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Biological Insights From 108 Schizophrenia-Associated Genetic Loci

Schizophrenia Working Group of the Psychiatric Genomics Consortium, 1 , 2 , 1 , 2 , 3 , 4 , 5 , 6 , 1 ,   6 , 7 , 1 , 2 , 4 , 1 , 2 , 8 , 9 , 1 , 3 , 3 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 2 , 24 , 25 , 2 , 26 , 2 , 22 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 6 , 39 , 41 , 2 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 5 , 6 , 7 , 51 , 52 , 53 , 54 , 36 , 55 , 56 , 57 , 17 , 58 , 59 , 60 , 61 , 14 , 62 , 5 , 63 , 36 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 6 , 72 , 73 , 74 , 75 , 76 , 51 , 77 , 78 , 79 , 80 , 81 , 36 , 1 , 2 , 4 , 82 , 2 , 6 , 81 , 83 , 51 , 84 ,   1 , 3 , 85 , 86 , 87 , 88 , 23 , 6 , 89 , 17 , 90 , 36 , 91 , 92 , 81 , 39 , 93 , 94 , 55 , 56 , 95 , 3 , 11 , 96 , 55 , 56 , 95 , 55 , 56 , 97 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 78 , 6 , 105 , 106 , 107 , 108 , 109 , 51 , 110 , 111 , 81 , 112 , 112 , 113 , 114 , 26 , 19 , 115 , 47 , 116 , 87 , 6 , 117 , 118 , 119 , 120 , 121 , 109 , 39 , 122 , 123 , 124 , 113 , 114 , 26 , 125 , 126 , 127 , 100 , 17 , 58 , 59 , 128 , 14 , 129 , 130 , 131 , 132 , 133 , 134 , 77 , 88 , 24 , 25 , 14 , 135 , 130 , 136 , 137 , 39 , 138 , 137 , 139 , 8 , 5 , 63 , 17 , 58 , 140 , 141 , 142 , 143 , 144 , 145 , 146 , 137 , 147 , 148 , 149 , 150 , 110 , 151 , 152 , 153 , 2 , 154 , 155 , 79 , 17 , 90 , 143 , 156 , Psychosis Endophenotypes International Consortium 157 , 39 , 158 , 60 , 23 , 36 , 111 , 159 , 160 , 161 , 162 , 160 , 163 , 53 , 6 , 142 , 164 , 149 , 82 , 165 , 17 , 90 , 36 , 166 , 6 , 7 , 30 , 32 , 82 , 167 , 82 , 71 , 64 , 65 , 39 , 122 , 168 , 77 , 169 , 170 , 2 , 39 , 171 , 172 , 130 , 136 , 173 , 174 , 175 , 36 , 176 , 47 , 109 , 2 , 4 , 43 , 177 , 3 , 82 , 178 , 178 , 179 , 180 , 181 , 182 , 77 , 121 , 47 , 124 , 48 , 51 , 12 , 183 , 104 , 184 , 185 , 186 , 187 , 188 , 86 , 119 , 22 , 54 , 189 , 190 , 51 , 77 , 166 , 43 , 22 , 191 , 106 , 107 , 192 , 179 , 87 , 178 , 87 , Wellcome Trust Case-Control Consortium 2 193 , 152 , 14 , 135 , 134 , 194 , 35 , 36 , 91 , 195 , 17 , 58 , 59 , 140 , 55 , 56 , 95 , 196 , 197 , 198 , 23 , 3 , 11 , 96 , 137 , 64 , 65 , 5 , 53 , 26 , 98 , 39 , 199 , 200 , 201 , 12 , 202 , 6 , 106 , 107 , 108 , 203 , 204 , 205 , 19 , 86 , 192 , 206 , 203 , 204 , 205 , 2 , 96 , 53 , 2 , 15 , 16 , 17 , 87 , 207 , 55 , 56 , 38 , 80 , 208 , 6 , 7 , 4 , 163 , 209 , 111 , 130 , 209 , 210 , 211 , 212 , 213 , 77 , 202 , 81 , 83 , 214 , 82 , 91 , 167 , 215 , 180 , 216 , 168 , 17 , 90 , 217 , 1 , 26 , 51 , 162 , 6 , 7

Nature

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      Summary

      Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here, we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain providing biological plausibility for the findings. Many findings have the potential to provide entirely novel insights into aetiology, but associations at DRD2 and multiple genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that play important roles in immunity, providing support for the hypothesized link between the immune system and schizophrenia.

