Gottingen 37077, Germany. ; 1] European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK. [2] European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK. ; University of Bari, Department of Biology, Via Orabona 4, 70125, Bari, Italy. ; Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA. ; Louisiana State University, Department of Biological Sciences, Baton Rouge, Louisiana 70803, USA. ; European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK. ; University of Paul Sabatier, Toulouse 31062, France. ; The Johns Hopkins University School of Medicine, Department of Oncology, Division of Biostatistics and Bioinformatics, Baltimore, Maryland 21205, USA. ; University of Utah, Salt Lake City, Utah 84112, USA. ; Texas A&M University, Department of Ecosystem Science and Management, College Station, Texas 77843, USA. ; Human Genome Sequencing Center, Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA. ; Babes-Bolyai-University, Institute for Interdisciplinary Research in Bio-Nano-Sciences, Molecular Biology Center, Cluj-Napoca 400084, Romania. ; Children's Hospital Oakland Research Institute, BACPAC Resources, Oakland, California 94609, USA. ; University of Colorado School of Medicine, Department of Biochemistry and Molecular Genetics, Aurora, Colorado 80045, USA. ; Max Delbruck Center for Molecular Medicine, Berlin 13125, Germany. ; Centro Nacional de Analisis Genomico (CNAG), Parc Cientific de Barcelona, Barcelona 08028, Spain. ; Indiana University, School of Informatics and Computing, Bloomington, Indiana 47408, USA. ; The Genome Center at Washington University, Washington University School of Medicine, 4444 Forest Park Avenue, Saint Louis, Missouri 63108, USA. ; Institute for Systems Biology, Seattle, Washington 98109-5234, USA. ; The Pennsylvania State University, Department of Anthropology, University Park, Pennsylvania 16802, USA. ; University of Arizona, ARL Division of Biotechnology, Tucson, Arizona 85721, USA. ; University of Pittsburgh School of Medicine, Department of Developmental Biology, Department of Computational and Systems Biology, Pittsburg, Pennsylvania 15261, USA. ; Oregon Health &Science University, Bioinformatics and Computational Biology Division, Department of Medical Informatics &Clinical Epidemiology, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, USA. ; 1] The Genome Center at Washington University, Washington University School of Medicine, 4444 Forest Park Avenue, Saint Louis, Missouri 63108, USA. [2] Bill Lyons Informatics Center, UCL Cancer Institute, University College London, London WC1E 6DD, UK (J.He); Seven Bridges Genomics, Cambridge, Massachusetts 02138, USA (D.P.L.); Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA (F.L.M.); BioNano Genomics, San Diego, California 92121, USA (B.t.H.); University of Chicago, Department of Human Genetics, Chicago, Illinois 60637, USA (M.C.W.); Stanley Center for Psychiatric Research, Broad Institute, Cambridge, Massachusetts 02138, USA (C.W.W.); The CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China (B.Z.). ; Harvard Medical School, Department of Genetics, Boston, Massachusetts 02115, USA. ; 1] University of Arizona, ARL Division of Biotechnology, Tucson, Arizona 85721, USA. [2] Bill Lyons Informatics Center, UCL Cancer Institute, University College London, London WC1E 6DD, UK (J.He); Seven Bridges Genomics, Cambridge, Massachusetts 02138, USA (D.P.L.); Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA (F.L.M.); BioNano Genomics, San Diego, California 92121, USA (B.t.H.); University of Chicago, Department of Human Genetics, Chicago, Illinois 60637, USA (M.C.W.); Stanley Center for Psychiatric Research, Broad Institute, Cambridge, Massachusetts 02138, USA (C.W.W.); The CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China (B.Z.). ; Oregon National Primate Research Center, Division of Neuroscience, 505 NW 185th Avenue, Beaverton, Oregon 97006, USA. ; 1] European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK. [2] University of Cambridge, Cancer Research UK-Cambridge Institute, Cambridge CB2 0RE, UK. ; 1] University of California, Gladstone Institutes, San Francisco, California 94158-226, USA. [2] Institute for Human Genetics, University of California, San Francisco, California 94143-0794, USA. [3] Division of Biostatistics, University of California, San Francisco, California 94143-0794, USA. ; Paul Ehrlich Institute, Division of Medical Biotechnology, 63225 Langen, Germany. ; European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK. ; Gibbon Conservation Center, 19100 Esguerra Rd, Santa Clarita, California 91350, USA. ; 1] Oregon Health &Science University, Bioinformatics and Computational Biology Division, Department of Medical Informatics &Clinical Epidemiology, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, USA. [2] Oregon Health &Science University, Center for Spoken Language Understanding, Institute on Development and Disability, Portland, Oregon 97239, USA. ; 1] Children's Hospital Oakland Research Institute, BACPAC Resources, Oakland, California 94609, USA. [2] Bill Lyons Informatics Center, UCL Cancer Institute, University College London, London WC1E 6DD, UK (J.He); Seven Bridges Genomics, Cambridge, Massachusetts 02138, USA (D.P.L.); Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA (F.L.M.); BioNano Genomics, San Diego, California 92121, USA (B.t.H.); University of Chicago, Department of Human Genetics, Chicago, Illinois 60637, USA (M.C.W.); Stanley Center for Psychiatric Research, Broad Institute, Cambridge, Massachusetts 02138, USA (C.W.W.); The CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China (B.Z.). ; Louisiana State University, School of Electrical Engineering and Computer Science, Baton Rouge, Louisiana 70803, USA. ; 1] Institute for Human Genetics, University of California, San Francisco, California 94143-0794, USA. [2] Division of Biostatistics, University of California, San Francisco, California 94143-0794, USA. ; 1] University of Cambridge, Cancer Research UK-Cambridge Institute, Cambridge CB2 0RE, UK. [2] Bill Lyons Informatics Center, UCL Cancer Institute, University College London, London WC1E 6DD, UK (J.He); Seven Bridges Genomics, Cambridge, Massachusetts 02138, USA (D.P.L.); Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA (F.L.M.); BioNano