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Pleiotropic Meta-Analysis of Cognition, Education, and Schizophrenia Differentiates Roles of Early Neurodevelopmental and Adult Synaptic Pathways.
Lam, Max; Hill, W David; Trampush, Joey W; Yu, Jin; Knowles, Emma; Davies, Gail; Stahl, Eli; Huckins, Laura; Liewald, David C; Djurovic, Srdjan; Melle, Ingrid; Sundet, Kjetil; Christoforou, Andrea; Reinvang, Ivar; DeRosse, Pamela; Lundervold, Astri J; Steen, Vidar M; Espeseth, Thomas; Räikkönen, Katri; Widen, Elisabeth; Palotie, Aarno; Eriksson, Johan G; Giegling, Ina; Konte, Bettina; Hartmann, Annette M; Roussos, Panos; Giakoumaki, Stella; Burdick, Katherine E; Payton, Antony; Ollier, William; Chiba-Falek, Ornit; Attix, Deborah K; Need, Anna C; Cirulli, Elizabeth T; Voineskos, Aristotle N; Stefanis, Nikos C; Avramopoulos, Dimitrios; Hatzimanolis, Alex; Arking, Dan E; Smyrnis, Nikolaos; Bilder, Robert M; Freimer, Nelson A; Cannon, Tyrone D; London, Edythe; Poldrack, Russell A; Sabb, Fred W; Congdon, Eliza; Conley, Emily Drabant; Scult, Matthew A; Dickinson, Dwight.
Afiliação
  • Lam M; Institute of Mental Health, Singapore, 539747, Singapore; Division of Psychiatry Research, The Zucker Hillside Hospital, Glen Oaks, NY 11004, USA; Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
  • Hill WD; Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, Scotland, EH8 9JZ, United Kingdom; Department of Psychology, University of Edinburgh, Edinburgh, Scotland, EH8 9JZ, United Kingdom.
  • Trampush JW; Department of Psychiatry and the Behavioral Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
  • Yu J; Division of Psychiatry Research, The Zucker Hillside Hospital, Glen Oaks, NY 11004, USA.
  • Knowles E; Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06511, USA.
  • Davies G; Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, Scotland, EH8 9JZ, United Kingdom; Department of Psychology, University of Edinburgh, Edinburgh, Scotland, EH8 9JZ, United Kingdom.
  • Stahl E; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Institute for Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
  • Huckins L; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Institute for Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
  • Liewald DC; Department of Psychology, University of Edinburgh, Edinburgh, Scotland, EH8 9JZ, United Kingdom.
  • Djurovic S; Department of Medical Genetics, Oslo University Hospital, University of Bergen, Bergen 4956, Nydalen 0424, Norway; Norsk Senter for Forskning på Mentale Lidelser, K.G. Jebsen Centre for Psychosis Research, University of Bergen, Bergen 4956, Nydalen 0424, Norway.
  • Melle I; Norsk Senter for Forskning på Mentale Lidelser, K.G. Jebsen Centre for Psychosis Research, University of Bergen, Bergen 4956, Nydalen 0424, Norway; Division of Mental Health and Addiction, Oslo University Hospital, Oslo 1039, Blindern 0315, Norway.
  • Sundet K; Division of Mental Health and Addiction, Oslo University Hospital, Oslo 1039, Blindern 0315, Norway; Department of Psychology, University of Oslo, Oslo 1094, Blindern 0317, Norway.
  • Christoforou A; Dr. Einar Martens Research Group for Biological Psychiatry, Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen 7804, N-5020 Bergen, Norway.
  • Reinvang I; Department of Psychology, University of Oslo, Oslo 1094, Blindern 0317, Norway.
  • DeRosse P; Division of Psychiatry Research, The Zucker Hillside Hospital, Glen Oaks, NY 11004, USA.
  • Lundervold AJ; Department of Biological and Medical Psychology, University of Bergen, 7807, N-5020, Norway.