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      Most cited references 58

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      Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets.

      We predict regulatory targets of vertebrate microRNAs (miRNAs) by identifying mRNAs with conserved complementarity to the seed (nucleotides 2-7) of the miRNA. An overrepresentation of conserved adenosines flanking the seed complementary sites in mRNAs indicates that primary sequence determinants can supplement base pairing to specify miRNA target recognition. In a four-genome analysis of 3' UTRs, approximately 13,000 regulatory relationships were detected above the estimate of false-positive predictions, thereby implicating as miRNA targets more than 5300 human genes, which represented 30% of our gene set. Targeting was also detected in open reading frames. In sum, well over one third of human genes appear to be conserved miRNA targets.
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        A map of human genome variation from population-scale sequencing.

        The 1000 Genomes Project aims to provide a deep characterization of human genome sequence variation as a foundation for investigating the relationship between genotype and phenotype. Here we present results of the pilot phase of the project, designed to develop and compare different strategies for genome-wide sequencing with high-throughput platforms. We undertook three projects: low-coverage whole-genome sequencing of 179 individuals from four populations; high-coverage sequencing of two mother-father-child trios; and exon-targeted sequencing of 697 individuals from seven populations. We describe the location, allele frequency and local haplotype structure of approximately 15 million single nucleotide polymorphisms, 1 million short insertions and deletions, and 20,000 structural variants, most of which were previously undescribed. We show that, because we have catalogued the vast majority of common variation, over 95% of the currently accessible variants found in any individual are present in this data set. On average, each person is found to carry approximately 250 to 300 loss-of-function variants in annotated genes and 50 to 100 variants previously implicated in inherited disorders. We demonstrate how these results can be used to inform association and functional studies. From the two trios, we directly estimate the rate of de novo germline base substitution mutations to be approximately 10(-8) per base pair per generation. We explore the data with regard to signatures of natural selection, and identify a marked reduction of genetic variation in the neighbourhood of genes, due to selection at linked sites. These methods and public data will support the next phase of human genetic research.
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          Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease

          Crohn’s disease (CD) and ulcerative colitis (UC), the two common forms of inflammatory bowel disease (IBD), affect over 2.5 million people of European ancestry with rising prevalence in other populations 1 . Genome-wide association studies (GWAS) and subsequent meta-analyses of CD and UC 2,3 as separate phenotypes implicated previously unsuspected mechanisms, such as autophagy 4 , in pathogenesis and showed that some IBD loci are shared with other inflammatory diseases 5 . Here we expand knowledge of relevant pathways by undertaking a meta-analysis of CD and UC genome-wide association scans, with validation of significant findings in more than 75,000 cases and controls. We identify 71 new associations, for a total of 163 IBD loci that meet genome-wide significance thresholds. Most loci contribute to both phenotypes, and both directional and balancing selection effects are evident. Many IBD loci are also implicated in other immune-mediated disorders, most notably with ankylosing spondylitis and psoriasis. We also observe striking overlap between susceptibility loci for IBD and mycobacterial infection. Gene co-expression network analysis emphasizes this relationship, with pathways shared between host responses to mycobacteria and those predisposing to IBD.
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            Author and article information

            Affiliations
            [1 ]Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
            [2 ]Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
            [3 ]Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
            [4 ]Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
            [5 ]Neuropsychiatric Genetics Research Group, Department of Psychiatry, Trinity College Dublin, Ireland.
            [6 ]MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK.
            [7 ]National Centre for Mental Health, Cardiff University, Cardiff, Wales.