Genomics, San Diego, California 92121, USA (B.t.H.); University of Chicago, Department of Human Genetics, Chicago, Illinois 60637, USA (M.C.W.); Stanley Center for Psychiatric Research, Broad Institute, Cambridge, Massachusetts 02138, USA (C.W.W.); The CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China (B.Z.). ; 1] Oregon Health &Science University, Center for Spoken Language Understanding, Institute on Development and Disability, Portland, Oregon 97239, USA. [2] Bill Lyons Informatics Center, UCL Cancer Institute, University College London, London WC1E 6DD, UK (J.He); Seven Bridges Genomics, Cambridge, Massachusetts 02138, USA (D.P.L.); Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA (F.L.M.); BioNano Genomics, San Diego, California 92121, USA (B.t.H.); University of Chicago, Department of Human Genetics, Chicago, Illinois 60637, USA (M.C.W.); Stanley Center for Psychiatric Research, Broad Institute, Cambridge, Massachusetts 02138, USA (C.W.W.); The CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China (B.Z.). ; 1] IBE, Institut de Biologia Evolutiva (UPF-CSIC), Universitat Pompeu Fabra, PRBB, Doctor Aiguader, 88, 08003 Barcelona, Spain. [2] Centro Nacional de Analisis Genomico (CNAG), Parc Cientific de Barcelona, Barcelona 08028, Spain.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25209798" target="_blank"〉PubMed〈/a〉

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: Arising from M. A. Nowak, C. E. Tarnita & E. O. Wilson 466, 1057-1062 (2010); Nowak et al. reply. Nowak et al. argue that inclusive fitness theory has been of little value in explaining the natural world, and that it has led to negligible progress in explaining the evolution of eusociality. However, we believe that their arguments are based upon a misunderstanding of evolutionary theory and a misrepresentation of the empirical literature. We will focus our comments on three general issues.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3836173/" 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/PMC3836173/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Abbot, Patrick -- Abe, Jun -- Alcock, John -- Alizon, Samuel -- Alpedrinha, Joao A C -- Andersson, Malte -- Andre, Jean-Baptiste -- van Baalen, Minus -- Balloux, Francois -- Balshine, Sigal -- Barton, Nick -- Beukeboom, Leo W -- Biernaskie, Jay M -- Bilde, Trine -- Borgia, Gerald -- Breed, Michael -- Brown, Sam -- Bshary, Redouan -- Buckling, Angus -- Burley, Nancy T -- Burton-Chellew, Max N -- Cant, Michael A -- Chapuisat, Michel -- Charnov, Eric L -- Clutton-Brock, Tim -- Cockburn, Andrew -- Cole, Blaine J -- Colegrave, Nick -- Cosmides, Leda -- Couzin, Iain D -- Coyne, Jerry A -- Creel, Scott -- Crespi, Bernard -- Curry, Robert L -- Dall, Sasha R X -- Day, Troy -- Dickinson, Janis L -- Dugatkin, Lee Alan -- El Mouden, Claire -- Emlen, Stephen T -- Evans, Jay -- Ferriere, Regis -- Field, Jeremy -- Foitzik, Susanne -- Foster, Kevin -- Foster, William A -- Fox, Charles W -- Gadau, Juergen -- Gandon, Sylvain -- Gardner, Andy -- Gardner, Michael G -- Getty, Thomas -- Goodisman, Michael A D -- Grafen, Alan -- Grosberg, Rick -- Grozinger, Christina M -- Gouyon, Pierre-Henri -- Gwynne, Darryl -- Harvey, Paul H -- Hatchwell, Ben J -- Heinze, Jurgen -- Helantera, Heikki -- Helms, Ken R -- Hill, Kim -- Jiricny, Natalie -- Johnstone, Rufus A -- Kacelnik, Alex -- Kiers, E Toby -- Kokko, Hanna -- Komdeur, Jan -- Korb, Judith -- Kronauer, Daniel -- Kummerli, Rolf -- Lehmann, Laurent -- Linksvayer, Timothy A -- Lion, Sebastien -- Lyon, Bruce -- Marshall, James A R -- McElreath, Richard -- Michalakis, Yannis -- Michod, Richard E -- Mock, Douglas -- Monnin, Thibaud -- Montgomerie, Robert -- Moore, Allen J -- Mueller, Ulrich G -- Noe, Ronald -- Okasha, Samir -- Pamilo, Pekka -- Parker, Geoff A -- Pedersen, Jes S -- Pen, Ido -- Pfennig, David -- Queller, David C -- Rankin, Daniel J -- Reece, Sarah E -- Reeve, Hudson K -- Reuter, Max -- Roberts, Gilbert -- Robson, Simon K A -- Roze, Denis -- Rousset, Francois -- Rueppell, Olav -- Sachs, Joel L -- Santorelli, Lorenzo -- Schmid-Hempel, Paul -- Schwarz, Michael P -- Scott-Phillips, Tom -- Shellmann-Sherman, Janet -- Sherman, Paul W -- Shuker, David M -- Smith, Jeff -- Spagna, Joseph C -- Strassmann, Beverly -- Suarez, Andrew V -- Sundstrom, Liselotte -- Taborsky, Michael -- Taylor, Peter -- Thompson, Graham -- Tooby, John -- Tsutsui, Neil D -- Tsuji, Kazuki -- Turillazzi, Stefano -- Ubeda, Francisco -- Vargo, Edward L -- Voelkl, Bernard -- Wenseleers, Tom -- West, Stuart A -- West-Eberhard, Mary Jane -- Westneat, David F -- Wiernasz, Diane C -- Wild, Geoff -- Wrangham, Richard -- Young, Andrew J -- Zeh, David W -- Zeh, Jeanne A -- Zink, Andrew -- BB/H022716/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- England -- Nature. 2011 Mar 24;471(7339):E1-4; author reply E9-10. doi: 10.1038/nature09831.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21430721" target="_blank"〉PubMed〈/a〉

Description: For 10,000 years pigs and humans have shared a close and complex relationship. From domestication to modern breeding practices, humans have shaped the genomes of domestic pigs. Here we present the assembly and analysis of the genome sequence of a female domestic Duroc pig (Sus scrofa) and a comparison with the genomes of wild and domestic pigs from Europe and Asia. Wild pigs emerged in South East Asia and subsequently spread across Eurasia. Our results reveal a deep phylogenetic split between European and Asian wild boars approximately 1 million years ago, and a selective sweep analysis indicates selection on genes involved in RNA processing and regulation. Genes associated with immune response and olfaction exhibit fast evolution. Pigs have the largest repertoire of functional olfactory receptor genes, reflecting the importance of smell in this scavenging animal. The pig genome sequence provides an important resource for further improvements of this important livestock species, and our identification of many putative disease-causing variants extends the potential of the pig as a biomedical model.