  • Steen VM; Norsk Senter for Forskning på Mentale Lidelser, K.G. Jebsen Centre for Psychosis Research, University of Bergen, Bergen 4956, Nydalen 0424, Norway; Dr. Einar Martens Research Group for Biological Psychiatry, Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen 78
  • Espeseth T; Division of Mental Health and Addiction, Oslo University Hospital, Oslo 1039, Blindern 0315, Norway; Department of Psychology, University of Oslo, Oslo 1094, Blindern 0317, Norway.
  • Räikkönen K; Institute of Behavioural Sciences, University of Helsinki, Helsinki, 00014, Finland.
  • Widen E; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, 00014, Finland.
  • Palotie A; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, 00014, Finland; Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge CB10 1SA, United Kingdom; Department of Medical Genetics, University of Helsinki and University Central Hospital, Helsinki, 00014, Finland
  • Eriksson JG; Department of General Practice, University of Helsinki and Helsinki University Hospital, Helsinki, 00014, Finland; National Institute for Health and Welfare, Helsinki FI-00271, Finland; Folkhälsan Research Center, Helsinki 00290, Finland.
  • Giegling I; Department of Psychiatry, Martin Luther University of Halle-Wittenberg, Halle 06108, Germany.
  • Konte B; Department of Psychiatry, Martin Luther University of Halle-Wittenberg, Halle 06108, Germany.
  • Hartmann AM; Department of Psychiatry, Martin Luther University of Halle-Wittenberg, Halle 06108, Germany.
  • Roussos P; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Institute for Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
  • Giakoumaki S; Department of Psychology, University of Crete, Crete 74100, Greece.
  • Burdick KE; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Mental Illness Research, Education, and Clinical Center (VISN 2), James J. Peters VA Medical Center, Bronx, NY 10468, USA; Department of Psychiatry, Brigham and Women's Hospital, Harvard Medical School, Bosto
  • Payton A; Division of Informatics, Imaging, and Data Sciences, School of Health Sciences, University of Manchester, Manchester M139NT, United Kingdom.
  • Ollier W; Centre for Epidemiology, Division of Population Health, Health Services Research and Primary Care, University of Manchester, Manchester M139PL, United Kingdom; School of Healthcare Sciences, Manchester Metropolitan University, Manchester M15 6BH, United Kingdom.
  • Chiba-Falek O; Department of Neurology, Bryan Alzheimer Disease Research Center, Duke University Medical Center, Durham, NC 27705, USA; Center for Genomic and Computational Biology, Duke University Medical Center, Durham, NC 27705, USA.
  • Attix DK; Department of Neurology, Bryan Alzheimer Disease Research Center, Duke University Medical Center, Durham, NC 27705, USA; Center for Genomic and Computational Biology, Duke University Medical Center, Durham, NC 27705, USA; Psychiatry and Behavioral Sciences, Division of Medical Psychology, Duke Unive
  • Need AC; Division of Brain Sciences, Department of Medicine, Imperial College, London W12 0NN, UK.
  • Cirulli ET; Helix Inc, San Diego, CA 92121, USA.
  • Voineskos AN; Campbell Family Mental Health Institute, Centre for Addiction and Mental Health, University of Toronto, Toronto M6J 1H4, Canada.
  • Stefanis NC; Department of Psychiatry, National and Kapodistrian University of Athens Medical School, Eginition Hospital, Athens, Greece; University Mental Health Research Institute, Athens 115 27, Greece; Neurobiology Research Institute, Theodor-Theohari Cozzika Foundation, Athens, Greece.
  • Avramopoulos D; Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
  • Hatzimanolis A; Campbell Family Mental Health Institute, Centre for Addiction and Mental Health, University of Toronto, Toronto M6J 1H4, Canada; Department of Psychiatry, National and Kapodistrian University of Athens Medical School, Eginition Hospital, Athens, Greece; University Mental Health Research Institute, A
  • Arking DE; Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
  • Smyrnis N; Campbell Family Mental Health Institute, Centre for Addiction and Mental Health, University of Toronto, Toronto M6J 1H4, Canada; Department of Psychiatry, National and Kapodistrian University of Athens Medical School, Eginition Hospital, Athens, Greece.