            [8 ]Eli Lilly and Company Limited, Erl Wood Manor, Sunninghill Road, Windlesham, Surrey, UK.
            [9 ]Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King’s College London, London, UK.
            [10 ]Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Lyngby, Denmark.
            [11 ]Division of Endocrinology and Center for Basic and Translational Obesity Research, Boston Children’s Hospital, Boston, MA, USA.
            [12 ]Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
            [13 ]Department of Psychiatry, Diakonhjemmet Hospital, Oslo, Norway.
            [14 ]NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
            [15 ]Centre for Integrative Register-based Research, CIRRAU, Aarhus University, Aarhus, Denmark.
            [16 ]National Centre for Register-based Research, Aarhus University, Aarhus, Denmark.
            [17 ]The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Denmark.
            [18 ]State Mental Hospital, Haar, Germany.
            [19 ]Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA.
            [20 ]Department of Psychiatry and Behavioral Sciences, Atlanta Veterans Affairs Medical Center, Atlanta, GA, USA.
            [21 ]Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, USA.
            [22 ]Virginia Institute for Psychiatric and Behavioral Genetics, Department of Psychiatry, Virginia Commonwealth University, Richmond, VA, USA.
            [23 ]Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
            [24 ]Department of Medical Genetics, University of Pécs, Pécs, Hungary.
            [25 ]Szentagothai Research Center, University of Pécs, Pécs, Hungary.
            [26 ]Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
            [27 ]Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA, USA.
            [28 ]University Medical Center Groningen, Department of Psychiatry, University of Groningen, The Netherlands.
            [29 ]School of Nursing, Louisiana State University Health Sciences Center, New Orleans, LA, USA.
            [30 ]Athinoula A. Martinos Center, Massachusetts General Hospital, Boston, MA, USA.
            [31 ]Center for Brain Science, Harvard University, Cambridge MA, USA.
            [32 ]Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.
            [33 ]Department of Psychiatry, University of California at San Francisco, San Francisco, CA, USA.
            [34 ]University Medical Center Utrecht, Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, The Netherlands.
            [35 ]Department of Human Genetics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
            [36 ]Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
            [37 ]Centre Hospitalier du Rouvray and INSERM U1079 Faculty of Medicine, Rouen, France.
            [38 ]Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
            [39 ]Schizophrenia Research Institute, Sydney, Australia.
            [40 ]School of Psychiatry, University of New South Wales, Sydney, Australia.
            [41 ]Royal Brisbane and Women’s Hospital, University of Queensland, Brisbane, Australia.
            [42 ]Institute of Psychology, Chinese Academy of Science, Beijing, PR China.
            [43 ]Department of Psychiatry, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, PR China.
            [44 ]Department of Psychiatry and State Ket Laboratory for Brain and Cognitive Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, PR China.
            [45 ]Department of Computer Science, University of North Carolina, Chapel Hill, NC, USA.
            [46 ]Castle Peak Hospital, Hong Kong SAR, PR China.
            [47 ]Institute of Mental Health, Singapore.
            [48 ]Department of Psychiatry, Washington University, St. Louis, MO, USA.
            [49 ]Department of Child and Adolescent Psychiatry, Pierre and Marie Curie Faculty of Medicine and Brain and Spinal Cord Institute (ICM), Paris, France.
            [50 ]Formerly of Neuroscience Therapeutic Area, Janssen Research and Development, LLC, Raritan, NJ, USA.
            [51 ]Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
            [52 ]Department of Psychological Medicine, Queen Mary University of London, UK.
            [53 ]Molecular Psychiatry Laboratory, Division of Psychiatry, University College London, UK.
            [54 ]Sheba Medical Center, Tel Hashomer, Israel.
            [55 ]Department of Genomics, Life and Brain Center, Bonn, Germany.
            [56 ]Institute of Human Genetics, University of Bonn, Bonn, Germany.
            [57 ]Applied Molecular Genomics Unit, VIB Department of Molecular Genetics, University of Antwerp, Antwerp, Belgium.
            [58 ]Centre for Integrative Sequencing, iSEQ, Aarhus University, Aarhus, Denmark.