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3566564/" 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/PMC3566564/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Groenen, Martien A M -- Archibald, Alan L -- Uenishi, Hirohide -- Tuggle, Christopher K -- Takeuchi, Yasuhiro -- Rothschild, Max F -- Rogel-Gaillard, Claire -- Park, Chankyu -- Milan, Denis -- Megens, Hendrik-Jan -- Li, Shengting -- Larkin, Denis M -- Kim, Heebal -- Frantz, Laurent A F -- Caccamo, Mario -- Ahn, Hyeonju -- Aken, Bronwen L -- Anselmo, Anna -- Anthon, Christian -- Auvil, Loretta -- Badaoui, Bouabid -- Beattie, Craig W -- Bendixen, Christian -- Berman, Daniel -- Blecha, Frank -- Blomberg, Jonas -- Bolund, Lars -- Bosse, Mirte -- Botti, Sara -- Bujie, Zhan -- Bystrom, Megan -- Capitanu, Boris -- Carvalho-Silva, Denise -- Chardon, Patrick -- Chen, Celine -- Cheng, Ryan -- Choi, Sang-Haeng -- Chow, William -- Clark, Richard C -- Clee, Christopher -- Crooijmans, Richard P M A -- Dawson, Harry D -- Dehais, Patrice -- De Sapio, Fioravante -- Dibbits, Bert -- Drou, Nizar -- Du, Zhi-Qiang -- Eversole, Kellye -- Fadista, Joao -- Fairley, Susan -- Faraut, Thomas -- Faulkner, Geoffrey J -- Fowler, Katie E -- Fredholm, Merete -- Fritz, Eric -- Gilbert, James G R -- Giuffra, Elisabetta -- Gorodkin, Jan -- Griffin, Darren K -- Harrow, Jennifer L -- Hayward, Alexander -- Howe, Kerstin -- Hu, Zhi-Liang -- Humphray, Sean J -- Hunt, Toby -- Hornshoj, Henrik -- Jeon, Jin-Tae -- Jern, Patric -- Jones, Matthew -- Jurka, Jerzy -- Kanamori, Hiroyuki -- Kapetanovic, Ronan -- Kim, Jaebum -- Kim, Jae-Hwan -- Kim, Kyu-Won -- Kim, Tae-Hun -- Larson, Greger -- Lee, Kyooyeol -- Lee, Kyung-Tai -- Leggett, Richard -- Lewin, Harris A -- Li, Yingrui -- Liu, Wansheng -- Loveland, Jane E -- Lu, Yao -- Lunney, Joan K -- Ma, Jian -- Madsen, Ole -- Mann, Katherine -- Matthews, Lucy -- McLaren, Stuart -- Morozumi, Takeya -- Murtaugh, Michael P -- Narayan, Jitendra -- Nguyen, Dinh Truong -- Ni, Peixiang -- Oh, Song-Jung -- Onteru, Suneel -- Panitz, Frank -- Park, Eung-Woo -- Park, Hong-Seog -- Pascal, Geraldine -- Paudel, Yogesh -- Perez-Enciso, Miguel -- Ramirez-Gonzalez, Ricardo -- Reecy, James M -- Rodriguez-Zas, Sandra -- Rohrer, Gary A -- Rund, Lauretta -- Sang, Yongming -- Schachtschneider, Kyle -- Schraiber, Joshua G -- Schwartz, John -- Scobie, Linda -- Scott, Carol -- Searle, Stephen -- Servin, Bertrand -- Southey, Bruce R -- Sperber, Goran -- Stadler, Peter -- Sweedler, Jonathan V -- Tafer, Hakim -- Thomsen, Bo -- Wali, Rashmi -- Wang, Jian -- Wang, Jun -- White, Simon -- Xu, Xun -- Yerle, Martine -- Zhang, Guojie -- Zhang, Jianguo -- Zhang, Jie -- Zhao, Shuhong -- Rogers, Jane -- Churcher, Carol -- Schook, Lawrence B -- 095908/Wellcome Trust/United Kingdom -- 249894/European Research Council/International -- 5 P41 LM006252/LM/NLM NIH HHS/ -- 5 P41LM006252/LM/NLM NIH HHS/ -- BB/E010520/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- BB/E010520/2/Biotechnology and Biological Sciences Research Council/United Kingdom -- BB/E010768/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- BB/E011640/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- BB/G004013/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- BB/H005935/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- BB/I025328/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- G0900950/Medical Research Council/United Kingdom -- P20-RR017686/RR/NCRR NIH HHS/ -- P30 DA018310/DA/NIDA NIH HHS/ -- R13 RR020283A/RR/NCRR NIH HHS/ -- R13 RR032267A/RR/NCRR NIH HHS/ -- R21 DA027548/DA/NIDA NIH HHS/ -- R21 HG006464/HG/NHGRI NIH HHS/ -- T32 AI083196/AI/NIAID NIH HHS/ -- England -- Nature. 2012 Nov 15;491(7424):393-8. doi: 10.1038/nature11622.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Animal Breeding and Genomics Centre, Wageningen University, De Elst 1, 6708 WD, Wageningen, The Netherlands. martien.groenen@wur.nl〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23151582" target="_blank"〉PubMed〈/a〉

Description: Pancreatic cancer is a highly lethal malignancy with few effective therapies. We performed exome sequencing and copy number analysis to define genomic aberrations in a prospectively accrued clinical cohort (n = 142) of early (stage I and II) sporadic pancreatic ductal adenocarcinoma. Detailed analysis of 99 informative tumours identified substantial heterogeneity with 2,016 non-silent mutations and 1,628 copy-number variations. We define 16 significantly mutated genes, reaffirming known mutations (KRAS, TP53, CDKN2A, SMAD4, MLL3, TGFBR2, ARID1A and SF3B1), and uncover novel mutated genes including additional genes involved in chromatin modification (EPC1 and ARID2), DNA damage repair (ATM) and other mechanisms (ZIM2, MAP2K4, NALCN, SLC16A4 and MAGEA6). Integrative analysis with in vitro functional data and animal models provided supportive evidence for potential roles for these genetic aberrations in carcinogenesis. Pathway-based analysis of recurrently mutated genes recapitulated clustering in core signalling pathways in pancreatic ductal adenocarcinoma, and identified new mutated genes in each pathway. We also identified frequent and diverse somatic aberrations in genes described traditionally as embryonic regulators of axon guidance, particularly SLIT/ROBO signalling, which was also evident in murine Sleeping Beauty transposon-mediated somatic mutagenesis models of pancreatic cancer, providing further supportive evidence for the potential involvement of axon guidance genes in pancreatic carcinogenesis.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3530898/" 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/PMC3530898/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Biankin, Andrew V -- Waddell, Nicola -- Kassahn, Karin S -- Gingras, Marie-Claude -- Muthuswamy, Lakshmi B -- Johns, Amber L -- Miller, David K -- Wilson, Peter J -- Patch, Ann-Marie -- Wu, Jianmin -- Chang, David K -- Cowley, Mark J -- Gardiner, Brooke B -- Song, Sarah -- Harliwong, Ivon -- Idrisoglu, Senel -- Nourse, Craig -- Nourbakhsh, Ehsan -- Manning, Suzanne -- Wani, Shivangi -- Gongora, Milena -- Pajic, Marina -- Scarlett, Christopher J -- Gill, Anthony J -- Pinho, Andreia V -- Rooman, Ilse -- Anderson, Matthew -- Holmes, Oliver -- Leonard, Conrad -- Taylor, Darrin -- Wood, Scott -- Xu, Qinying -- Nones, Katia -- Fink, J Lynn -- Christ, Angelika -- Bruxner, Tim -- Cloonan, Nicole -- Kolle, Gabriel -- Newell, Felicity -- Pinese, Mark -- Mead, R Scott -- Humphris, Jeremy L -- Kaplan, Warren -- Jones, Marc D -- Colvin, Emily K -- Nagrial, Adnan M -- Humphrey, Emily S -- Chou, Angela -- Chin, Venessa T -- Chantrill, Lorraine A -- Mawson, Amanda -- Samra, Jaswinder S -- Kench, James G -- Lovell, Jessica A -- Daly, Roger J -- Merrett, Neil D -- Toon, Christopher -- Epari, Krishna -- Nguyen, Nam Q -- Barbour, Andrew -- Zeps, Nikolajs -- Australian Pancreatic Cancer Genome Initiative -- Kakkar, Nipun -- Zhao, Fengmei -- Wu, Yuan Qing -- Wang, Min -- Muzny, Donna M -- Fisher, William E -- Brunicardi, F Charles -- Hodges, Sally E -- Reid, Jeffrey G -- Drummond, Jennifer -- Chang, Kyle -- Han, Yi -- Lewis, Lora R -- Dinh, Huyen -- Buhay, Christian J -- Beck, Timothy -- Timms, Lee -- Sam, Michelle -- Begley, Kimberly -- Brown, Andrew -- Pai, Deepa -- Panchal, Ami -- Buchner, Nicholas -- De Borja, Richard -- Denroche, Robert E -- Yung, Christina K -- Serra, Stefano -- Onetto, Nicole -- Mukhopadhyay, Debabrata -- Tsao, Ming-Sound -- Shaw, Patricia A -- Petersen, Gloria M -- Gallinger, Steven -- Hruban, Ralph H -- Maitra, Anirban -- Iacobuzio-Donahue, Christine A -- Schulick, Richard D -- Wolfgang, Christopher L -- Morgan, Richard A -- Lawlor, Rita T -- Capelli, Paola -- Corbo, Vincenzo -- Scardoni, Maria -- Tortora, Giampaolo -- Tempero, Margaret A -- Mann, Karen M -- Jenkins, Nancy A -- Perez-Mancera, Pedro A -- Adams, David J -- Largaespada, David A -- Wessels, Lodewyk F A -- Rust, Alistair G -- Stein, Lincoln D -- Tuveson, David A -- Copeland, Neal G -- Musgrove, Elizabeth A -- Scarpa, Aldo -- Eshleman, James R -- Hudson, Thomas J -- Sutherland, Robert L -- Wheeler, David A -- Pearson, John V -- McPherson, John D -- Gibbs, Richard A -- Grimmond, Sean M -- 13031/Cancer Research UK/United Kingdom -- 2P50CA101955/CA/NCI NIH HHS/ -- P01CA134292/CA/NCI NIH HHS/ -- P50 CA101955/CA/NCI NIH HHS/ -- P50 CA102701/CA/NCI NIH HHS/ -- P50CA062924/CA/NCI NIH HHS/ -- R01 CA097075/CA/NCI NIH HHS/ -- R01 CA97075/CA/NCI NIH HHS/ -- U54 HG003273/HG/NHGRI NIH HHS/ -- Cancer Research UK/United Kingdom -- Wellcome Trust/United Kingdom -- England -- Nature. 2012 Nov 15;491(7424):399-405. doi: 10.1038/nature11547. Epub 2012 Oct 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Kinghorn Cancer Centre, 370 Victoria Street, Darlinghurst, Sydney, New South Wales 2010, Australia.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23103869" target="_blank"〉PubMed〈/a〉

Description: Integrated genomic analysis of 456 pancreatic ductal adenocarcinomas identified 32 recurrently mutated genes that aggregate into 10 pathways: KRAS, TGF-beta, WNT, NOTCH, ROBO/SLIT signalling, G1/S transition, SWI-SNF, chromatin modification, DNA repair and RNA processing. Expression analysis defined 4 subtypes: (1) squamous; (2) pancreatic progenitor; (3) immunogenic; and (4) aberrantly differentiated endocrine exocrine (ADEX) that correlate with histopathological characteristics. Squamous tumours are enriched for TP53 and KDM6A mutations, upregulation of the TP63N transcriptional network, hypermethylation of pancreatic endodermal cell-fate determining genes and have a poor prognosis. Pancreatic progenitor tumours preferentially express genes involved in early pancreatic development (FOXA2/3, PDX1 and MNX1). ADEX tumours displayed upregulation of genes that regulate networks involved in KRAS activation, exocrine (NR5A2 and RBPJL), and endocrine differentiation (NEUROD1 and NKX2-2). Immunogenic tumours contained upregulated immune networks including pathways involved in acquired immune suppression. These data infer differences in the molecular evolution of pancreatic cancer subtypes and identify opportunities for therapeutic development.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bailey, Peter -- Chang, David K -- Nones, Katia -- Johns, Amber L -- Patch, Ann-Marie -- Gingras, Marie-Claude -- Miller, David K -- Christ, Angelika N -- Bruxner, Tim J C -- Quinn, Michael C -- Nourse, Craig -- Murtaugh, L Charles -- Harliwong, Ivon -- Idrisoglu, Senel -- Manning, Suzanne -- Nourbakhsh, Ehsan -- Wani, Shivangi -- Fink, Lynn -- Holmes, Oliver -- Chin, Venessa -- Anderson, Matthew J -- Kazakoff, Stephen -- Leonard, Conrad -- Newell, Felicity -- Waddell, Nick -- Wood, Scott -- Xu, Qinying -- Wilson, Peter J -- Cloonan, Nicole -- Kassahn, Karin S -- Taylor, Darrin -- Quek, Kelly -- Robertson, Alan -- Pantano, Lorena -- Mincarelli, Laura -- Sanchez, Luis N -- Evers, Lisa -- Wu, Jianmin -- Pinese, Mark -- Cowley, Mark J -- Jones, Marc D -- Colvin, Emily K -- Nagrial, Adnan M -- Humphrey, Emily S -- Chantrill, Lorraine A -- Mawson, Amanda -- Humphris, Jeremy -- Chou, Angela -- Pajic, Marina -- Scarlett, Christopher J -- Pinho, Andreia V -- Giry-Laterriere, Marc -- Rooman, Ilse -- Samra, Jaswinder S -- Kench, James G -- Lovell, Jessica A -- Merrett, Neil D -- Toon, Christopher W -- Epari, Krishna -- Nguyen, Nam Q -- Barbour, Andrew -- Zeps, Nikolajs -- Moran-Jones, Kim -- Jamieson, Nigel B -- Graham, Janet S -- Duthie, Fraser -- Oien, Karin -- Hair, Jane -- Grutzmann, Robert -- Maitra, Anirban -- Iacobuzio-Donahue, Christine A -- Wolfgang, Christopher L -- Morgan, Richard A -- Lawlor, Rita T -- Corbo, Vincenzo -- Bassi, Claudio -- Rusev, Borislav -- Capelli, Paola -- Salvia, Roberto -- Tortora, Giampaolo -- Mukhopadhyay, Debabrata -- Petersen, Gloria M -- Australian Pancreatic Cancer Genome Initiative -- Munzy, Donna M -- Fisher, William E -- Karim, Saadia A -- Eshleman, James R -- Hruban, Ralph H -- Pilarsky, Christian -- Morton, Jennifer P -- Sansom, Owen J -- Scarpa, Aldo -- Musgrove, Elizabeth A -- Bailey, Ulla-Maja Hagbo -- Hofmann, Oliver -- Sutherland, Robert L -- Wheeler, David A -- Gill, Anthony J -- Gibbs, Richard A -- Pearson, John V -- Waddell, Nicola -- Biankin, Andrew V -- Grimmond, Sean M -- 103721/Z/14/Z/Wellcome Trust/United Kingdom -- A12481/Cancer Research UK/United Kingdom -- A18076/Cancer Research UK/United Kingdom -- C29717/A17263/Cancer Research UK/United Kingdom -- England -- Nature. 