  • Bilder RM; McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
  • Freimer NA; McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
  • Cannon TD; Department of Psychology, Yale University, New Haven, CT 06511, USA.
  • London E; UCLA Semel Institute for Neuroscience and Human Behavior, Los Angeles, CA 90024, USA.
  • Poldrack RA; Department of Psychology, Stanford University, Palo Alto, CA 94305, USA.
  • Sabb FW; Robert and Beverly Lewis Center for Neuroimaging, University of Oregon, Eugene, OR, 97401, USA.
  • Congdon E; UCLA Semel Institute for Neuroscience and Human Behavior, Los Angeles, CA 90024, USA.
  • Conley ED; 23andMe, Inc., Mountain View, CA, 94041, USA.
  • Scult MA; Laboratory of NeuroGenetics, Department of Psychology and Neuroscience, Duke University, Durham, NC 27708, USA.
  • Dickinson D; Clinical and Translational Neuroscience Branch, Intramural Research Program, National Institute of Mental Health, National Institute of Health, Bethesda, MD 20814, USA.
Am J Hum Genet ; 105(2): 334-350, 2019 08 01.
Article em En | MEDLINE | ID: mdl-31374203
Susceptibility to schizophrenia is inversely correlated with general cognitive ability at both the phenotypic and the genetic level. Paradoxically, a modest but consistent positive genetic correlation has been reported between schizophrenia and educational attainment, despite the strong positive genetic correlation between cognitive ability and educational attainment. Here we leverage published genome-wide association studies (GWASs) in cognitive ability, education, and schizophrenia to parse biological mechanisms underlying these results. Association analysis based on subsets (ASSET), a pleiotropic meta-analytic technique, allowed jointly associated loci to be identified and characterized. Specifically, we identified subsets of variants associated in the expected ("concordant") direction across all three phenotypes (i.e., greater risk for schizophrenia, lower cognitive ability, and lower educational attainment); these were contrasted with variants that demonstrated the counterintuitive ("discordant") relationship between education and schizophrenia (i.e., greater risk for schizophrenia and higher educational attainment). ASSET analysis revealed 235 independent loci associated with cognitive ability, education, and/or schizophrenia at p < 5 × 10-8. Pleiotropic analysis successfully identified more than 100 loci that were not significant in the input GWASs. Many of these have been validated by larger, more recent single-phenotype GWASs. Leveraging the joint genetic correlations of cognitive ability, education, and schizophrenia, we were able to dissociate two distinct biological mechanisms-early neurodevelopmental pathways that characterize concordant allelic variation and adulthood synaptic pruning pathways-that were linked to the paradoxical positive genetic association between education and schizophrenia. Furthermore, genetic correlation analyses revealed that these mechanisms contribute not only to the etiopathogenesis of schizophrenia but also to the broader biological dimensions implicated in both general health outcomes and psychiatric illness.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Esquizofrenia / Cognição / Transtornos Cognitivos / Transmissão Sináptica / Polimorfismo de Nucleotídeo Único / Escolaridade / Transtornos do Neurodesenvolvimento Tipo de estudo: Systematic_reviews Limite: Adult / Humans Idioma: En Revista: Am J Hum Genet Ano de publicação: 2019 Tipo de documento: Article País de afiliação: Estados Unidos
Texto completo
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Esquizofrenia / Cognição / Transtornos Cognitivos / Transmissão Sináptica / Polimorfismo de Nucleotídeo Único / Escolaridade / Transtornos do Neurodesenvolvimento Tipo de estudo: Systematic_reviews Limite: Adult / Humans Idioma: En Revista: Am J Hum Genet Ano de publicação: 2019 Tipo de documento: Article País de afiliação: Estados Unidos