            [59 ]Department of Biomedicine, Aarhus University, Aarhus, Denmark.
            [60 ]First Department of Psychiatry, University of Athens Medical School, Athens, Greece.
            [61 ]Department of Psychiatry, University College Cork, Ireland.
            [62 ]Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
            [63 ]Cognitive Genetics and Therapy Group, School of Psychology and Discipline of Biochemistry, National University of Ireland Galway, Ireland.
            [64 ]Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL, USA.
            [65 ]Department of Psychiatry and Behavioral Sciences, NorthShore University HealthSystem, Evanston, IL, USA.
            [66 ]Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK.
            [67 ]Department of Child and Adolescent Psychiatry, University Clinic of Psychiatry, Skopje, Republic of Macedonia.
            [68 ]Department of Psychiatry, University of Regensburg, Regensburg, Germany.
            [69 ]Department of General Practice, Helsinki University Central Hospital, Helsinki, Finland.
            [70 ]Folkhälsan Research Center, Helsinki, Finland.
            [71 ]National Institute for Health and Welfare, Helsinki, Finland.
            [72 ]Translational Technologies and Bioinformatics, Pharma Research and Early Development, F.Hoffman-La Roche, Basel, Switzerland.
            [73 ]Department of Psychiatry, Georgetown University School of Medicine, Washington DC, USA.
            [74 ]Department of Psychiatry, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA.
            [75 ]Department of Psychiatry, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
            [76 ]Mental Health Service Line, Washington VA Medical Center, Washington DC, USA.
            [77 ]Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany.
            [78 ]Department of Genetics, University of Groningen, University Medical Centre Groningen, The Netherlands.
            [79 ]Department of Psychiatry, University of Colorado Denver, Aurora, CO, USA.
            [80 ]Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA, USA.
            [81 ]Department of Psychiatry, University of Halle, Halle, Germany.
            [82 ]Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
            [83 ]Department of Psychiatry, University of Munich, Munich, Germany.
            [84 ]Departments of Psychiatry and Human and Molecular Genetics, INSERM, Institut de Myologie, Hôpital de la Pitiè-Salpêtrière, Paris, France.
            [85 ]Mental Health Research Centre, Russian Academy of Medical Sciences, Moscow, Russia.
            [86 ]Neuroscience Therapeutic Area, Janssen Research and Development, LLC, Raritan, NJ, USA.
            [87 ]Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia.
            [88 ]Academic Medical Centre University of Amsterdam, Department of Psychiatry, Amsterdam, The Netherlands.
            [89 ]Illumina, Inc., La Jolla, CA, USA.
            [90 ]Institute of Biological Psychiatry, MHC Sct. Hans, Mental Health Services Copenhagen, Denmark.
            [91 ]Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
            [92 ]JJ Peters VA Medical Center, Bronx, NY, USA.
            [93 ]Priority Research Centre for Health Behaviour, University of Newcastle, Newcastle, Australia.
            [94 ]School of Electrical Engineering and Computer Science, University of Newcastle, Newcastle, Australia.
            [95 ]Division of Medical Genetics, Department of Biomedicine, University of Basel, Basel, Switzerland.
            [96 ]Department of Genetics, Harvard Medical School, Boston, MA, USA.
            [97 ]Section of Neonatal Screening and Hormones, Department of Clinical Biochemistry, Immunology and Genetics, Statens Serum Institut, Copenhagen, Denmark.
            [98 ]Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Aichi, Japan.
            [99 ]Regional Centre for Clinical Research in Psychosis, Department of Psychiatry, Stavanger University Hospital, Stavanger, Norway.
            [100 ]Rheumatology Research Group, Vall d’Hebron Research Institute, Barcelona, Spain.
            [101 ]Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands.
            [102 ]Centre for Medical Research, The University of Western Australia, Perth, Western Australia, Australia.
            [103 ]Perkins Institute for Medical Research, The University of Western Australia, Perth, Western Australia, Australia.
            [104 ]Department of Medical Genetics, Medical University, Sofia, Bulgaria.