2016 Mar 3;531(7592):47-52. doi: 10.1038/nature16965. Epub 2016 Feb 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia. ; Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK. ; The Kinghorn Cancer Centre, 370 Victoria St, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia. ; Department of Surgery, Bankstown Hospital, Eldridge Road, Bankstown, Sydney, New South Wales 2200, Australia. ; South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Liverpool, New South Wales 2170, Australia. ; QIMR Berghofer Medical Research Institute, Herston, Queensland 4006, Australia. ; Department of Molecular and Human Genetics, Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA. ; Michael DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas 77030, USA. ; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA. ; Department of Human Genetics, University of Utah, Salt Lake City, Utah 84112, USA. ; Genetic and Molecular Pathology, SA Pathology, Adelaide, South Australia 5000, Australia. ; School of Biological Sciences, The University of Adelaide, Adelaide, South Australia 5000, Australia. ; Harvard Chan Bioinformatics Core, Harvard T. H. Chan School of Public Health, Boston, Massachusetts 02115, USA. ; Macarthur Cancer Therapy Centre, Campbelltown Hospital, New South Wales 2560, Australia. ; Department of Pathology. SydPath, St Vincent's Hospital, Sydney, NSW 2010, Australia. ; St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, New South Wales 2052, Australia. ; School of Environmental &Life Sciences, University of Newcastle, Ourimbah, New South Wales 2258, Australia. ; Department of Surgery, Royal North Shore Hospital, St Leonards, Sydney, New South Wales 2065, Australia. ; University of Sydney, Sydney, New South Wales 2006, Australia. ; Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown New South Wales 2050, Australia. ; School of Medicine, University of Western Sydney, Penrith, New South Wales 2175, Australia. ; Fiona Stanley Hospital, Robin Warren Drive, Murdoch, Western Australia 6150, Australia. ; Department of Gastroenterology, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia 5000, Australia. ; Department of Surgery, Princess Alexandra Hospital, Ipswich Rd, Woollongabba, Queensland 4102, Australia. ; School of Surgery M507, University of Western Australia, 35 Stirling Hwy, Nedlands 6009, Australia and St John of God Pathology, 12 Salvado Rd, Subiaco, Western Australia 6008, Australia. ; Academic Unit of Surgery, School of Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow Royal Infirmary, Glasgow G4 OSF, UK. ; West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow G31 2ER, UK. ; Department of Medical Oncology, Beatson West of Scotland Cancer Centre, 1053 Great Western Road, Glasgow G12 0YN, UK. ; Department of Pathology, Southern General Hospital, Greater Glasgow &Clyde NHS, Glasgow G51 4TF, UK. ; GGC Bio-repository, Pathology Department, Southern General Hospital, 1345 Govan Road, Glasgow G51 4TY, UK. ; Department of Surgery, TU Dresden, Fetscherstr. 74, 01307 Dresden, Germany. ; Departments of Pathology and Translational Molecular Pathology, UT MD Anderson Cancer Center, Houston Texas 77030, USA. ; The David M. Rubenstein Pancreatic Cancer Research Center and Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ; Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA. ; Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA. ; ARC-Net Applied Research on Cancer Centre, University and Hospital Trust of Verona, Verona 37134, Italy. ; Department of Pathology and Diagnostics, University of Verona, Verona 37134, Italy. ; Department of Surgery, Pancreas Institute, University and Hospital Trust of Verona, Verona 37134, Italy. ; Department of Medical Oncology, Comprehensive Cancer Centre, University and Hospital Trust of Verona, Verona 37134, Italy. ; Mayo Clinic, Rochester, Minnesota 55905, USA. ; Elkins Pancreas Center, Baylor College of Medicine, One Baylor Plaza, MS226, Houston, Texas 77030-3411, USA. ; Cancer Research UK Beatson Institute, Glasgow G61 1BD, UK. ; Institute for Cancer Science, University of Glasgow, Glasgow G12 8QQ, UK. ; University of Melbourne, Parkville, Victoria 3010, Australia.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26909576" target="_blank"〉PubMed〈/a〉

Description: Anaemia is a chief determinant of global ill health, contributing to cognitive impairment, growth retardation and impaired physical capacity. To understand further the genetic factors influencing red blood cells, we carried out a genome-wide association study of haemoglobin concentration and related parameters in up to 135,367 individuals. Here we identify 75 independent genetic loci associated with one or more red blood cell phenotypes at P 〈 10(-8), which together explain 4-9% of the phenotypic variance per trait. Using expression quantitative trait loci and bioinformatic strategies, we identify 121 candidate genes enriched in functions relevant to red blood cell biology. The candidate genes are expressed preferentially in red blood cell precursors, and 43 have haematopoietic phenotypes in Mus musculus or Drosophila melanogaster. Through open-chromatin and coding-variant analyses we identify potential causal genetic variants at 41 loci. Our findings provide extensive new insights into genetic mechanisms and biological pathways controlling red blood cell formation and function.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3623669/" 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/PMC3623669/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉van der Harst, Pim -- Zhang, Weihua -- Mateo Leach, Irene -- Rendon, Augusto -- Verweij, Niek -- Sehmi, Joban -- Paul, Dirk S -- Elling, Ulrich -- Allayee, Hooman -- Li, Xinzhong -- Radhakrishnan, Aparna -- Tan, Sian-Tsung -- Voss, Katrin -- Weichenberger, Christian X -- Albers, Cornelis A -- Al-Hussani, Abtehale -- Asselbergs, Folkert W -- Ciullo, Marina -- Danjou, Fabrice -- Dina, Christian -- Esko, Tonu -- Evans, David M -- Franke, Lude -- Gogele, Martin -- Hartiala, Jaana -- Hersch, Micha -- Holm, Hilma -- Hottenga, Jouke-Jan -- Kanoni, Stavroula -- Kleber, Marcus E -- Lagou, Vasiliki -- Langenberg, Claudia -- Lopez, Lorna M -- Lyytikainen, Leo-Pekka -- Melander, Olle -- Murgia, Federico -- Nolte, Ilja M -- O'Reilly, Paul F -- Padmanabhan, Sandosh -- Parsa, Afshin -- Pirastu, Nicola -- Porcu, Eleonora -- Portas, Laura -- Prokopenko, Inga -- Ried, Janina S -- Shin, So-Youn -- Tang, Clara S -- Teumer, Alexander -- Traglia, Michela -- Ulivi, Sheila -- Westra, Harm-Jan -- Yang, Jian -- Zhao, Jing Hua -- Anni, Franco -- Abdellaoui, Abdel -- Attwood, Antony -- Balkau, Beverley -- Bandinelli, Stefania -- Bastardot, Francois -- Benyamin, Beben -- Boehm, Bernhard O -- Cookson, William O -- Das, Debashish -- de Bakker, Paul I W -- de Boer, Rudolf A -- de Geus, Eco J C -- de Moor, Marleen H -- Dimitriou, Maria -- Domingues, Francisco S -- Doring, Angela -- Engstrom, Gunnar -- Eyjolfsson, Gudmundur Ingi -- Ferrucci, Luigi -- Fischer, Krista -- Galanello, Renzo -- Garner, Stephen F -- Genser, Bernd -- Gibson, Quince D -- Girotto, Giorgia -- Gudbjartsson, Daniel Fannar -- Harris, Sarah E -- Hartikainen, Anna-Liisa -- Hastie, Claire E -- Hedblad, Bo -- Illig, Thomas -- Jolley, Jennifer -- Kahonen, Mika -- Kema, Ido P -- Kemp, John P -- Liang, Liming -- Lloyd-Jones, Heather -- Loos, Ruth J F -- Meacham, Stuart -- Medland, Sarah E -- Meisinger, Christa -- Memari, Yasin -- Mihailov, Evelin -- Miller, Kathy -- Moffatt, Miriam F -- Nauck, Matthias -- Novatchkova, Maria -- Nutile, Teresa -- Olafsson, Isleifur -- Onundarson, Pall T -- Parracciani, Debora -- Penninx, Brenda W -- Perseu, Lucia -- Piga, Antonio -- Pistis, Giorgio -- Pouta, Anneli -- Puc, Ursula -- Raitakari, Olli -- Ring, Susan M -- Robino, Antonietta -- Ruggiero, Daniela -- Ruokonen, Aimo -- Saint-Pierre, Aude -- Sala, Cinzia -- Salumets, Andres -- Sambrook, Jennifer -- Schepers, Hein -- Schmidt, Carsten Oliver -- Sillje, Herman H W -- Sladek, Rob -- Smit, Johannes H -- Starr, John M -- Stephens, Jonathan -- Sulem, Patrick -- Tanaka, Toshiko -- Thorsteinsdottir, Unnur -- Tragante, Vinicius -- van Gilst, Wiek H -- van Pelt, L Joost -- van Veldhuisen, Dirk J -- Volker, Uwe -- Whitfield, John B -- Willemsen, Gonneke -- Winkelmann, Bernhard R -- Wirnsberger, Gerald -- Algra, Ale -- Cucca, Francesco -- d'Adamo, Adamo Pio -- Danesh, John -- Deary, Ian J -- Dominiczak, Anna F -- Elliott, Paul -- Fortina, Paolo -- Froguel, Philippe -- Gasparini, Paolo -- Greinacher, Andreas -- Hazen, Stanley L -- Jarvelin, Marjo-Riitta -- Khaw, Kay Tee -- Lehtimaki, Terho -- Maerz, Winfried -- Martin, Nicholas G -- Metspalu, Andres -- Mitchell, Braxton D -- Montgomery, Grant W -- Moore, Carmel -- Navis, Gerjan -- Pirastu, Mario -- Pramstaller, Peter P -- Ramirez-Solis, Ramiro -- Schadt, Eric -- Scott, James -- Shuldiner, Alan R -- Smith, George Davey -- Smith, J Gustav -- Snieder, Harold -- Sorice, Rossella -- Spector, Tim D -- Stefansson, Kari -- Stumvoll, Michael -- Tang, W H Wilson -- Toniolo, Daniela -- Tonjes, Anke -- Visscher, Peter M -- Vollenweider, Peter -- Wareham, Nicholas J -- Wolffenbuttel, Bruce H R -- Boomsma, Dorret I -- Beckmann, Jacques S -- Dedoussis, George V -- Deloukas, Panos -- Ferreira, Manuel A -- Sanna, Serena -- Uda, Manuela -- Hicks, Andrew A -- Penninger, Josef Martin -- Gieger, Christian -- Kooner, Jaspal S -- Ouwehand, Willem H -- Soranzo, Nicole -- Chambers, John C -- 092731/Wellcome Trust/United Kingdom -- 097117/Wellcome Trust/United Kingdom -- 14136/Cancer Research UK/United Kingdom -- CZB/4/505/Chief Scientist Office/United Kingdom -- ETM/55/Chief Scientist Office/United Kingdom -- G0600705/Medical Research Council/United Kingdom -- G0700704/Medical Research Council/United Kingdom -- G0801056/Medical Research Council/United Kingdom -- G1000143/Medical Research Council/United Kingdom -- G1002084/Medical Research Council/United Kingdom -- G9815508/Medical Research Council/United Kingdom -- HHSN268201100005C/HL/NHLBI NIH HHS/ -- HHSN268201100006C/HL/NHLBI NIH HHS/ -- HHSN268201100007C/HL/NHLBI NIH HHS/ -- HHSN268201100008C/HL/NHLBI NIH HHS/ -- HHSN268201100009C/HL/NHLBI NIH HHS/ -- HHSN268201100010C/HL/NHLBI NIH HHS/ -- HHSN268201100011C/HL/NHLBI NIH HHS/ -- HHSN268201100012C/HL/NHLBI NIH HHS/ -- HHSN271201100005C/DA/NIDA NIH HHS/ -- K12 RR023250/RR/NCRR NIH HHS/ -- MC_U106179471/Medical Research Council/United Kingdom -- MC_U106188470/Medical Research Council/United Kingdom -- N01AG12109/AG/NIA NIH HHS/ -- P01 HL076491/HL/NHLBI NIH HHS/ -- P01 HL098055/HL/NHLBI NIH HHS/ -- P20 HL113452/HL/NHLBI NIH HHS/ -- P30 DK072488/DK/NIDDK NIH HHS/ -- R01 AG018728/AG/NIA NIH HHS/ -- R01 CA165001/CA/NCI NIH HHS/ -- R01 GM053275/GM/NIGMS NIH HHS/ -- R01 HD042157/HD/NICHD NIH HHS/ -- R01 HL059367/HL/NHLBI NIH HHS/ -- R01 HL086694/HL/NHLBI NIH HHS/ -- R01 HL087641/HL/NHLBI NIH HHS/ -- R01 HL087679/HL/NHLBI NIH HHS/ -- R01 HL088119/HL/NHLBI NIH HHS/ -- R01 HL103866/HL/NHLBI NIH HHS/ -- R01 HL103931/HL/NHLBI NIH HHS/ -- R01 LM010098/LM/NLM NIH HHS/ -- R01 MH081802/MH/NIMH NIH HHS/ -- RG/09/012/28096/British Heart Foundation/United Kingdom -- RL1 MH083268/MH/NIMH NIH HHS/ -- U01 GM074518/GM/NIGMS NIH HHS/ -- U01 HG004402/HG/NHGRI NIH HHS/ -- U01 HL072515/HL/NHLBI NIH HHS/ -- U01 HL084756/HL/NHLBI NIH HHS/ -- U24 MH068457/MH/NIMH NIH HHS/ -- U54 RR020278/RR/NCRR NIH HHS/ -- UL1 RR025005/RR/NCRR NIH HHS/ -- UL1 TR000439/TR/NCATS NIH HHS/ -- England -- Nature. 2012 Dec 20;492(7429):369-75. doi: 10.1038/nature11677. Epub 2012 Dec 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cardiology, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, The Netherlands. p.van.der.harst@umcg.nl〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23222517" target="_blank"〉PubMed〈/a〉

Description: Platelets are the second most abundant cell type in blood and are essential for maintaining haemostasis. Their count and volume are tightly controlled within narrow physiological ranges, but there is only limited understanding of the molecular processes controlling both traits. Here we carried out a high-powered meta-analysis of genome-wide association studies (GWAS) in up to 66,867 individuals of European ancestry, followed by extensive biological and functional assessment. We identified 68 genomic loci reliably associated with platelet count and volume mapping to established and putative novel regulators of megakaryopoiesis and platelet formation. These genes show megakaryocyte-specific gene expression patterns and extensive network connectivity. Using gene silencing in Danio rerio and Drosophila melanogaster, we identified 11 of the genes as novel regulators of blood cell formation. Taken together, our findings advance understanding of novel gene functions controlling fate-determining events during megakaryopoiesis and platelet formation, providing a new example of successful translation of GWAS to function.