            [105 ]Department of Psychology, University of Colorado Boulder, Boulder, CO, USA.
            [106 ]Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
            [107 ]Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.
            [108 ]Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
            [109 ]Institute of Molecular Genetics, Russian Academy of Sciences, Moscow, Russia.
            [110 ]Latvian Biomedical Research and Study Centre, Riga, Latvia.
            [111 ]Department of Psychiatry and Zilkha Neurogenetics Institute, Keck School of Medicine at University of Southern California, Los Angeles, CA, USA.
            [112 ]Faculty of Medicine, Vilnius University, Vilnius, Lithuania.
            [113 ]2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic.
            [114 ]Department of Biology and Medical Genetics, Charles University Prague, Prague, Czech Republic.
            [115 ]Pierre and Marie Curie Faculty of Medicine, Paris, France.
            [116 ]Duke-NUS Graduate Medical School, Singapore.
            [117 ]Department of Psychiatry, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
            [118 ]Centre for Genomic Sciences and Department of Psychiatry, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, PR China.
            [119 ]Mental Health Centre and Psychiatric Laboratory, West China Hospital, Sichuan University, Chendu, Sichuan, PR China.
            [120 ]Department of Biostatistics, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, USA.
            [121 ]Department of Psychiatry, Columbia University, New York, NY, USA.
            [122 ]Priority Centre for Translational Neuroscience and Mental Health, University of Newcastle, Newcastle, Australia.
            [123 ]Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University in Szczecin, Szczecin, Poland.
            [124 ]Department of Mental Health and Substance Abuse Services; National Institute for Health and Welfare, Helsinki, Finland.
            [125 ]Department of Mental Health, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.
            [126 ]Department of Psychiatry, University of Bonn, Bonn, Germany.
            [127 ]Centre National de la Recherche Scientifique, Laboratoire de Génétique Moléculaire de la Neurotransmission et des Processus Neurodégénératifs, Hôpital de la Pitié Salpêtrière, Paris, France.
            [128 ]Department of Genomics Mathematics, University of Bonn, Bonn, Germany.
            [129 ]Research Unit, Sørlandet Hospital, Kristiansand, Norway.
            [130 ]Department of Psychiatry, Harvard Medical School, Boston, MA, USA.
            [131 ]VA Boston Health Care System, Brockton, MA, USA.
            [132 ]Department of Psychiatry, National University of Ireland Galway, Ireland.
            [133 ]Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, UK.
            [134 ]Division of Psychiatry, University of Edinburgh, Edinburgh, UK.
            [135 ]Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
            [136 ]Massachusetts Mental Health Center Public Psychiatry Division of the Beth Israel Deaconess Medical Center, Boston, MA, USA.
            [137 ]Estonian Genome Center, University of Tartu, Tartu, Estonia.
            [138 ]School of Psychology, University of Newcastle, Newcastle, Australia.
            [139 ]First Psychiatric Clinic, Medical University, Sofia, Bulgaria.
            [140 ]Department P, Aarhus University Hospital, Risskov, Denmark.
            [141 ]Department of Psychiatry, Royal College of Surgeons in Ireland, Ireland.
            [142 ]King’s College London, UK.
            [143 ]Maastricht University Medical Centre, South Limburg Mental Health Research and Teaching Network, EURON, Maastricht, The Netherlands.
            [144 ]Institute of Translational Medicine, University Liverpool, UK.
            [145 ]Max Planck Institute of Psychiatry, Munich, Germany.
            [146 ]Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
            [147 ]Department of Psychiatry and Psychotherapy, Jena University Hospital, Jena, Germany.
            [148 ]Department of Psychiatry, Queensland Brain Institute and Queensland Centre for Mental Health Research, University of Queensland, Brisbane, Queensland, Australia.
            [149 ]Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
            [150 ]Department of Psychiatry, Trinity College Dublin, Ireland.
            [151 ]Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, USA.
            [152 ]Department of Clinical Sciences, Psychiatry, Umeå University, Umeå, Sweden.
            [153 ]DETECT Early Intervention Service for Psychosis, Blackrock, Dublin, Ireland.
            [154 ]Centre for Public Health, Institute of Clinical Sciences, Queens University Belfast, Belfast, UK.
            [155 ]Lawrence Berkeley National Laboratory, University of California at Berkeley, Berkeley, CA, USA.
            [156 ]Institute of Psychiatry at King’s College London, London, UK.
            [157 ]PEIC.
            [158 ]Melbourne Neuropsychiatry Centre, University of Melbourne & Melbourne Health, Melbourne, Australia.
            [159 ]Department of Psychiatry, University of Helsinki, Finland.
            [160 ]Public Health Genomics Unit, National Institute for Health and Welfare, Helsinki, Finland.
            [161 ]Medical Faculty, University of Belgrade, Belgrade, Serbia.
            [162 ]Department of Psychiatry, University of North Carolina, Chapel Hill, NC, USA.
            [163 ]Institute for Molecular Medicine Finland, FIMM, Helsinki, Finland.
            [164 ]Department of Epidemiology, Harvard University, Boston, MA, USA.
            [165 ]Department of Psychiatry, University of Oxford, Oxford, UK.
            [166 ]Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA.
            [167 ]Institute for Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
            [168 ]PharmaTherapeutics Clinical Research, Pfizer Worldwide Research and Development, Cambridge, MA, USA.
            [169 ]Department of Psychiatry and Psychotherapy, University of Gottingen, Göttingen, Germany.
            [170 ]Psychiatry and Psychotherapy Clinic, University of Erlangen, Germany.
            [171 ]Hunter New England Health Service, Newcastle, Australia.
            [172 ]School of Biomedical Sciences, University of Newcastle, Newcastle, Australia.
            [173 ]Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
            [174 ]University of Iceland, Landspitali, National University Hospital, Reykjavik, Iceland.
            [175 ]Department of Psychiatry and Drug Addiction, Tbilisi State Medical University (TSMU), Tbilisi, Georgia.
            [176 ]Research and Development, Bronx Veterans Affairs Medical Center, New York, NY, USA.
            [177 ]Wellcome Trust Centre for Human Genetics, Oxford, UK.
            [178 ]deCODE Genetics, Reykjavik, Iceland.
            [179 ]Department of Clinical Neurology, Medical University of Vienna, Austria.
            [180 ]Lieber Institute for Brain Development, Baltimore, MD, USA.
            [181 ]Department of Medical Genetics, University Medical Centre, Utrecht, The Netherlands.
            [182 ]Rudolf Magnus Institute of Neuroscience, University Medical Centre Utrecht, The Netherlands.
            [183 ]Berkshire Healthcare NHS Foundation Trust, Bracknell, UK.
            [184 ]Section of Psychiatry, University of Verona, Verona, Italy.
            [185 ]Department of Psychiatry, University of Oulu, Finland.
            [186 ]University Hospital of Oulu, Oulu, Finland.
            [187 ]Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland.
            [188 ]Health Research Board, Dublin, Ireland.
            [189 ]Department of Psychiatry and Clinical Neurosciences, School of Psychiatry and Clinical Neurosciences, Queen Elizabeth II Medical Centre, Perth, Western Australia, Australia.
            [190 ]Department of Psychological Medicine and Neurology, MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Cardiff, Wales, UK.
            [191 ]Computational Sciences CoE, Pfizer Worldwide Research and Development, Cambridge, MA, USA.
            [192 ]Human Genetics, Genome Institute of Singapore, A*STAR, Singapore.
            [193 ]WTCCC2.
            [194 ]University College London, UK.
            [195 ]Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
            [196 ]Institute of Neuroscience and Medicine (INM-1), Research Center Juelich, Juelich, Germany.
            [197 ]Department of Genetics, The Hebrew University of Jerusalem, Jerusalem, Israel.
            [198 ]Neuroscience Discovery and Translational Area, Pharma Research and Early Development, F.Hoffman-La Roche, Basel, Switzerland.
            [199 ]School of Psychiatry and Clinical Neurosciences, The University of Western Australia, Perth, Australia.