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3335296/" 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/PMC3335296/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gieger, Christian -- Radhakrishnan, Aparna -- Cvejic, Ana -- Tang, Weihong -- Porcu, Eleonora -- Pistis, Giorgio -- Serbanovic-Canic, Jovana -- Elling, Ulrich -- Goodall, Alison H -- Labrune, Yann -- Lopez, Lorna M -- Magi, Reedik -- Meacham, Stuart -- Okada, Yukinori -- Pirastu, Nicola -- Sorice, Rossella -- Teumer, Alexander -- Voss, Katrin -- Zhang, Weihua -- Ramirez-Solis, Ramiro -- Bis, Joshua C -- Ellinghaus, David -- Gogele, Martin -- Hottenga, Jouke-Jan -- Langenberg, Claudia -- Kovacs, Peter -- O'Reilly, Paul F -- Shin, So-Youn -- Esko, Tonu -- Hartiala, Jaana -- Kanoni, Stavroula -- Murgia, Federico -- Parsa, Afshin -- Stephens, Jonathan -- van der Harst, Pim -- Ellen van der Schoot, C -- Allayee, Hooman -- Attwood, Antony -- Balkau, Beverley -- Bastardot, Francois -- Basu, Saonli -- Baumeister, Sebastian E -- Biino, Ginevra -- Bomba, Lorenzo -- Bonnefond, Amelie -- Cambien, Francois -- Chambers, John C -- Cucca, Francesco -- D'Adamo, Pio -- Davies, Gail -- de Boer, Rudolf A -- de Geus, Eco J C -- Doring, Angela -- Elliott, Paul -- Erdmann, Jeanette -- Evans, David M -- Falchi, Mario -- Feng, Wei -- Folsom, Aaron R -- Frazer, Ian H -- Gibson, Quince D -- Glazer, Nicole L -- Hammond, Chris -- Hartikainen, Anna-Liisa -- Heckbert, Susan R -- Hengstenberg, Christian -- Hersch, Micha -- Illig, Thomas -- Loos, Ruth J F -- Jolley, Jennifer -- Khaw, Kay Tee -- Kuhnel, Brigitte -- Kyrtsonis, Marie-Christine -- Lagou, Vasiliki -- Lloyd-Jones, Heather -- Lumley, Thomas -- Mangino, Massimo -- Maschio, Andrea -- Mateo Leach, Irene -- McKnight, Barbara -- Memari, Yasin -- Mitchell, Braxton D -- Montgomery, Grant W -- Nakamura, Yusuke -- Nauck, Matthias -- Navis, Gerjan -- Nothlings, Ute -- Nolte, Ilja M -- Porteous, David J -- Pouta, Anneli -- Pramstaller, Peter P -- Pullat, Janne -- Ring, Susan M -- Rotter, Jerome I -- Ruggiero, Daniela -- Ruokonen, Aimo -- Sala, Cinzia -- Samani, Nilesh J -- Sambrook, Jennifer -- Schlessinger, David -- Schreiber, Stefan -- Schunkert, Heribert -- Scott, James -- Smith, Nicholas L -- Snieder, Harold -- Starr, John M -- Stumvoll, Michael -- Takahashi, Atsushi -- Tang, W H Wilson -- Taylor, Kent -- Tenesa, Albert -- Lay Thein, Swee -- Tonjes, Anke -- Uda, Manuela -- Ulivi, Sheila -- van Veldhuisen, Dirk J -- Visscher, Peter M -- Volker, Uwe -- Wichmann, H-Erich -- Wiggins, Kerri L -- Willemsen, Gonneke -- Yang, Tsun-Po -- Hua Zhao, Jing -- Zitting, Paavo -- Bradley, John R -- Dedoussis, George V -- Gasparini, Paolo -- Hazen, Stanley L -- Metspalu, Andres -- Pirastu, Mario -- Shuldiner, Alan R -- Joost van Pelt, L -- Zwaginga, Jaap-Jan -- Boomsma, Dorret I -- Deary, Ian J -- Franke, Andre -- Froguel, Philippe -- Ganesh, Santhi K -- Jarvelin, Marjo-Riitta -- Martin, Nicholas G -- Meisinger, Christa -- Psaty, Bruce M -- Spector, Timothy D -- Wareham, Nicholas J -- Akkerman, Jan-Willem N -- Ciullo, Marina -- Deloukas, Panos -- Greinacher, Andreas -- Jupe, Steve -- Kamatani, Naoyuki -- Khadake, Jyoti -- Kooner, Jaspal S -- Penninger, Josef -- Prokopenko, Inga -- Stemple, Derek -- Toniolo, Daniela -- Wernisch, Lorenz -- Sanna, Serena -- Hicks, Andrew A -- Rendon, Augusto -- Ferreira, Manuel A -- Ouwehand, Willem H -- Soranzo, Nicole -- 092731/Wellcome Trust/United Kingdom -- 098051/Wellcome Trust/United Kingdom -- BB/F019394/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- CZB/4/505/Chief Scientist Office/United Kingdom -- ETM/55/Chief Scientist Office/United Kingdom -- G0000111/Medical Research Council/United Kingdom -- G0601966/Medical Research Council/United Kingdom -- G0700704/Medical Research Council/United Kingdom -- G0700931/Medical Research Council/United Kingdom -- G0701120/Medical Research Council/United Kingdom -- G0701863/Medical Research Council/United Kingdom -- G0801056/Medical Research Council/United Kingdom -- G1000143/Medical Research Council/United Kingdom -- K12 RR023250/RR/NCRR NIH HHS/ -- K12 RR023250-05/RR/NCRR NIH HHS/ -- M01 RR016500/RR/NCRR NIH HHS/ -- M01 RR016500-08/RR/NCRR NIH HHS/ -- MC_U105260799/Medical Research Council/United Kingdom -- MC_U106179471/Medical Research Council/United Kingdom -- MC_U106188470/Medical Research Council/United Kingdom -- N01 HC055015/HC/NHLBI NIH HHS/ -- N01 HC055016/HC/NHLBI NIH HHS/ -- N01 HC055018/HC/NHLBI NIH HHS/ -- N01 HC055019/HC/NHLBI NIH HHS/ -- N01 HC055020/HC/NHLBI NIH HHS/ -- N01 HC055021/HC/NHLBI NIH HHS/ -- N01 HC055022/HC/NHLBI NIH HHS/ -- N01 HC085079/HC/NHLBI NIH HHS/ -- P01 HL076491/HL/NHLBI NIH HHS/ -- P01 HL076491-09/HL/NHLBI NIH HHS/ -- P01 HL098055/HL/NHLBI NIH HHS/ -- P01 HL098055-03/HL/NHLBI NIH HHS/ -- P30 DK072488/DK/NIDDK NIH HHS/ -- P30 DK072488-08/DK/NIDDK NIH HHS/ -- P41 HG003751/HG/NHGRI NIH HHS/ -- R01 AG018728/AG/NIA NIH HHS/ -- R01 AG018728-05S1/AG/NIA NIH HHS/ -- R01 GM053275/GM/NIGMS NIH HHS/ -- R01 GM053275-14/GM/NIGMS NIH HHS/ -- R01 HD042157/HD/NICHD NIH HHS/ -- R01 HD042157-01A1/HD/NICHD NIH HHS/ -- R01 HL059367/HL/NHLBI NIH HHS/ -- R01 HL059367-11/HL/NHLBI NIH HHS/ -- R01 HL068986/HL/NHLBI NIH HHS/ -- R01 HL068986-06/HL/NHLBI NIH HHS/ -- R01 HL073410/HL/NHLBI NIH HHS/ -- R01 HL073410-08/HL/NHLBI NIH HHS/ -- R01 HL085251/HL/NHLBI NIH HHS/ -- R01 HL085251-04/HL/NHLBI NIH HHS/ -- R01 HL086694/HL/NHLBI NIH HHS/ -- R01 HL086694-05/HL/NHLBI NIH HHS/ -- R01 HL087641/HL/NHLBI NIH HHS/ -- R01 HL087641-03/HL/NHLBI NIH HHS/ -- R01 HL087679-03/HL/NHLBI NIH HHS/ -- R01 HL088119/HL/NHLBI NIH HHS/ -- R01 HL088119-04/HL/NHLBI NIH HHS/ -- R01 HL103866/HL/NHLBI NIH HHS/ -- R01 HL103866-03/HL/NHLBI NIH HHS/ -- R01 HL105756/HL/NHLBI NIH HHS/ -- RG/09/012/28096/British Heart Foundation/United Kingdom -- RL1 MH083268/MH/NIMH NIH HHS/ -- RL1 MH083268-05/MH/NIMH NIH HHS/ -- U01 GM074518/GM/NIGMS NIH HHS/ -- U01 GM074518-04/GM/NIGMS NIH HHS/ -- U01 HL072515/HL/NHLBI NIH HHS/ -- U01 HL072515-06/HL/NHLBI NIH HHS/ -- U01 HL084756/HL/NHLBI NIH HHS/ -- U01 HL084756-03/HL/NHLBI NIH HHS/ -- U54 RR020278/RR/NCRR NIH HHS/ -- U54 RR020278-06/RR/NCRR NIH HHS/ -- UL1 RR025005/RR/NCRR NIH HHS/ -- UL1 RR025005-05/RR/NCRR NIH HHS/ -- WT077037/Z/05/Z/Wellcome Trust/United Kingdom -- WT077047/Z/05/Z/Wellcome Trust/United Kingdom -- WT082597/Z/07/Z/Wellcome Trust/United Kingdom -- England -- Nature. 2011 Nov 30;480(7376):201-8. doi: 10.1038/nature10659.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute of Genetic Epidemiology, Helmholtz Zentrum Munchen, German Research Center for Environmental Health, Ingolstadter Landstr 1, 85764 Neuherberg, Germany. christian.gieger@helmholtz-muenchen.de〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22139419" target="_blank"〉PubMed〈/a〉