            [200 ]The Perkins Institute of Medical Research, Perth, Australia.
            [201 ]UWA Centre for Clinical Research in Neuropsychiatry.
            [202 ]Virginia Institute for Psychiatric and Behavioral Genetics, Departments of Psychiatry and Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA, USA.
            [203 ]The Feinstein Institute for Medical Research, Manhasset, NY, USA.
            [204 ]The Hofstra NS-LIJ School of Medicine, Hempstead, NY, USA.
            [205 ]The Zucker Hillside Hospital, Glen Oaks, NY, USA.
            [206 ]Saw Swee Hock School of Public Health, National University of Singapore, Singapore.
            [207 ]Queensland Centre for Mental Health Research, University of Queensland, Brisbane, Queensland, Australia.
            [208 ]Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, The Netherlands.
            [209 ]The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
            [210 ]Center for Human Genetic Research and Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.
            [211 ]Department of Child and Adolescent Psychiatry, Erasmus University Medical Centre, Rotterdam, The Netherlands.
            [212 ]Department of Complex Trait Genetics, Neuroscience Campus Amsterdam, VU University Medical Center Amsterdam, Amsterdam, The Netherlands.
            [213 ]Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, Amsterdam, The Netherlands.
            [214 ]Centre for Genomic Sciences, State Ket Laboratory for Brain and Cognitive Sciences, and Department of Psychiatry, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, PR China.
            [215 ]University of Aberdeen, Institute of Medical Sciences, Aberdeen, Scotland, UK.
            [216 ]Departments of Psychiatry, Neurology, Neuroscience and Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA.
            [217 ]Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
            Author notes
            Correspondence and requests for materials should be addressed to Michael O’Donovan: odonovanmc@ 123456cardiff.ac.uk or odonovanmc@ 123456cf.ac.uk

            Contributions The individual studies or consortia contributing to the GWAS meta-analysis were led by R.A., O.A.A, D.H.R.B., A.D.B., E. Bramon, J.D.B., A.C., D.A.C., S.C., A.D., E. Domenici, H.E., T.E., P.V.G., M.G., H.G., C.M.H., N.I., A.V.J., E.G.J., K.S.K., G.K., J. Knight, T. Lencz, D.F.L., Q.S.L., J.Liu, A.K.M., S.A.M., A. McQuillin, J.L.M., P.B.M., B.J.M., M.M.N., M.C.O’D., R.A.O., M.J.O., A. Palotie, C.N.P., T.L.P., M.R., B.P.R., D.R., P.C.S., P. Sklar., D.St.C., P.F.S., D.R.W., J.R.W., J.T.R.W. and T.W. Together with the core statistical analysis group led by M.J.D. comprising S.R., B.M.N., and P.A.H., this group comprised the management group led by M.C.O’D. who were responsible for the management of the study and the overall content of the manuscript. Additional analyses and interpretations were contributed by E.A., B.B-S., D.K., KH.F., M. Fromer, H.H., P.L., P.B.M., S.M.P., T.H.P., N.R.W., and P.M.V. The phenotype supervisory group comprised A.C., A.H.F., P.V.G., K.K.K., and B.J.M., D.A.C. led the candidate selected genes subgroup comprised of M.J.D., E. Dominici, J.A.K., A.M.H., M.C.O’D., B.P.R., D.R., E.M.S. and P. Sklar. Replication results were provided by S.S., H.S., and K.S. The remaining authors contributed to the recruitment, genotyping, or data processing for the contributing components of the meta-analysis. A.C., M.J.D., B.M.N., S.R., P.F.S. and M.C.O’D. took responsibility for the primary drafting of the manuscript which was shaped by the management group. All other authors had sight of, had the opportunity to comment on, and approved the final draft.

            Journal
            0410462
            6011
            Nature
            Nature
            Nature
            0028-0836
            1476-4687
            18 July 2014
            22 July 2014
            24 July 2014
            24 January 2015
            : 511
            : 7510
            : 421-427
            25056061
            4112379
            10.1038/nature13595
            EMS59304
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