Description: Brazil has experienced an unprecedented epidemic of Zika virus (ZIKV), with ~30,000 cases reported to date. ZIKV was first detected in Brazil in May 2015, and cases of microcephaly potentially associated with ZIKV infection were identified in November 2015. We performed next-generation sequencing to generate seven Brazilian ZIKV genomes sampled from four self-limited cases, one blood donor, one fatal adult case, and one newborn with microcephaly and congenital malformations. Results of phylogenetic and molecular clock analyses show a single introduction of ZIKV into the Americas, which we estimated to have occurred between May and December 2013, more than 12 months before the detection of ZIKV in Brazil. The estimated date of origin coincides with an increase in air passengers to Brazil from ZIKV-endemic areas, as well as with reported outbreaks in the Pacific Islands. ZIKV genomes from Brazil are phylogenetically interspersed with those from other South American and Caribbean countries. Mapping mutations onto existing structural models revealed the context of viral amino acid changes present in the outbreak lineage; however, no shared amino acid changes were found among the three currently available virus genomes from microcephaly cases. Municipality-level incidence data indicate that reports of suspected microcephaly in Brazil best correlate with ZIKV incidence around week 17 of pregnancy, although this correlation does not demonstrate causation. Our genetic description and analysis of ZIKV isolates in Brazil provide a baseline for future studies of the evolution and molecular epidemiology of this emerging virus in the Americas.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Faria, Nuno Rodrigues -- Azevedo, Raimunda do Socorro da Silva -- Kraemer, Moritz U G -- Souza, Renato -- Cunha, Mariana Sequetin -- Hill, Sarah C -- Theze, Julien -- Bonsall, Michael B -- Bowden, Thomas A -- Rissanen, Ilona -- Rocco, Iray Maria -- Nogueira, Juliana Silva -- Maeda, Adriana Yurika -- Vasami, Fernanda Giseli da Silva -- Macedo, Fernando Luiz de Lima -- Suzuki, Akemi -- Rodrigues, Sueli Guerreiro -- Cruz, Ana Cecilia Ribeiro -- Nunes, Bruno Tardeli -- Medeiros, Daniele Barbosa de Almeida -- Rodrigues, Daniela Sueli Guerreiro -- Nunes Queiroz, Alice Louize -- da Silva, Eliana Vieira Pinto -- Henriques, Daniele Freitas -- Travassos da Rosa, Elisabeth Salbe -- de Oliveira, Consuelo Silva -- Martins, Livia Caricio -- Vasconcelos, Helena Baldez -- Casseb, Livia Medeiros Neves -- Simith, Darlene de Brito -- Messina, Jane P -- Abade, Leandro -- Lourenco, Jose -- Carlos Junior Alcantara, Luiz -- de Lima, Maricelia Maia -- Giovanetti, Marta -- Hay, Simon I -- de Oliveira, Rodrigo Santos -- Lemos, Poliana da Silva -- de Oliveira, Layanna Freitas -- de Lima, Clayton Pereira Silva -- da Silva, Sandro Patroca -- de Vasconcelos, Janaina Mota -- Franco, Luciano -- Cardoso, Jedson Ferreira -- Vianez-Junior, Joao Lidio da Silva Goncalves -- Mir, Daiana -- Bello, Gonzalo -- Delatorre, Edson -- Khan, Kamran -- Creatore, Marisa -- Coelho, Giovanini Evelim -- de Oliveira, Wanderson Kleber -- Tesh, Robert -- Pybus, Oliver G -- Nunes, Marcio R T -- Vasconcelos, Pedro F C -- 090532/Z/09/Z/Wellcome Trust/United Kingdom -- 095066/Wellcome Trust/United Kingdom -- 102427/Wellcome Trust/United Kingdom -- MR/L009528/1/Medical Research Council/United Kingdom -- R24 AT 120942/AT/NCCIH NIH HHS/ -- New York, N.Y. -- Science. 2016 Apr 15;352(6283):345-9. doi: 10.1126/science.aaf5036. Epub 2016 Mar 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Technological Innovation, Evandro Chagas Institute, Ministry of Health, Ananindeua, PA 67030-000, Brazil. Department of Zoology, University of Oxford, South Parks Road, Oxford OX1 3PS, UK. ; Department of Arbovirology and Hemorrhagic Fevers, Evandro Chagas Institute, Ministry of Health, Ananindeua, Para State, Brazil. ; Department of Zoology, University of Oxford, South Parks Road, Oxford OX1 3PS, UK. ; Instituto Adolfo Lutz, University of Sao Paulo, Sao Paulo, Brazil. ; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. ; Department of Zoology, University of Oxford, South Parks Road, Oxford OX1 3PS, UK. Metabiota, San Francisco, CA 94104, USA. ; Oswaldo Cruz Foundation (FIOCRUZ), Salvador, Bahia, Brazil. ; Centre of Post Graduation in Collective Health, Department of Health, Universidade Estadual de Feira de Santana, Feira de Santana, Bahia, Brazil. ; Institute for Health Metrics and Evaluation, University of Washington, Seattle, WA 98121, USA. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. ; Center for Technological Innovation, Evandro Chagas Institute, Ministry of Health, Ananindeua, PA 67030-000, Brazil. ; Laboratorio de AIDS and Imunologia Molecular, Instituto Oswaldo Cruz, FIOCRUZ, Rio de Janeiro, Brazil. ; Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada. Department of Medicine, Division of Infectious Diseases, University of Toronto, Toronto, Ontario, Canada. ; Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada. ; Brazilian Ministry of Health, Brasilia, Brazil. ; Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA. ; Department of Zoology, University of Oxford, South Parks Road, Oxford OX1 3PS, UK. Metabiota, San Francisco, CA 94104, USA. oliver.pybus@zoo.ox.ac.uk marcionunesbrasil@yahoo.com.br pedrovasconcelos@iec.pa.gov.br. ; Center for Technological Innovation, Evandro Chagas Institute, Ministry of Health, Ananindeua, PA 67030-000, Brazil. Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA. oliver.pybus@zoo.ox.ac.uk marcionunesbrasil@yahoo.com.br pedrovasconcelos@iec.pa.gov.br. ; Department of Arbovirology and Hemorrhagic Fevers, Evandro Chagas Institute, Ministry of Health, Ananindeua, Para State, Brazil. oliver.pybus@zoo.ox.ac.uk marcionunesbrasil@yahoo.com.br pedrovasconcelos@iec.pa.gov.br.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27013429" target="_blank"〉PubMed〈/a〉